Incidence, Etiology, and Pathogenesis

The aspiration of gastric contents under anesthesia is fortunately a rare event but one that can be associated with serious morbidity and even mortality. Despite a greater understanding of the risk factors, prevention, and management, there has been no appreciable decrease in its incidence. The consequences of aspiration include bronchospasm, laryngospasm, aspiration pneumonitis, aspiration pneumonia, and the acute respiratory distress syndrome.

Historically, the syndrome of aspiration pneumonitis was first described by Mendelson in 1946 in a group of obstetric patients undergoing general anesthesia. He was also the first to describe the role of the acidity of gastric contents in the pathogenesis of this syndrome. Installation of gastric contents into the lung was indistinguishable pathologically from the effect of the introduction of 0.1 N hydrochloric acid. Later, it was shown that neutralization of gastric acid prior to aspiration reduced the damage to the lungs. In experimental studies, the degree of pulmonary injury increased significantly with a decrease in pH and an increase in volume.

The commonly cited values of a gastric volume of 0.3 to 0.4 mL/kg and a gastric pH of lower than 2.5 for the development of aspiration pneumonitis come from animal studies that involved the direct installation of acid into the lungs of Rhesus monkeys. However, gastric contents are not purely liquid and the presence of particulate matter can cause inflammation and lung injury, even with a pH higher than 2.5. Also, the volume of gastric fluid present does not seem to correlate to the risk for aspiration or the amount aspirated, Many appropriately fasted patients have gastric volumes that exceed 0.4 mL/kg and demonstrate no evidence of aspiration. Extrapolating gastric volume to the potential aspirated volume is therefore speculative at best, and it is further complicated by the difficulty of accurately measuring gastric volumes. The Cochrane Database review on perioperative fasting found some studies that show an increase in gastric emptying with the ingestion of clear fluids.

The anatomic and physiologic mechanisms that prevent reflux include the upper esophageal sphincter (UES), the lower esophageal sphincter (LES), and the laryngeal reflexes. Alteration of any of these can increase the risk of aspiration. The LES forms a barrier between the stomach and the esophagus that prevents aspiration. When gastric pressure exceeds the LES barrier pressure, aspiration is possible. A decrease in the LES pressure is the most significant physiologic derangement in patients who aspirate during anesthesia and in those who suffer from gastroesophageal reflux disease (GERD). Many of the drugs used in anesthesia can alter the LES pressure, thus affecting the risk for aspiration. In general, opiates, anesthetic induction agents, volatile anesthetics, and anticholinergics all cause a decrease in LES pressure, whereas cholinergics, prokinetics, and alpha agonists all increase LES pressure ( Table 25.1 ).

The UES is best considered a region of increased pressure in the peristaltic wave formation of the hypopharyngeal region. Classically, the cricopharyngeus is considered the largest contributor to the UES. However, there are large contributions from the thyropharyngeus (itself a part of the inferior pharyngeal constrictor) and direct contributions from the proximal esophagus. The contributions belie the interplay between the apparatus involved in airway control and deglutition that are altered when aspiration is encountered.

The cricopharyngeus is often the focus of most discussions regarding the prevention of aspiration in the preoperative period. It extends around the pharynx and in healthy conscious adults it prevents the entrance of gastric contents from the esophagus into the hypopharynx. The tone of the UES, like that of the LES, is altered by many of the anesthetic induction agents as well as by neuromuscular blockers and sleep. These factors may combine and further increase the risk for aspiration. Of particular importance is the effect of residual neuromuscular blockade on the UES. In a study using fluoroscopy and manometry, it was shown that at a train-of-four (TOF) ratio of 0.8, resting UES and pharyngeal muscle tone was decreased significantly. These investigators were also able to demonstrate alterations in swallowing and found discordant activity of the pharyngeal muscles and the UES. These alterations in UES and pharyngeal tone could be clinically significant and could lead to an increased risk of aspiration in the postoperative period.

Risk Factors

The best defined risk factor for aspiration is an emergent operation. There are several theories as to why this should be the case. First, patients scheduled for emergent surgeries are not appropriately fasted and thus have increased gastric volumes. The sympathetic response to pain also decreases gastric motility. Second, any opiate administered to such patients in the preoperative period will slow gastric emptying. Finally, traumatic brain or spinal cord injuries have been shown to cause gastroparesis.

Late-term pregnancy, with its alterations in gastric morphology, increases in intra-abdominal pressure, and increases in progesterone levels, predisposes patients to passive regurgitation. There is controversy, however, over whether there is a delay in gastric emptying in parturient women. Obstetric labor is also known to delay gastric emptying. This most likely results from the effect of pain and the administration of central neuraxial opiates, both of which are known to slow gastric transit time. In addition to having these physiologic and anatomic factors, parturient women may also have increased upper airway edema and tissue mass, which may necessitate multiple attempts to perform a laryngoscopy and a longer duration of that procedure, leaving the pregnant patient with an unprotected airway for a longer time than a nonpregnant patient.

Obese patients are also thought to be at higher risk of aspiration. Although no decrease in the rate of gastric emptying has been demonstrated, the airway difficulties of obese patients could place them at increased risk of aspiration for the same reasons as pregnant patients.

Other systemic diseases such as scleroderma, diabetes mellitus type I, and Parkinson disease are all known to cause either delays in gastric emptying or alterations in the LES, leading to an increased risk of aspiration ( Box 25.1 ).

Risk Reduction

Recent work has begun to look at data that point to preventable causes of aspiration in the operating room, and focus has been on the practitioners. The element of human error is being examined because it is the most preventable risk factor. The paucity of a proper level of knowledge regarding the causes, especially when paired with the inappropriate decision-making that can come from lack of either experience or inadequate training, are the most significant elements of human error.

Knowledge of the risk factors for aspiration allows the clinician to alter the anesthetic plan to reduce the perioperative risk for this condition. The clinician can use four broad strategies to facilitate this. First, decrease the chance of gastric contents entering the hypopharynx. Second, inhibit the passage of the contents from the pharynx and esophagus into the trachea and lungs. Third, alter the pH of the gastric fluid (by the use of histamine-2 [H ₂ ] blockers, proton pump inhibitors, and particulate antacids). Finally, decrease the volume of gastric fluid.

The most common way to prevent the gastric contents from entering the hypopharynx, trachea, and lungs is by using cricoid pressure, first described by Sellick in 1961. The anatomic theory behind this maneuver is that pressure on the circular cricoid ring will occlude the esophagus against the fifth cervical vertebrae, thus inhibiting gastric contents from entering the tracheobronchial tree. Although this technique is attractive in theory, its application has many pitfalls. There is evidence that the application of cricoid pressure can cause a decrease in LES tone, perhaps through a mechanoreceptor-mediated reflex mechanism. The suggested force of 44 newtons (N) of pressure has been shown in endoscopic studies to cause cricoid deformation, airway closure, and increased difficulty in ventilation. Further, most anesthesia assistants misapply the cricoid pressure (with variations in force between 10 and 90 N), which can lead to difficulties in visualizing the glottic opening. The maneuver itself is not without risk and there have been reports of esophageal rupture when cricoid pressure has been applied to a patient who is vomiting.

Alteration of the pH of gastric fluid is the most common pharmacologic method to reduce morbidity should aspiration occur. The three classes of drugs used to accomplish this goal are H ₂ -receptor blockers, proton pump inhibitors (PPIs), and nonparticulate antacids. None of these has been subjected to a rigorous clinical trial. With the actual event rate of aspiration being so small, surrogate measures such as gastric fluid volume have been used instead, but some question the use of gastric fluid volume as a clinically significant endpoint.

H ₂ -receptor antagonists are commonly used agents to increase gastric pH. They bind the histamine type 2 receptor on gastric parietal cells and inhibit gastric acid secretion. Pharmacologic features of these drugs that should be recognized, however, include the lack of correlation between acid suppression and peak plasma concentration, significant interindividual variation in the degree of acid suppression, and the development of tolerance.

PPIs are a newer class of medications that form a covalent bond with the H ⁺ ,K ⁺ -ATPase of the parietal cell. To be effective in increasing gastric pH in the preoperative period, these medications must be given the night before and the morning of surgery.

Many head-to-head studies of the H ₂ -receptor antagonists and PPIs have shown an increase in gastric pH and a decrease in gastric volume. Whether these surrogate endpoints are clinically relevant has engendered much debate. Even if a reduction in morbidity or mortality could be demonstrated, the number needed to treat (see later) would be too large to recommend widescale adoption of this practice for all patients. In fact, the American Society of Anesthesiologists (ASA) 2017 task force has not endorsed the use of H ₂ antagonists for patients who are not at risk for aspiration.

Nonparticulate antacids (e.g., sodium citrate, sodium bicarbonate) have been shown to increase the pH of gastric fluid but to have no effect on gastric volume. These agents are attractive because they increase gastric pH rapidly, making their use with the emergency surgical patient more feasible than that of the PPIs or H ₂ blockers. Nonetheless, these agents should only be used in patients with an increased risk for pulmonary aspiration. As noted by the ASA in its 2017 guidelines, they should not be used routinely in the preoperative setting before general anesthesia, regional anesthesia, or procedural sedation.

NPO Guidelines

Anesthetics and sedatives—used in general anesthesia, regional anesthesia, and monitored anesthesia care—are known to reduce the airway protective mechanisms. Reduction of aspiration risk starts with following fasting guidelines. These guidelines are primarily based on gastric physiology and apply to patients having elective procedures during all types of anesthesia. As mentioned previously, studies have shown that particulate matters, acidic contents with pH of lower than 2.5, and large gastric volumes of greater than 0.3 to 0.4 mL/kg, are associated with worse outcomes.

After reviewing the patient’s medical records, interviewing the patient and performing physical examination, the anesthesiologist should take into consideration the ASA physical status, age, sex, type of surgery, potential of difficult airway, consideration of GERD and other gastrointestinal (GI) motility and metabolic disorders (e.g., diabetes mellitus). Subsequently, both educating the patient in advance prior to the surgery date and choosing plain language or more detailed language based on the patient’s mental status play a crucial role in patient compliance with fasting requirements. Having noncompliant, nonfasted patients on the day of surgery puts them at unnecessary increased risk of aspiration. Decision to proceed or delay the procedure at that time can be based on the amount and type of food ingested and the effects of delaying the procedure.

Clear liquids include water, juices without pulp, coffee or tea without milk, and carbohydrate drinks. Alcohol is prohibited. These liquids are allowed for up to 2 hours prior to the procedure with no restriction of the volume of the clear liquid. This is based on evidence that patients who were allowed clear fluids up to 2 hours prior to their surgery had similar gastric fluid volumes and pH when compared with those who fasted longer. Fasting for several hours puts the patient at the consequence of hypoglycemia and hypovolemia, particularly in the pediatric population. Thus drinking clear carbohydrate-rich liquids should be encouraged up until 2 hours prior surgery. It may also reduce thirst, hunger, and anxiety prior to surgery, particularly when prolonged nil per os (NPO) times are caused by delays in the nature of unpredictable scheduling of operation times.

The ingestion of a light meal (such as toast with a clear liquid) on the morning of surgery and its relation to gastric volume and emptying has been investigated. Although gastric volume was not increased, particulate matter was still present in the stomach up to 4 hours after ingestion, which is particularly worrisome because particulate material in the lung elicits a profound inflammatory response. Gastric emptying time is longer with larger meal weight, higher calorie content, and higher fat content. Heavy meals (such as those containing fried foods) took up to 9 hours to exit the stomach. The ASA taskforce on perioperative fasting has therefore recommended that a period of 6 hours elapse before the conduct of general anesthesia in patients who have had a light meal and up to 8 hours for those who have consumed a meal that contains fatty foods.

Enteral tube formula often contains carbohydrates, proteins, and fat. Therefore, it is considered a fatty meal and should be stopped 8 hours before elective surgeries. Exceptions may include postpyloric tube feeds.

The presence of chewing gum in the preoperative period deserves mention. In recent studies, the presence of chewing gum upon initial encounter with the patient has been thought to increase gastric fluid volumes and decrease pH of that fluid, thereby increasing the risk for aspiration events and sequelae. Although it appears that chewing gum is associated with statistically notable increases in intragastric fluid, the increase does not appear to be enough to increase the risk of aspiration of that fluid. Furthermore, there does not seem to be an increase in the acidity of the fluid. It can be argued that patients who chew gum up to the time of the surgery can proceed to the operating room because of the minimal effects of chewing gum on gastric volume and pH. Nonetheless, chewing generates saliva and stimulates gastric secretion and is therefore not recommended within 2 hours prior to surgery. On the other hand, swallowing a piece of chewing gum is considered equivalent to ingestion of solid food, which may necessitate delaying the surgery for 6 hours.

Patients can continue their routine medications on the morning of surgery with a sip of water or a clear liquid, preferably up to 2 hours from time of surgery.

These guidelines, however, apply only to patients without GI pathology. Certain populations pose extra risk of pulmonary aspiration. For example, long-standing diabetes mellitus can cause delayed gastric emptying and these patients may benefit from a longer fasting duration. In contrast, in both obese patients and women who are not in labor, gastric emptying is normal and standard fasting guidelines can be followed. Pediatric patients can follow the standard guidelines, with additional guidelines for breast milk and infant formula. Children can have breast milk up to 4 hours and infant formula up to 6 hours prior to the surgical procedure. One study found that 70% of patients fasted for longer than the recommended time thereby further increasing the risk of hypoglycemia and hypovolemia.

As mentioned previously, pregnant patients are a group for whom preoperative fasting has been extensively investigated. Parturients are a unique subset of patients because they might need an operative intervention at some time during the course of their labor, but keeping them NPO for a procedure that might not occur is not practical. Most obstetric units allow patients clear fluids (including gelatin) while in labor, recognizing that this may place them at increased risk for aspiration should they require a regional or general anesthetic.

Management Strategy

The spectrum of clinical problems encountered when a patient aspirates ranges from asymptomatic aspiration, bronchospasm, laryngospasm, aspiration pneumonitis, aspiration pneumonia, and acute respiratory distress syndrome.

The initial management of the patient who has aspirated focuses on suctioning the oropharynx of any aspirated material and on urgent airway control ( Fig. 25.1 ). Once the airway has been secured, a tracheal suction catheter should be passed down the endotracheal tube to try to remove any particulate matter from the lungs. At this point, a decision must be made as to whether surgery should proceed. Several factors influence this decision, such as the duration of the case, the emergent nature of the procedure, and the patient’s respiratory stability. Early hypoxemia, bronchospasm, or high peak airway pressures are all signs that portend an aspiration event, and they are likely to worsen over the ensuing several hours. Clinicians should have a low threshold for canceling elective cases in this scenario. Emergent cases (when most aspiration events occur) pose more of a problem, and many times the anesthesiologist is left little choice but to proceed with the case, knowing the potential for a worsening pulmonary status.

Algorithm for the treatment of the patient at risk of aspiration. GERD , Gastroesophageal reflux disease; PPI , proton pump inhibitor; RSI with CP , rapid sequence induction with cricoid pressure.

Aspiration of gastric contents may result in a severe chemical burn of the tracheobronchial tree with an ensuing inflammatory response. The lung injury is usually biphasic: initially (in the first 1–2 hours) the gastric fluid has direct acidic effects on the alveoli and then, approximately 4 to 6 hours later, the condition is worsened by the migration of neutrophils and the inflammatory cytokines that are liberated. Several adhesion molecules, complement, tumor necrosis factor-α, and a myriad of other mediators are responsible for this delayed reaction, which can be demonstrated histologically as an acute inflammatory response.

Because the stomach is acidic, the gastric contents are usually sterile, and early pneumonia of the patient who has aspirated is uncommon. Patients who have a bowel obstruction and aspirate feculent material are clearly more likely to have bacterial contamination of their lungs. Interestingly, increasing the gastric pH with H ₂ blockers may increase the rate of colonization of the stomach by pathogenic bacteria, increasing the risk of early pneumonia.

As emergent cases are the ones most involved, when deciding the course of action in the case of aspiration it is important to be mindful of the substance involved. Aspiration of fluid usually involve barium, water, or the last ingested content. As discussed previously, these are not bacteriogenic in themselves and can be suctioned through the endotracheal tube if suspected. If these patients are followed after the aspiration event and there appear to be no notable sequelae, observation can be appropriate.

If the aspirate is particulate, other considerations should be made. If the matter is larger, it may be lodged in the central airway related to the glottic airway and trachea. These situations manifest as difficulty ventilating the patient with rapid desaturation. If the matter is smaller and is able to pass unilaterally, the patient may present with increased airway pressures, wheezing, air-trapping, and more gradual desaturation. In these cases, flexible or rigid bronchoscopy should be considered for removal of whatever inciting material can be retrieved.

Despite the lack of evidence of efficacy, prophylactic antibiotics are commonly prescribed for patients who have aspirated. This is not recommended, as the early institution of antimicrobial therapy serves only to select for resistant organisms. The exception is the patient in whom the aspiration has occurred in the setting of a small bowel obstruction or those in whom gastric colonization is suspected. The development of a fever, radiographic infiltrate, and leukocytosis often prompts clinicians to initiate antibiotics. This is also discouraged because the clinical patterns of aspiration pneumonitis and pneumonia overlap significantly. Antibiotics should be given only in those cases where the pneumonitis persists for 48 hours or where there is documented evidence of infection. Documenting the infection has the further advantage of allowing the clinician to tailor the antibiotic regimen and of reducing the incidence of selecting for resistant organisms. Should antibiotics become necessary, broad-spectrum agents active against both gram-positive and gram-negative organisms are suggested. Empiric anaerobic coverage is not usually necessary. Levofloxacin, ceftazidime, ceftriaxone, and piperacillin-tazobactam are all good first-line agents to treat this condition. Treatment regimens should continue for 7 days, with a switch to oral antibiotics if the patient appears to improve clinically. It should be noted that evidence is lacking for the appropriate duration of treatment in these patients.

For several decades, steroids have been a mainstay of treatment for aspiration pneumonitis despite a lack of evidence showing their benefit. Theoretically, corticosteroids should help to reduce the inflammation caused by the aspiration event. One prospective placebo-controlled study showed an earlier improvement in radiographically evident aspiration pneumonitis, but these patients had longer stays in the intensive care unit (ICU) and had no change in overall outcome.

Very few patients develop an aspiration syndrome serious enough to result in acute respiratory distress syndrome (ARDS). If the anesthesiologist suspects ARDS, the management is largely supportive and early transfer to an ICU is recommended. While awaiting transfer, the ventilatory strategy used in the ARDSNet trial has been shown to decrease mortality in this condition. This study demonstrated that using a low tidal volume approach of 6.2 mL/kg ideal bodyweight, with the goal of limiting mean plateau pressures to 25 cm H ₂ O, mortality was decreased from 39.8% when tidal volumes of 11.8 mL/kg were used compared with 31.0% when lower tidal volumes were used. In fact, the trial was stopped in the fourth interval analysis as a result of the apparent efficacy in the lower tidal volume regimen group.

Background and Incidence

Postoperative nausea and vomiting (PONV) is a relatively common condition, occurring in 20% to 30% of patients. In certain high-risk populations, the incidence can approach 70%. The etiology of PONV is multifactorial, with patient, surgical, and anesthetic factors playing a role ( Box 25.2 ). PONV is among the 10 most undesirable outcomes for surgical patients, and Gan and colleagues found that patients were willing to pay up to $100 at their own expense to avoid it. Universal antiemetic prophylaxis is not cost effective; however, identifying high-risk patients allows cost-effective antiemetic prophylaxis to be used in the most economical fashion.

In general, the management of PONV includes: (1) the identification of patients at risk; (2) the reduction of baseline risk factors; (3) the appropriate prophylaxis of PONV on the basis of risk stratification; and (4) the treatment of established PONV in patients who did not receive antiemetics or in whom prophylaxis with antiemetics failed. Published guidelines on the recognition and management of PONV are periodically updated drawing from evidence-based efforts to address this issue adequately. The latest guidelines were published in 2014. This document was composed by an international panel of experts who reviewed the evidence for prophylaxis and treatment of PONV and, by rating the level of evidence (I to V), were able to suggest recommendations based on the strength of this evidence ( Box 25.3 ).

Risk Factors

Several scoring systems have been developed to try to identify patients at high risk. The most commonly cited patient risk factors for PONV are female sex, need for opioids for postoperative pain, younger age, duration of anesthesia, nonsmoking history, and a history of either PONV with prior anesthetics or motion sickness. The presence of none, one, two, three, or four risk factors leads to an incidence of 10%, 21%, 39%, 61%, or 79%, respectively.

Surgical factors may also play a role in the development of PONV. An increase in surgery time is directly correlated with an increase in PONV. Furthermore, ear-nose-and-throat (ENT), strabismus, gynecologic, and laparoscopic surgery have all been associated with an increase in the risk of PONV. The recent PONV consensus guidelines on the prevention and treatment of PONV note that the type of surgery as a risk factor for PONV is still debated. Special mention was made for the possibility that regardless of the type of surgery performed, if the surgical time is prolonged, the prolonged exposure to opioids and inhalational agents can in themselves explain increased emetogenicity.

The type of anesthetic can also influence the likelihood of PONV. Nitrous oxide and opioids have been the most consistently implicated agents in the development of this condition. However, more recent data suggest that nitrous oxide increases the risk only minimally. In the IMPACT study by Apfel and colleagues, TIVA with propofol without volatile anesthetic demonstrably reduced the risk. Furthermore, the consensus is that in order to reduce the risk of PONV, regional anesthesia (because of its opioid-sparing effects), the use of NSAIDs, and adequate intraoperative hydration as much as 30 mL/kg all contributed to a decrease in the incidence of PONV.

Recognition of the baseline risk factors in children is also discussed because age is an independent risk factor. These risk factors include duration of surgery greater than 30 minutes, age greater than 3 years, strabismus surgery, personal or family history of PONV. Regional techniques in children were noted to be of particular benefit even though most are under general anesthesia, presumably because this reduces the stress related to having these procedures performed. This results in a reduction in the use of opioids with the apparent reduction in perioperative nausea, as well as reduction in postoperative drowsiness with a decreased need for rescue analgesia.

Management of PONV

After the assessment of the patient’s baseline risk of PONV and reduction of baseline risk factors for PONV, the guidelines advocate a multimodal, cost-effective approach to the management of PONV. This centers around providing one or two interventions in adults that are deemed to be a moderate risk for PONV and three or four antiemetics for those in the high-risk group.

Pharmacologic Prophylaxis and Treatment

The four major receptor classes that have been implicated in the generation of PONV are serotonergic (5-HT3), cholinergic, dopaminergic (D ₂ ), and histaminergic (H ₂ ). Box 25.4 summarizes the different methods used to treat PONV. Numerous studies have looked at the various antiemetics both alone and in combination for the treatment and prophylaxis of PONV, and numerous meta-analyses have examined both the number needed to treat (NNT) and the number needed to harm (NNH) to determine which antiemetic regimen is the most efficacious. With respect to the antiemetics, the NNT is the number of patients who would have to be treated with a particular drug to prevent an episode of nausea or vomiting that would have occurred had the drug not been administered. The NNH is the number of patients who would have to receive the drug and demonstrate an adverse event that would not have occurred had they not received the medication.

Box 25.4

Options available for the management of postoperative nausea and vomiting.

Pharmacologic techniques

A

Monotherapy

• 1.
  

  Older generation antiemetics

  
  
  
  
  • a.
    

    Phenothiazines: aliphatic (promethazine, chlorpromazine), heterocyclic (perphenazine, prochlorperazine).

    
    
  • b.
    

    Buterophenones: droperidol, haloperidol.

    
    
  • c.
    

    Benzamides: metoclopramide, domperidone.

    
    
  • d.
    

    Anticholinergics: scopolamine.

    
    
  • e.
    

    Antihistamines: ethanolamines (dimenhydrinate, diphenhydramine), piperazines (cyclizine, hydroxyzine, meclizine).

  
  
  
  
• 2.
  

  Newer generation antiemetics:

  
  
  
  
  • a.
    

    Serotonin (5-HT3) receptor antagonists: ondansetron, granisetron, dolasetron, tropisetron, ramosetron, and palonosetron.

    
    
  • b.
    

    NK-1 receptor antagonists (aprepitant)

  
  
  
  
• 3.
  

  Other antiemetics: dexamethasone, propofol, ephedrine

B

Combination of two or more of the above antiemetics

• 1.
  

  5-HT3 receptor antagonists + droperidol

  
  
• 2.
  

  5-HT3 receptor antagonists + dexamethasone

  
  
• 3.
  

  Other combinations

Nonpharmacologic techniques

• 1.
  

  Acupuncture

  
  
• 2.
  

  Acupressure

  
  
• 3.
  

  Laser stimulation of the P6 point

  
  
• 4.
  

  Transcutaneous acupoint electrical stimulation

  
  
• 5.
  

  Hypnosis

• 
  

  Additional measures with potential antiemetic effects

  
  
  
  
  • 1.
    

    Supplemental oxygen

    
    
  • 2.
    

    Benzodiazepines

    
    
  • 3.
    

    Adequate hydration

    
    
  • 4.
    

    Good pain relief

    
    
  • 5.
    

    α-2-Adrenergic agonists

  
  
  
  
• 
  

  Multimodal approach

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