When Should a Non-gastrointestinal Cause of Nausea and Vomiting Be Considered?
Pearls and Pitfalls
• Nausea and vomiting are nonspecific complaints, so associated symptoms should be used to help focus and narrow the differential diagnosis.
• The history and physical examination will reveal the diagnosis in the majority of cases.
• Directed laboratory testing and imaging is most useful when guided by the history and physical examination.
Nausea and vomiting are a common complaint seen in acute care settings, accounting for more than 1 million emergency department visits in 2014. Most patients have benign, self-limited causes and can be managed with supportive care. However, nausea and vomiting may be symptoms of serious disease processes, many of which are shown in Fig. 35.1. “Gastroenteritis mimics” in the Additional Reading section also reviews worrisome gastrointestinal and non-gastrointestinal causes of nausea and vomiting.
History and physical examination are the most important tools to evaluate for underlying causes of nausea and vomiting and should therefore guide further diagnostic testing. No randomized controlled trials compare evaluation strategies for nausea and vomiting. The approach discussed below is based on multiple review articles and expert consensus.
Determining the time course of symptoms plays an important role in evaluating potential causes of nausea and vomiting. Acute and chronic (>1 month) causes often have very different etiologies (Table 35.1). Sudden-onset nausea and vomiting are more likely related to infectious or toxic sources. They suggest a potential pathologic response to an underlying process. Insidious onset of symptoms over days or weeks points to metabolic or endocrine causes. Chronic symptoms are more likely to have an underlying functional gastrointestinal or psychiatric（精神病学的） component.
Important historical factors include frequency, severity, content of the emesis（呕吐） (bloody血性, bilious胆汁性, etc.), provoking factors (oral intake), sick contacts, travel, past medical history, previous abdominal surgeries, and medication or drug use. Table 35.2 highlights medications that commonly cause vomiting, and Table 35.3 reviews common historical elements that may suggest specific diagnoses.
Symptoms associated with nausea and vomiting, along with past medical and social history, further narrow the differential diagnosis and guide additional investigation.
Headache and/or blurred vision suggest neurologic causes, as do slurred speech（言语迟钝）, ataxia（共济失调）, and vertigo（眩晕）, which may indicate posterior circulation stroke. Neurologic imaging should be considered in these patients and in patients who are at risk for intracranial pathology. High-risk patients include those with cancer that could metastasize to the brain and those with risk factors for intracranial hemorrhage, including hypertension, anticoagulation, and a history of aneurysm（动脉瘤） or polycystic kidney disease（多囊肾）. Recent head injury may also warrant imaging, especially in the setting of anticoagulation.
Fever suggests potential gastrointestinal or non-gastrointestinal infection. Dysuria（排尿困难） and flank pain （腰痛）with fever likely indicate pyelonephritis（肾盂肾炎）. Headache and stiff neck with fever suggest potential central nervous system infection.
Urinary or genital（生殖系统） complaints should prompt evaluation of these respective organ systems. Potential sources include gonadal torsion（性腺扭转） and nephrolithiasis(肾结石).
Confirmed or possible ingestion necessitates a toxicologic（毒理学的） workup including aspirin and acetaminophen（乙酰氨基酚） levels, electrocardiogram, and, if indicated, a urine toxicology screen.
A history of alcohol abuse could indicate pancreatitis or alcoholic ketoacidosis as the culprit（罪魁祸首）, whereas a history of marijuana（大麻） use may suggest cannabinoid hyperemesis syndrome（大麻素呕吐综合征） as the underlying cause.
Nausea and vomiting can also be a presenting complaint in acute myocardial infarction, and this etiology should be considered in patients with cardiac risk factors, those with diaphoresis, epigastric discomfort, and/or chest discomfort(发汗、上腹部不适和/或胸部不适).
Patients with known or suspected diabetes are at risk of developing diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome（高渗性高血糖综合征）.
Abnormal vitals should be acknowledged and often merit further workup. Evaluation for dehydration（脱水） (dry or tacky发黏的 mucous membranes, poor skin turgor) may prompt aggressive fluid resuscitation. Abdominal tenderness, especially when focal, may prompt laboratory testing and/or imaging with ultrasound or computed tomography. Vomiting patients presenting with head trauma, visual symptoms, or imbalance require a thorough neurological, ocular, and otic（耳） examination. These patients potentially require neuroimaging, even when there is another potential cause of nausea and vomiting.
The history and physical exam guide diagnostic testing with two exceptions: women of child-bearing age should have pregnancy testing, and patients with a history of diabetes (or suspected undiagnosed diabetes) should have their blood glucose level checked. Blood glucose testing should be considered in younger patients with otherwise unexplained nausea and vomiting to evaluate for undiagnosed diabetes (potentially complicated by ketoacidosis).
Electrolytes and/or serum chemistry testing should be considered with evidence of dehydration on exam or a prolonged history of vomiting. Urine ketones may help determine severity of dehydration and may suggest alcoholic or diabetic ketoacidosis. Additional laboratory workup, such as hepatic or pancreatic testing, is guided by the history and examination.
Likewise, imaging obtained should be based on the history and physical exam. A head CT should be considered if there is concern for an intracranial process, and abdominal imaging should be considered for patients with a concerning history and/or focal tenderness.
Electrocardiogram should be considered in appropriately selected patients with cardiac risk factors, including at-risk women and diabetics with nonspecific complaints, as these patients frequently have atypical presentations of acute coronary syndrome.
An approach to the undifferentiated patient with vomiting is shown in Fig. 35.2. Evaluation should begin with an assessment of acuity. Unstable patients should be resuscitated. Stable patients should have a thorough history and physical examination, followed by further workup if merited.
Customizing Your Antiemetic（止吐药）: What Should You Consider?
Pearls and Pitfalls
• Only about half of patients reporting nausea are treated for symptoms in the emergency department.
• Treating nausea and preventing emesis improve patient satisfaction, reduce distress, and improve the practice environment.
• Most head-to-head RCTs and meta-analyses have shown no single medication to be superior to other agents.
• Droperidol(氟哌利多) was shown to be superior in one small study but carries a black-box warning for QT interval prolongation.
• Ondansetron（昂丹司琼） may have risk during the first trimester of pregnancy. Antiemetic selection during pregnancy can be challenging. Further research is required.
Providers encounter nausea and vomiting frequently in the acute care setting, either as a presenting complaint or accompanying another disease process. Treating these symptoms reduces suffering and distress and improves patient satisfaction. It may also allow the patient to tolerate oral medications necessary to treat other conditions. A patient with active emesis or loud retching(干呕) may adversely affect the practice environment for other nearby patients and providers. Antiemetics often fully meet patient expectations for improvement; they frequently allow patients to feel comfortable with discharge.
Factors in Antiemetic Selection
The choice of antiemetic can be complex, with a wide array of available medications. When selecting an antiemetic, the provider must consider the potential underlying cause that necessitates the medication in the first place. Nausea and vomiting may arise from a variety of processes. Gastrointestinal causes are common, but other causes include neurologic, psychologic（心理）, metabolic, toxicologic, and iatrogenic（医源性）. The pathophysiology of nausea and vomiting is multimodal（多模式）, through the activation of one of four major pathways. The medications that manage these symptoms act on these different pathways, allowing for a breadth(宽度) of antiemetic options.
The route of administration is based on several factors. Oral agents are the simplest to administer. Some medications make orally dissolving formulations（口服溶解制剂）, so patients do not have to swallow pills. Some medications offer rectal formulations. Many patients requiring antiemetics will not tolerate oral medications and may require intravenous access for both antiemetics and fluid resuscitation. Intramuscular agents are typically more painful.
Patient age, weight, pregnancy status, and medication preference play roles in drug selection. Many providers fall into the practice pattern of having a first-line or “favorite” medication for all situations, and both providers and patients may have been exposed to marketing, affecting their choices and preferences. Finally, antiemetic medications have multiple side effects, and the choice of an agent may be dictated by comorbid conditions and/or the desire to avoid adverse reactions.
Pathophysiology of Vomiting
The vomiting center in the brain is located in the medulla oblongata（延髓）. Four main pathways send signals to the vomiting center, and each is mediated by different neurotransmitters(神经传导物质). There is a chemoreceptor trigger zone（化学感受器触发区） at the base of the skull(颅底) that receives a variety of signals, including dopamine, serotonin, histamine, muscarine, and vasopressin（多巴胺、5-羟色胺、组胺、毒蕈碱和加压素）. Toxins, metabolic abnormalities such as diabetic ketoacidosis, and medications may act on this center. Gastric inflammation and stretching of the gastrointestinal tract activate a vagal pathway via serotonin and dopamine. The vestibular center(前庭中心) activates a pathway through histamine and muscarine. Finally, the cerebral cortex, which processes anxiety, fear, and foul odors, can activate vomiting.
Mechanisms of Action and Adverse Drug Reactions
Antiemetic medications come from multiple different classes, with varying effects and adverse reactions shown in Table 36.1.
The serotonin antagonists（5-羟色胺拮抗剂） include ondansetron (Zofran)（昂丹司琼） and granisetron (Kytril)（格拉司琼）. Benzamides（苯甲酰胺） include metoclopramide (Reglan) （甲氧氯普胺）and trimethobenzamide (Tigan)（曲美苄胺）. Phenothiazines（吩噻嗪类） include prochlorperazine (Compazine) （丙氯拉嗪）and promethazine (Phenergan)（异丙嗪）. Antihistamines（抗组胺药） such as diphenhydramine (Benadryl) （苯海拉明）and meclizine (Antivert) （氯苯甲嗪）are also options. Other categories of medications shown to have antiemetic properties include antipsychotics（抗精神病药） such as haloperidol (Haldol)（氟哌啶醇） and droperidol (Inapsine)（氟哌利多）, benzodiazepines（苯二氮卓类）, and corticosteroids（皮质类固醇）.
Considering the source of nausea and vomiting can help providers select an appropriate agent. Ondansetron’s serotoninergic effects treat nausea due to toxic, idiopathic, and metabolic causes, as well as gastric irritation and inflammation. Metoclopramide acts primarily on dopamine and may work well in patients presenting with vomiting secondary to headaches, gastrointestinal dysmotility（动力障碍）, or other gastric causes. Haloperidol may work well for nausea and vomiting with cerebral cortex-associated causes. Similarly, benzodiazepines may work well as adjuvants to other medications and may manage symptoms caused by anxiety. Antihistamine and anticholinergic medications can be used for vestibular-related nausea, such as vertigo.
While these agents manage symptoms, they also have side effects. Some medications may cause mild sedation while others may cause agitation（躁动） or restlessness（不安） (akathisia静坐不能). Many medications may cause QT lengthening or non-specific repolarization abnormalities. Extrapyramidal symptoms (EPS)（锥体外系症状） may also occur: dystonia（肌张力障碍） (spasms), parkinsonism（帕金森病） (rigidity), bradykinesia（运动迟缓） (slowness), tardive dyskinesia（迟发性运动障碍） (irregular spasms), and akathisia.
Ondansetron use in pregnancy was shown in some studies to be associated with increased fetal cardiac abnormalities and increased cleft palate（腭裂）, but other large studies have shown no correlation. Metoclopramide, like ondansetron, is listed as pregnancy category B. Studies have not shown an association between metoclopramide and adverse fetal outcomes, but metoclopramide risks maternal（母性的） EPS while ondansetron does not. The decision regarding antiemetic choice during pregnancy is challenging and will remain so until further studies bring better clarification to the issue.
Providers frequently undertreat nausea. One recent study noted that only half of emergency department patients with nausea were treated with an antiemetic. However, the majority of patients with vomiting were treated with antiemetics.
Antiemetics are effective at managing symptoms of nausea and vomiting; however, research has shown that placebos or IV fluids alone can also be effective. Some randomized trials and meta-analyses comparing agents have shown no significant difference among medications or when medications were compared to placebo. A large review comparing multiple trials of metoclopramide, ondansetron, prochlorperazine, promethazine, and droperidol showed no medication was significantly better than placebo. One small trial did show droperidol was superior to placebo. While more commonly used in the past, droperidol use has become limited due to risk of QT prolongation. Most studies did not control for either administration of intravenous fluids or causes of nausea and vomiting.
Since many agents have been shown to have equal or non-inferior efficacy, the side effect profile for a medication may weigh most heavily in its selection or exclusion. For patients with long QT syndrome or at risk for repolarization abnormalities, providers should avoid serotonin antagonists and haloperidol. For patients on typical antipsychotics or with other risk factors, providers should avoid phenothiazines and benzamides, which may increase the risk of EPS. Many medications have sedative effects and should be used with caution in conjunction with other sedating agents. When treating pregnant patients, providers may consider using pyridoxine（吡哆醇（辛）；维生素B7）, antihistamines, or metoclopramide if they are concerned about risks with ondansetron.
In conclusion, the selection of an agent to treat nausea and vomiting remains complex but approachable. Symptoms often go undertreated but improve with most treatments. It is important to remain aware of medications side effects and how they apply to specific patient presentations. There is no “always right” answer when choosing an antiemetic, and certain agents may be more appropriate based on the suspected etiology of symptoms.
When Should QT Prolongation Be Considered in Antiemetic Use?
Pearls and Pitfalls
• QTc prolongation from routine doses of 4–8 mg of ondansetron is minimal and is unlikely to be clinically significant or cause a dangerous arrhythmia.
• A patient who receives a single dose of an antiemetic does not require routine screening electrolytes or an electrocardiogram (ECG).
• Patients receiving greater than 8 mg of ondansetron（昂丹司琼） within 4 h and patients taking other QTc-prolonging agents should receive a screening ECG.
• Metoclopramide（甲氧氯普胺） may be a safe alternative to 5-HT3 receptor antagonists in patients with underlying QTc prolongation, but it is not studied well enough to fully establish safety in this regard.
• Benzodiazepines(苯二氮卓类） are effective for nausea and vomiting and do not carry a significant risk of QTc prolongation.
Management of nausea and vomiting with antiemetics is a common occurrence in the acute care setting. Patients frequently receive 5-HT3 (serotonin), dopamine, or histamine receptor antagonists for treatment. These drugs are highly effective; however, nearly all carry a potential side effect of QTc prolongation, which may lead to fatal arrhythmias including torsades de pointes（尖端扭转性室速） (TdP). Ondansetron likely produces its QTc-prolonging effects through its interaction with rapidly acting potassium channels（快速钾通道） during myocardial depolarization（心肌去极化）. Several other common classes of medications potentiate（增强）these effects. While some providers routinely screen vomiting patients for underlying QTc prolongation or electrolyte abnormalities prior to administration of antiemetic medications, others administer multiple doses of antiemetic medications without screening. Emerging evidence suggests that screening is unnecessary in most patients but may benefit patients with known risk factors for QTc prolongation. Table 38.1 depicts various antiemetics and their associations with QTc interval prolongation and cardiac arrhythmias.
Ondansetron is the most commonly administered antiemetic in the US emergency departments. While it carries an FDA warning for QTc prolongation, recent studies have found inconsistent evidence for this. A 2013 study of 100 pediatric patients given ondansetron showed no change in the QTc interval at peak effect and 1 h post-peak effect. A more recent study in 22 adult patients showed a mean increase in QTc of 20 ms, with no adverse cardiac events reported. The Federal Drug Administration (FDA) recommends that no single intravenous (IV) dose exceed 16 mg, due to evidence that a dose of 32 mg caused a QTc increase of 20 ms. More typical 4 or 8 mg doses were demonstrated to cause more modest increases in QTc interval (6 ms) . Overall, the evidence for QTc prolongation with typical doses of 4–8 mg appears to be mixed and inconclusive, suggesting that a routine screening ECG for patients receiving ondansetron in the acute care setting is unnecessary.
While some studies do show QTc prolongation associated with low doses of ondansetron and other 5-HT3 receptor blockers, newer literature suggests that this prolongation may not be clinically significant and is unlikely to be associated with cardiac arrhythmia in the absence of other risk factors. In a post-marketing analysis of single oral ondansetron doses, no cardiac arrhythmias were reported despite over 20 years of frequent use in both ambulatory and inpatient settings. Some argue that this data can likely be extrapolated （推测的）to single intravenous doses, as the pharmacokinetics（药代动力学） is quite similar. There are a small number of cardiac arrhythmias reported in the literature, but the majority of these were associated with repeated intravenous administration, long-term use, concomitant（相伴的） use of other QTc-prolonging agents including chemotherapy drugs, or underlying electrolyte abnormalities. Similarly, a 2016 study evaluating the effect of ondansetron on pediatric intensive care unit patients showed a statistically significant increase in QTc to greater than 500 ms in 11% of patients; however, this increase was associated with underlying electrolyte abnormalities and/or organ failure. Ondansetron alone, in the absence of other risk factors, was less likely to cause significant QTc prolongation. Another 2016 pediatric study retrospectively analyzed nearly 200,000 doses of ondansetron administered in the emergency department. The authors reported seven incidences of ventricular arrhythmias within 24 h of administration; all seven were associated with underlying major cardiac diagnoses or congenital conduction abnormalities.
Taken together, these studies suggest that, in the absence of other known causes of cardiac arrhythmia, including underlying cardiac conduction abnormality, electrolyte abnormality, or organ failure, cardiac arrhythmia associated with ondansetron is highly unlikely, and the typical doses of 4–8 mg of ondansetron are safe for the majority of patients. A screening ECG should be considered in patients with underlying congenital or acquired heart disease, as well as in patients with significant electrolyte abnormalities that may prolong the QTc, including hypokalemia, hypocalcemia, or hypomagnesemia（低钾血症、低钙血症或低镁血症）. Screening ECG should also be considered in those who are taking QTc-prolonging medications, including antiarrhythmic, antipsychotic, or antibiotic agents（抗心律失常药、抗精神病药或抗生素）.
Metoclopramide has a different mechanism of action from the more commonly used 5-HT3 receptor antagonists, as it is a competitive antagonist of dopamine D1 and D2 receptors, in addition to having 5-HT3 antagonist activity at higher doses. There have been fewer studies examining its effects on the QTc interval. A small 2015 study comparing intravenous metoclopramide to intravenous haloperidol showed no effect on QTc with either drug. However, there have been sporadic（零星的） case reports of significant adverse cardiac events immediately after IV administration of metoclopramide, typically associated with underlying electrolyte abnormalities or organ dysfunction. While some providers feel that metoclopramide is a safe alternative to ondansetron in higher-risk patients, more thorough studies are needed before a recommendation can be made.
Medications Without QTc Prolongation
Several 5-HT3 receptor antagonist medications have been shown not to carry a risk of QTc prolongation. FDA labeling suggests that, if available, palonosetron（盐酸帕洛诺司琼） and granisetron（格拉司琼） are safe for patients with underlying long QTc or other risk factors for cardiac arrhythmias.
Trimethobenzamide（曲美苄胺） is a D2 receptor antagonist without apparent 5-HT3 receptor antagonist effects that has not been shown to have any effect on QTc interval and is also safe for patients with congenital long QT syndromes or other risk factors. These drugs are not likely to be available to most emergency providers, and they are not cost-effective.
Lorazepam and other benzodiazepines are more available and cost-effective alternatives to QTc-prolonging agents. They have been shown to be effective for preventing and treating nausea and vomiting, and they do not carry a significant risk of QTc prolongation. If there is a contraindication to benzodiazepines or if patients require more than one agent to control symptoms, then patients who are felt to be high risk for developing an arrhythmia can receive low doses of more common antiemetics if they are appropriately screened with an ECG prior to administration and observed on a cardiac monitor following administration.
Ondansetron (and other 5-HT3 receptor antagonists) and metoclopramide are the most commonly administrated antiemetics in emergency settings. While ondansetron carries an FDA warning for prolonged QTc interval and cardiac arrhythmias at higher doses, the FDA has not provided recommendations for screening patients. Routine ECG and blood testing create delays in patient care, discomfort for patients, and the increased expense of potentially unnecessary investigations. A review of the literature shows that it is unclear whether ondansetron causes QTc prolongation at typical doses of 4–8 mg. Even if it does, this increase is highly unlikely to be clinically significant or result in cardiac arrhythmia. Patients with underlying congenital conduction delay, electrolyte abnormalities, or organ failure may be at a higher risk for developing QTc prolongation with repeated doses of antiemetics and may require more monitoring and screening. Patients who chronically use other QTc-prolonging agents, who are receiving multiple intravenous doses of antiemetics, or who have underlying conditions that increase their risk for fatal cardiac arrhythmias (such as cardiac or renal failure) should also be more closely monitored with a screening ECG and a period of cardiac monitoring. The vast majority of patients receiving a single dose of an oral or intravenous antiemetic in the emergency setting can do so without any screening or monitoring. If higher-risk patients are to be discharged with a prescription for multiple doses of an antiemetic, it would be preferable to use agents such as promethazine（异丙嗪） or prochlorperazine（丙氯拉嗪）, which carry a risk of QTc prolongation but have not been associated with clinically significant cardiac toxicity.
Opioids（阿片类药物） in Gastroparesis(胃瘫): Is There a Better Way?
Pearls and Pitfalls
• Gastroparesis is a chronic illness causing vomiting and pain that can be a challenge to manage in the acute care setting.
• National opioid prescribing guidelines recommend avoiding ******** pain medication in gastroparesis.
• Antipsychotics（抗精神病药） are an effective class of antiemetic with increasing evidence for use in acute exacerbations of gastroparesis.
• Low-dose ketamine（氯胺酮）, which has been used safely in acute pain management and reduces opioid use, has potential benefit in gastroparesis.
Gastroparesis is a chronic illness with a significant negative impact on a patient’s quality of life. Patients tend to be older and female, with most cases secondary to diabetes; however, post-infectious and idiopathic causes are also documented. Patients tend to report chronic nausea and vomiting as their primary complaints, but a significant number live with chronic abdominal pain related to the delayed gastric emptying. Outpatient management includes pro-motility agents, antiemetics, pain medication, specialized diets, and, in some cases, implantable gastric pacemakers.
Patients typically present for acute care with worsening of chronic symptoms: nausea, emesis, and abdominal pain. A study of 200,000 emergency department encounters for gastroparesis primarily demonstrated approximately 54% of patients required admission. The admission rate approaches 75% when gastroparesis is listed as either a primary or secondary condition.
Management of patients with acute exacerbations of gastroparesis can be challenging, especially from a pain control standpoint. Many patients receive outpatient opioid pain medications and often request them for acute exacerbations in the emergency department; however, new guidelines recommend against opioids as a first-line treatment and should be avoided in patients with chronic abdominal pain and gastroparesis. Because they receive outpatient opioid management, patients may expect opioids when they present for acute care.
Few studies evaluate management options in patients with acute gastroparesis flares（发作）. The use of antipsychotics（抗精神病药） such as olanzapine, haloperidol, and mirtazapine（奥氮平、氟哌啶醇和米氮平） for chronic nausea and vomiting has been well studied in the palliative care（姑息治疗） setting, and recent studies have started to evaluate their utility for acute symptom management. In a retrospective case-matched review of 52 patients receiving 5 mg of intramuscular haloperidol for treatment of gastroparesis-related vomiting, haloperidol was associated with reduced opioid requirements and a lower admission rate. Another small prospective study evaluated 5 mg of intramuscular haloperidol compared to placebo and showed that 1 h after administration, those who received haloperidol showed significant reductions in both nausea and pain. Patients in both studies still received opioids for pain control, but the overall ******** equivalent used was lower in patients receiving haloperidol.
Case reports have described other potential management options for acute gastroparesis flares. One described how phentolamine（酚妥拉明） administration (0.5 mg/kg over 60 min) led to complete resolution of abdominal pain in a patient with a gastric stimulator for gastroparesis. An outpatient case report described drastic(激烈的) symptom improvement after a patient took 15 mg of mirtazapine（米氮平） as an orally disintegrating tablet（口腔速崩片）.
A recent review of 11 studies using low-dose ketamine（氯胺酮） (<1 mg/kg) showed that it was as effective as opioids for acute pain management. Ketamine also produced fewer adverse events and was effective in opioid tolerant patients. Although ketamine use in gastroparesis has not been studied, it has been evaluated in chronic pain patients, including those with chronic abdominal pain. Ketamine for analgesia can be administered as an intravenous push (IVP), an infusion, or a combination. Most studies showed that doses between 0.1 and 0.5 mg/kg IVP provided adequate pain relief. One study showed significant pain relief with minimal adverse events using 15 mg ketamine IVP followed by 20 mg infused over 60 min. Because of its utility for pain control in various circumstances, ketamine holds promise as a potential treatment for gastroparesis-related pain, but future studies are necessary to elucidate（阐明） what specific role, if any, it will play.
Continued research on the optimal management of acute gastroparesis flares remains crucial as physicians look to reduce opioid use and find safer analgesic therapies.