COLLECTIVE REVIEW hiccups

Hiccups (Singultus): Review and Approach to Management [KolodzJk PW, Eilers MA: Hiccups (singultus): Review and approach to management. Ann Emerg Med May 199I;20.'565-573.] INTRODUCTION Hiccups, a transient and benign annoyance experienced occasionally by most people, can be debilitating to people in whom this ailment persists for more than a brief period. Hiccups also may be a manifestation of a serious underlying pathological process. Individuals experiencing hiccups for long periods may present to the emergency department seeking relief of their symptoms. A thorough review of the diagnostic and therapeutic considerations pertinent to the evaluation and management of patients with hiccups is presented. Although hiccups are a frequent and nearly universally experienced phenomenon, they remain a medical enigma. Hiccups serve no known useful function. In some cases, despite exhaustive investigation, their etiologies cannot be determined. Therapeutic recommendations for the management of hiccups encompass a spectrum of approaches ranging from universally known home remedies to new synthetic pharmacological agents. It is unlikely that the physiological, diagnostic, and therapeutic issues relating to hiccups will be completely resolved soon. However, an orderly approach to treatment of the patient presenting to the ED with hiccups can be defined.

Paul W Kolodzik, MD*t Dayton and Marion, Ohio Mark A Eilers, MD, FACEP* Dayton, Ohio From the Department of Emergency Medicine, Wright State University School of Medicine, Dayton, Ohio;* and Marion General Hospital, Marion, Ohio.¢ Received for publication December 29, 1989. Revision received October 8, 1990. Accepted for publication November 6, 1990. Address for reprints: Mark A Eiters, MD, FACER Wright State University School of Medicine, PO Box 927, Dayton, Ohio 45401-0927.

DEFINITIONS

The origin of the word "hiccup" is uncertain, but it is thought to be an onomatopOetic derivation of the sound resulting from the act of hiccupping. Singultus is the proper medical term for hiccups. The origin of the word "singultus" is thought to be derived from the Latin singult, which can be roughly translated as "the act of attempting to catch one's breath while sobbing. ''1 The medical literature demonstrates a distinct preference for the use of hiccup over singultus, a convention that will be adhered to in this review. Hiccups can be more precisely defined by noting the episode's duration. Various terms have been used to describe episodes of hiccups lasting longer than a few minutes, including hiccup bout, persistent hiccups, protracted hiccups, and intractable hiccups, z-9 A hiccup bout is any episode of hiccups comprisirig more than several hiccups. Hiccup bouts can last as long as 48 hours. When an episode of hiccups continues for more than 48 hours, it can be considered persistent or protracted, with a preference for the former term demonstrated in the recent literature. Hiccups lasting longer than one month are considered intractable. EPIDEMIOLOGY

Hiccups have been observed in not only human beings but also many other mammals.lO In human beings, hiccups are known to occur even before birth and can be an annoyance to women during the third trimester of pregnancy. 1~ Preterm infants and neonates hiccup much more frequently than infants, children, and adults. Brouillette and colleagues noted that preterm infants spend as much as 2.5% of their time hiccuping, xa A definitive cause of hiccups is seldom found in infants and children; conse-

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quently, most of these episodes are labeled as idiopathic. As infants mature, hiccups become increasingly less frequent.~3 For an undetermined reason, however, persistent and intractable hiccup episodes occur more frequently in adults than in younger age groups. No clear male or female preponderance for transient hiccup episodes has been noted. However, it is well established that persistent hiccups and intractable hiccups occur much more frequently in men.14,15 There also appears to be a circadian variation to hiccup episodes. Short hiccup bouts as well as persistent and intractable hiccups tend to occur more frequently in the evening. 16 No distinguishable racial, geographic, or soc i o e c o n o m i c variation in the frequency of hiccup episodes has been described. ANATOMICAL AND PHYSIOLOGICAL CONSIDERATIONS T Shortt, an English physician, first recognized the relationship between phrenic nerve irritation and hiccups in 1833.17 During the first half of this century, it was recognized that hiccups may result from a central or peripheral nervous system process. 17-19 In 1943, Bailey proposed the existence of a "hiccup reflex," a principal component of which was a "hiccup center" located somewhere in the upper cervical segments of the spinal cord. 2° Since then, Bailey's findings have been modified and expanded; it is now known that hiccups result from stimulation of one or more components of a hiccup reflex arc. 21-24 The afferent portion of the hiccup reflex arc comprises the phrenic and vagus nerves and the sympathetic chain arising from thoracic segments T6-12. 23,24 The central connection between the afferent and efferent limbs of the reflex arc cannot be ascribed to a discrete and specific anatomical location, such as the analogous and recognized chemoreceptor trigger zone for vomiting. Instead., the central coordination of hiccuping is attributed to a nonspecific anatomical location somewhere in the spinal cord b e t w e e n s e g m e n t s C-3 and O5.1,13,25 It was recently proposed that the central connection for hiccups probably also involves a complex interac136/566

tion among brainstem and midbrain areas, including the respiratory center, phrenic nerve nuclei, medullary r e t i c u l a r f o r m a t i o n , and h y p o thalamus. 13 The argument for supraspinal coordination of the efferent portion of the arc is supported by recent studies delineating the existence of several different efferent components of the hiccup arc. This means that the phrenic nerve (C3-5) is no longer considered to be the only efferent component of the hiccup response. E l e c t r o m y o g r a p h i c studies have demonstrated simultaneous firing of m o t o r n e u r o n s to t h e a n t e r i o r scalene muscles (C5-7), external intercostal muscles (TI-ll), and glottis (recurrent laryngeal component of the vagus nerve).6,26,27 It was also recently noted that normal esophageal contractile tone and lower esophageal sphincter pressure are reduced during hiccupping, suggesting the existence of simultaneous inhibitory autonomic processes. '-5 Fluoroscopic studies revealed that hiccups are most often unilateral with regard to diaphragmatic contraction, the left hemidiaphragm being much more frequently involved than the right.X6, 27 However, complete bilateral spasm may occasionally also occur. 28,29 Hiccups tend to occur in discrete quantities of less than seven or more than 63.16 Anthoney and coworkers suggested that if more than several hiccups occur sequentially, they become "established" and do not term i n a t e until a certain m i n i m u m n u m b e r of h i c c u p s h a v e t a k e n place.16 Hiccups generally occur with a frequency of between four and 60 per minute, with the frequency of separate episodes in a given individual r e m a i n i n g r e l a t i v e l y c o n s i s tent. 13,21 The frequency of hiccups is known to increase with a fall in arterial P c o 2 and decrease as Pc02 rises. This provides the physiological basis for the common and occasionally effective technique of managing hiccups by having the affected individual breathe into a paper bag. Hiccup amplitude, that is, the relative vigor of a given hiccup, varies considerably among individuals, among separate episodes within an individual, and even among hiccups during a given hiccup episode) It was thought for many years that Annals of Emergency Medicine

the origin of the hiccup reflex was respiratory in nature.30, 31 This thinking was recently challenged. Davis monitored diaphragmatic and intercostal electromyographic recordings and pulmonary spirometric function simultaneously to demonstrate that hiccups have only a minimal effect on ventilation. 1 He arrived at this conclusion by determining that glottic closure was noted to be very transient and to occur only 35 ms after the onset of inspiratory muscle motor discharge. Based on these findings and the widely accepted knowledge that hiccups are often triggered by intra-abdominal stimuli (ie, gastric distension), Davis suggested that hiccups may be more gastrointestinal than respiratory in nature. This issue remains unresolved.

PATHOPHYSIOLO GY Classification schemes have been proposed to categorize the multitude of pathophysiological processes that can incite hiccups. Several authors have categorized hiccup episodes into those of a benign, self-limited nature and those causing persistent or intractable episodes; the latter is believed to more likely result from a s e r i o u s p a t h o p h y s i o l o g i c a l process. 4,22 Benign, self-limited hiccup episodes may be caused by gastric distension from varying causes, including excessive food or alcohol ingestion, aerophagia, and gastric insufflation; sudden changes in ambient or gastrointestinal temperatures (eg, physically moving from a relatively hot or cold' area to another of contrasting t e m p e r a t u r e or ingesting beverages or foods at extremes of temperature); alcohol ingestion; and tobacco use. 21 The origin of persistent or intractable h i c c u p episodes can be very broadly classified as organic, psychogenic, or idiopathic. 26 The labeling of a given episode of hiccups as psychogenic or idiopathic is appropriate only after ruling out organic causes. Consequently, use of these terms is not usually appropriate after a limited ED evaluation. The psychogenic causes of hiccups include stress and excitement, conversion and grief reactions, anorexia nervosa, and malingering. 14,19,21,32,33 Psychiatric problems resulting in suicidal ingestions and anorexia nervosa may also lead to organic problems that cause hiccups. Intractable hiccup episodes are 20:5 May 1991

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more often than not the results of organic causes. Organic triggering mechanisms can be divided into three subgroups: central; peripheral; and toxic, metabolic, o r p h a r m a c o l o g i c a l . 6 , 9 , 1 3 , 2 4 , 26,34-36

Central and peripheral classifications are subject to further division based on anatomical considerations. One of three pathophysiological adjectives can be applied to the central nervous system causes of hiccups: structural, vascular, or infectious. 21 Peripheral n e r v o u s s y s t e m e t i o l o g i e s are thought to ultimately derive from either phrenic or vagus nerve stimulation or direct diaphragmatic stimulation. 13,21,26

Central Nervous System Causes of Organic Hiccups Central nervous system structural lesions, including neoplasms, hydrocephalus, ventriculoperitoneal shunts, and multiple sclerosis, are known to cause hiccups. 37-40 Vascular and infectious central nervous system etiologies for hiccups are, however, more common.14 Vascular causes to consider w h e n evaluating a p a t i e n t w i t h h i c c u p s i n c l u d e ischemic or hemorrhagic stroke (especially those caused by subarachnoid hemorrhage) and arteriovenous malformation; lesions resulting from heTJ trauma, including diffuse axonal injury, cerebral contusion, and epidural or subdural hematoma; and temporal arteritis.14,19 Of the infectious causes for hiccups, encephalitis is c o n s i d e r e d t h e m o s t c o m mon.2],41, 42 Meningitis, brain abscess, and neurosyphilis are other k n o w n c a u s e s . 13,41,42

Peripheral Nervous System Causes of Organic Hiccups Irritation of the vagus nerve anywhere along its-course can result in hiccups. 21 Stimulation of the meningeal afferents by meningitis or of the pharyngeal afferents or recurrent laryngeal nerve by pharyngitis, laryngitis, retropharyngeal or peritonsillar abscess, goiter, cysts, or tumors of the neck may incite hiccups. Irritation of the auricular branches of the vagus by injury to or a foreign body in contact with the tympanic membrane may also result in persistent or intractable hiccup b o u t s . 21,43,44 Irritation of the thoracic or abd o m i n a l b r a n c h e s of t h e v a g u s nerve may also be a cause of persis20:5 May 1991

tent or intractable episodes of hiccups. 14,22,45,46 S t i m u l a t i o n of the thoracic branches may result from chest trauma, neoplasm of the lung or mediastinum, myocardial infarction, pulmonary edema, pericarditis, pleuritis, mediastinitis, esophagitis or esophageal obstruction, thoracic a o r t i c a n e u r y s m or d i s s e c t i o n , asthma, bronchitis, pneumonia, empyema, or i n t r a o p e r a t i v e m a n i p u l a t i o n of t h e o r g a n s of t h e chest.8,9,21,23,45-47 A wide variety of conditions may cause s t i m u l a t i o n of the afferent branches of the vagus nerve in the abdomen as well; these include gastric distension, gastritis, gastric or duodenal ulcer, pancreatic or biliary disease, bowel obstruction, appendicitis, inflammatory bowel disease, genitourinary disorders such as pylonephritis or renal lithiasis, hepatitis and hepatic or splenic injury, and intra-abdominal surgical manipulation. 14,23,46,47-50 Phrenic nerve irritation anywhere along the course of the nerve may also result in hiccups. Goiter, tumors, or cysts causing phrenic nerve compression are the most c o m m o n reasons for phrenic nerve irritation in the neck.13,14 These many causes for vagus nerve irritation in the chest can also cause phrenic nerve irritation. The most common of these includes compression of the phrenic nerve by mediastinal carcinoma or enlarged lymph nodes secondary to pulmonary neoplasm or infection (ie, tuberculosis or histoplasmosis).21, 51 Both pericarditis and aberrant cardiac pacemaker electrode placement are well-documented sources of phrenic nerve stimulation and associated persistent or intractable hiccup episodes. 52-ss Sources of phrenic nerve irritation near the diaphragm include h i a t a l h e r n i a and d i a p h r a g m a t i c eventration. Inflammation of the diaphragm directly from nearby infectious processes such as perihepatitis or subphrenic abscess and intraoperarive diaphragmatic irritation can also cause hiccups. 14,23,48,56

Other Causes of Organic Hiccups Many postoperative, drug-related, and toxic-metabolic states are also k n o w n to cause hiccups. Hiccups also frequently result from general anesthesia, although the reason for this is uncertain and has been variaAnnals of Emergency Medicine

bly attributed to suppression of central nervous system influenceg normally inhibitory to hiccups, hyperextension of the neck with traction on the phrenic nerve, glottic stimulation related to intubation, and gastric distension secondary to mask ventilation. 18,56 Several pharmacological agents are believed to precipitate hiccups. Several case reports have cited IV steroid therapy with methylprednisolone or d e x a m e t h a s o n e as a cause of hiccups. 7 Barbiturates in both therapeutic and toxic doses are also thought to occasionally incite hiccups.5, 28 Various benzodiazipines have been cited as both causes and cures of hiccups. 57,5s R-Methyldopa use for the management of hypertension is also thought to be a possible cause of hiccup episodes, t Several toxic and pathophysiological m e t a b o l i c states m a y be etiologies of persistent or intractable hiccup episodes. Alcohol intoxication, as noted previously, may be the best k n o w n c a u s e of h i c c u p s . 34 Sepsis f r o m v a r i o u s s o u r c e s is thought to occasionally induce hiccups. 48 Uremia, hypocalcemia, and hyponatremia are other conditions believed to contribute to persistent or i n t r a c t a b l e e p i s o d e s of hiccups.39,43

ED APPROACH TO THE PATIENT WITH PERSISTENT OR INTRACTABLE HICCUPS Patients usually present to the ED for treatment of hiccups only when their maladies have continued without resolution for a number of days or have become incapacitating. Alt h o u g h some of these individuals m a y d i s p l a y e m b a r r a s s m e n t or a m u s e m e n t w i t h their condition, most of these patients are anxious or frankly distraught. An individualized approach to these patients is necessary and dependent on a thorough history and careful physical examination. 13,43 The goal of this orderly approach is the recognition of potentially serious etiologies of the episode and s u c c e s s f u l t h e r a p e u t i c intervention.

History A thorough history is critical in the evaluation of patients with persistent or intractable hiccup episodes for two primary reasons. First, this information may allow the diagnosis 567/137

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of a serious underlying problem. Second, a good history may suggest an effective therapeutic intervention. Prolonged historical evaluation should, however, not delay the initiation of therapy. Key information to be obtained includes the severity and duration of the present episode, specific characteristics of this episode, a history of previous episodes and associated successful treatments, and a brief medical history and review of systems. The current episode's severity and duration may provide insight to the degree of discomfort and anxiety experienced by the patient as well as the likelihood of associated complications such as dehydration, electrolyte i m b a l a n c e , and e s o p h a g i t i s . Many individuals with intractable hiccups will have u n s u c c e s s f u l l y sought relief from family, friends, or other health care providers. Although intractable hiccups frequently have a discoverable organic origin, it is important to realize that "benign" hiccups may occasionally be just as recalcitrant as those resulting from a more serious cause; the case has been cited of an Iowa man who had been hiccupping for more than 60 years without any identifiable cause. 59 Hiccup i n t e n s i t y cannot be directly correlated with the likelihood of serious, underlying, organic pathology. However, the relation of hiccups to sleep may provide some insight as to the origin of the episode. In a study of 220 patients with intractable hiccups, Souadjian and Cain concluded that the persistence of hiccups during sleep suggests an organic cause. 14 Conversely, if an individual is unable to sleep during hiccups or if the hiccups stop during sleep and recur promptly on awakening, a psychogenic or idiopathic etiology is suggested. 1,7 Signs and s y m p t o m s associated with hiccup episodes may provide information regarding the presence of a c o m p l i c a t i n g process. A s s o c i a t e d neurologic, cardiac, respiratory, and gastrointestinal complaints should be specifically sought. The patient should be questioned about recent events such as trauma, surgery, or acute illness. A medication history should also be recorded, and inquiry should be made regarding alcohol and illicit drug use. A thorough review of past medical and surgical problems may be helpful, as may a 138/568

brief but focused review of systems. For example, recent constitutional s y m p t o m s (ie, weight loss, fatigue, night sweats) might suggest the presence of malignancy. Finally, any information relating to previous hiccup episodes should be noted because this information m a y be helpful in determining both a cause of and an a p p r o p r i a t e initial t h e r a p e u t i c approach to the current episode.

Physical Examination The purpose of the physical examination of the patient with hiccups is the detection of potentially serious causes of the episode. On general examination, the emergency physician should ask himself if the patient appears cachectic, intoxicated, or toxic. Such findings suggest possible malignant, metabolic, or infectious etiologies, respectively. A review of vital signs may raise concern for an infectious, cardiac, or r e s p i r a t o r y problem. Thorough head, ears, eyes, nose, and throat, and neck examinations may suggest a traumatic or neurologic problem, including any of various structural central nervous syst e m lesions. Causes as easy to resolve as a foreign body irritating the t y m p a n i c m e m b r a n e have been reported as triggering hiccups. 43,44 A tender temporal artery may suggest temporal arteritisA 4 Pharyngitis and laryngitis have also been cited as causes of hiccups. 22,43 Recurrent lar y n g e a l n e r v e i r r i t a t i o n m a y be caused by goiter, cysts, or tumors that m a y be appreciated by a thorough examination of the neck. Cervical lymphadenopathy is suggestive of the presence of an inflammatory, malignant, or infectious process.14,23, 56 Examination of the chest is often the most helpful component of the physical examination. Physical findings may suggest pneumonia, 57 thoracic aortic aneurysm or dissection, 60 myocardial infarction,61, 62 pericarditis,]9, 2° or pulmonary or mediastihal tumor. 21 Acute abdominal processes, including abdominal aortic aneurysm, 9 ruptured hollow viscus, 14 appendicitis, 19 bowel obstruction, 21 splenic injury, intra-abdominal abscess, and upper or lower gastrointestinal bleeding, 23 are recognized etiologies of hiccups and should be considered as the abdomen is examined. Other gastrointestinal or genitourinary processes such as gastritis, panAnnals of Emergency Medicine

creatitis, biliary disease, hepatitis, i n f l a m m a t o r y b o w e l disease, pylonephritis, uretal obstruction, and postoperative complications may warrant consideration.13, 2~ Neurologic causes of hiccups inc l u d e h e m o r r h a g i c or i s c h e m i c stroke, 19,63 arteriovenous malformation, 63 t r a u m a t i c i n t r a c r a n i a l injury, 23 central nervous system neoplasm, 46 ventriculoperitoneal shunt malfunction, 48 meningitis, and encephalitis. 31 Early multiple sclerosis is thought to be one of the most frequent neurologic causes of intractable hiccups in young adults, and this diagnosis should be considered. 64 Finally, a brief mental status examination should be performed to discern psychiatric problems that may have p r e c i p i t a t e d a m e t a b o l i c derangement. Foremost among these metabolic processes are acute or chronic alcohol intoxication, anorexia nervosa, p s y c h o g e n i c polydipsia, and suicidal ingestion.14, 21

Laboratory Studies Truly extensive and diverse laboratory studies have been advocated in the w o r k u p of p a t i e n t s w i t h hiccups. 6,8,23,29,35,43,65-67 However, ED ancillary evaluation of hiccups can be limited to studies required to evaluate the presence or absence of pot e n t i a l l y serious u n d e r l y i n g problems. With the exception of several routine laboratory studies with the purpose of detecting the more serious causes of hiccups, the ordering of laboratory studies should be dictated by the concerns and suspicions derived from a thorough history and physical examination. The chest radiograph is probably the m o s t useful routine laboratory screening examination for the patient with hiccups. It should be ordered routinely to rule out evident pulm o n a r y , m e d i a s t i n a l , or c a r d i a c sources of phrenic or vagal nerve or diaphragmatic irritation in patients with persistent or intractable hiccups. 6,17,25,43,65 O t h e r t e s t s to be considered in the routine laboratory workup of these patients include a CBC w i t h differential, e l e c t r o l y t e studies (particularly sodium), and an alcohol level. The CBC may be helpful in detecting signs of occult infect i o n or m a l i g n a n c y . 6 , 43 H y p o n a tremia is a well-known cause of persistent or intractable hiccups, and other e l e c t r o l y t e i m b a l a n c e s m a y 20:5 May 1991

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complicate the presentation of persistent or intractable hiccups as a result of dehydration or polydipsia.14,34 Other laboratory tests may be ordered by the emergency physician as warranted depending on the degree of concern for specific inciting serious pathology. Studies to be considered include blood sugar, calcium level, liver and renal studies, urinalysis, t o x i c o l o g y screen, ECG, arterial blood gases, cerebral spinal fluid studies, and additional radiological studies, including head and chest computed tomography scanning.6,8,25,39,43 The scheduling of other studies to be undertaken soon after admission to the hospital or on an outpatient basis m a y also be a p p r o p r i a t e . Studies to be considered include electroencephalography,39,64, 6s magnetic resonance imaging, brain scan, somatosensory evoked potential studies, 64 electromyography, 66 bronchoscopy, 8 pulmonary function s t u d i e s , 67 p u l m o n a r y f l u o r o s c o p y , 66,67 e n d o s c o p y , 8 , 3s r a d i o contrast upper gastrointestinal studies,8,3s, 64 e s o p h a g e a l m a n ometric studies,a, 3s and Bernstein esophageal acid perfusion testing.8, 3s If these studies are to be scheduled, emergency physician c o n s u l t a t i o n with the physician who is to provide ongoing management of the involved patient is advisable. COMPLICATIONS Many authors have cited complications resulting from intractable hiccups,4,8,2t,35, 38,68 and the emergency physician must consider these potential problems at the time of ED evaluation. The most c o m m o n serious complications of hiccups are dehydration and weight loss resulting from inability to tolerate fluids and food.23, 47 S t r o m b e r g cites several cases in which patients with intractable hiccups required hospitalization and intensive supportive care because of these complications. 63 Exhaustion and insomnia may occasionally complicate hiccup presentations, t8,68 Only rarely may intractable hiccups precipitate ventricular dysrhythmias, probably as a result of d i s t u r b a n c e s in s e r u m p o t a s s i um.69, 70 Hiccups have been implicated in patient deaths for this reason.7 I It is important to be aware that several entities have been cited as 20:5 May 1991

both cause and complication of intractable hiccups. Hyponatremia is thought to trigger a central neurogenic type of hiccup, and it is believed that polydipsia precipitated by persistent attempts of patients to rid themselves of hiccups can also lead to hyponatremia.2~, 34 Esophagitis is a w e l l - d o c u m e n t e d c o m p l i c a t i o n of intractable hiccup episodes, apparently by causing recurrent gastroesophageal reflux.g5, 47 However, because esophageal disease is known to be one of the underlying organic etiologies of hiccups, whether esophagitis is a cause or complication of a given hiccup episode is frequently difficult to determine.

THERAPY The emergency treatment of persistent or intractable hiccups might be considered to be more art than science. The observation has been made by several authors that the wide variety of treatments put forth for the treatment of hiccups underscores the lack of effectiveness of any one therapy. 33,63 Perhaps Mayo put it best when he stated in 1932 of hiccups that "the amount of knowledge on any subject such as this can be considered as being in inverse proportion to the number of different treatments suggested and tried for it. ''L7 The reason for the lack of consensus regarding the appropriate treatment of hiccups is in large part related to the ancedotal nature of the i n f o r m a t i o n available regarding hiccup therapy. T h e r a p y directives are therefore based on information derived from case reports and small series. When considering the therapeutic approach to the patient with persistent or intractable hiccups, it is critical to keep in mind the primary importance of determining the etiology of the hiccup episode and, if possible, correcting it. For example, if hiccups result from diaphragmatic irritation caused by a p u l m o n a r y or intraabdominal process, the thrust of therapeutic management is directed toward the correction of this problem. Treatment modalities for hiccups can be roughly categorized as pharmacological or nonpharmacological. Pharmacological therapy for hiccups has continued to evolve in recent years with several medications appearing to be helpful in controlling hiccups. However, no one drug is universally accepted for its usefulAnnals of Emergency Medicine

ness for this p u r p o s e . N o n p h a r macological interventions range from many well-known home remedies to surgical ablation of anatomical components of the hiccup reflex arc.

Nonpharmacological Hiccup Management There are many time-honored but equivocally effective remedies of hiccups that are frequently used by patients before they seek professional help. A l t h o u g h m a n y of these remedies' origins are ancient and obscure, some have sound physiological bases. Several involve stimulation of the nasopharynx, a method that may serve as a means of interruption of the vagal afferent limb of the hiccup reflex arc. Techniques that rely on some m e t h o d of n a s o p h a r y n g e a l stimulation include forcible traction of the tongue, 24 gargling with water,21, 72 sipping ice water, 21 swallowing granulated sugar, 63J3 biting on a lemon,34, 63 inhaling noxious agents (eg, ammonia),63, 73 and drinking from the far side of a glass, t8,21,74,75 Another less widely known home remedy - stimulation of the dermatomal area C5 by tapping of or rubbing the back of the neck - has also been suggested. The mechanism of effectiveness of this therapy is also thought to be hiccup reflex arc interruption.~4, 73 Somewhat more aggressive measures of nasopharyngeal, gastrointestinal, and cervical d e r m a t o m a l trigger point stimulation have been advocated. Direct pharyngeal stimulation either orally or nasally with a rubber catheter has been reported as being as much as 90% effective in the termination of idiopathic episodes of hiccups. 73,75,76 Similarly, direct uvular stimulation by "lifting of the uvula" with a spoon or cotton-tip applicator has been found to be a suc cessful mechanism of hiccup termination in relatively large numbers of patients.6, 21 Removal of gastric contents by the use of emetics or nasogastric suction is also a known effective mechanism of relieving hiccups resulting from overindulgence of food. Vagal afferent stimulation and hiccup arc i n t e r r u p t i o n m a y be the mechanisms by which nasogastric suction terminates hiccups, but several authors believe that direct diaphragmatic stimulation may play a role. 2~,63,73 Iced gastric lavage has also been suggested and is known to 569/139

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be effective in some patients. Several additional methods of vagal stimulation have been used in attempts to terminate hiccup episodes; these include the Valsalva maneuver, carotid massage, digital ocular globe pressure, and digital rectal massage. 7s Other m e t h o d s of cervical dermatomal stimulation used for hiccup episode resolution include the use of v a p o c o o l a n t sprays and a c u p u n c ture. 24,77 A l t h o u g h s t i m u l a t i o n of the aforementioned appropriate anat o m i c a l a r e a s w i t h t h e u s e of vapocoolant sprays is not thought to be of great benefit in the vast majority of recalcitrant hiccup episodes, acupuncture applied to the neck has been curative in many patients.77, 78 Interference with normal respiratory function is the foundation of a v a r i e t y of w e l l - k n o w n h o m e remedies for bothersome episodes of hiccups. These include induction of sneezing or c o u g h i n g by various means, 73 breath holding,18,19 hyperventilation, 18 and "gasping" like that precipitated by fright. 73 The most well k n o w n of h o m e remedies is breathing into a paper bag. It has been suggested that the acute but mild respiratory acidosis resulting from this maneuver may terminate hiccups by a direct inhibitory effect on diaphragmatic contractility.2179 The use of continuous positive airway pressure has also been advocated for hiccup relief, although its use has been limited to anesthetized surgical patients. Satto et a] obtained 100% efficacy in relief of hiccups in 16 patients treated with 25 to 35 cm H20 c o n t i n u o u s positive airway pressure. 8° The use of this technique for patients with prolonged or intractable hiccups has not been addressed. Many additional nonpharmacological techniques have been used in the management of intractable hiccup episodes not responsive t o routine mechanical or pharmacological intervention. Although not routinely used by emergency physicians, such techniques may be considered in the intractable hiccup patient who has been refractory to other forms of therapy. These techniques are mentioned to provide a comprehensive perspective of therapeutic options, although their routine ED use is generally not appropriate. These include behavioral conditioning, hypnosis, phrenic nerve or direct diaphragmatic stimulation by operative placement 140/570

of pacing electrodes, S4,5s p h r e n i c nerve blockade with bupivacaine,~l, 67 and surgical phrenic nerve interruption. ~,2~,8~-86

Pharmacological Hiccup Management Suggested pharmacological agents for h i c c u p m a n a g e m e n t are numerous, with little more than anecdotal support for the vast majority. Several of these agents have gained fairly widespread acceptance for the treatment of persistent or intractable hiccup episodes and should be included in the emergency physician's therapeutic armamentarium. There are additional medications that are less frequently used for this purpose that have relatively few contraindications and may be considered in the refractory patient. Several oral medications, used to prevent hiccup recurrence, may be used in the management of patients discharged from the ED. C h l o r p r o m a z i n e is an antipsychotic of the phenothiazine type and may be the most widely accepted agent for the treatment of persistent a n d i n t r a c t a b l e hiccups.6,~3, 21, 65,7s,s6-s8 This drug is a centrally acting agent whose precise mechanism of action in hiccup management is u n c e r t a i n . In several c o n t r o l l e d studies, c h l o r p r o m a z i n e has been found to effect a "permanent" cure in approximately 80% of patients with intractable hiccups, with an additional 10% experiencing "temporary" relief.S7, 89 There are also anecdotal reports that support the use of chlorpromazine for the treatment of hiccups. Several authors, however, have found the drug to be ineffective.33, 56 Chlorpromazine has been touted as most effective when administered intravenously. If the drug is to be given by this route, the treating physician should be aware that the complication of postural hypotension is quite common and that a distributive type of shock has been reported.SS, 9° Dosage recommendations call for the administration of 25 to 50 mg chlorpromazine in 500 to 1,000 mL normal saline IV over one to several hours with frequent blood pressure monitoring. Chlorpromazine may alternatively be administered intramuscularly in a dose of 25 to 50 mg. If resolution of hiccups is achieved, the drug may be prescribed (25 to 50 mg three or four times daily) at the Annals of Emergency Medicine

time of ED discharge in an attempt to p r e v e n t r e c u r r e n c e . P a t i e n t s should be advised regarding potential side effects of this medication, including postura] hypotension, drowsiness, and dystonic reactions. Haloperidol, another antipsychotic, but of the b u t y r o p h e n o n e class, has been touted by several authors as an effective therapy for the management of hiccups. 7s,86,91 Ives et al documented 100% efficacy with the use of IM haloperidol in patients with intractable hiccups resulting from a variety of causes. 91 The authors suggest that IM haloperidol is a useful alternative to chlorpromazine. Haloperidol has a lower potential for hypotension, especially in elderly patients. The r e c o m m e n d e d dose of haloperidol is 2 to 5 mg IM. If good results are achieved with IM administration, the patient may be placed on a maintenance regimen of 1 to 4 mg orally three times daily. Side effects include sedation and dystonic reactions. Many anticonvulsants have been described as effective in the management of hiccups, including phenytoin, phenobarbitol, carbamazepam, 1 and valproic acid. Phenytoin given by the oral or IV route has been suggested by several as an effective treatment for the management of intractable hiccups.21, 66 It has been suggested that phenytoin may be most efficacious in patients with a central neurological etiology of their hiccups. 6 6 The recommended initial IV dose of phenytoin is 200 mg slow IV push (not to be given at a rate of more than 50 mg/min). Larger doses (up to 18 mg/kg) are usually well tolerated and may increase the likelihood of hiccup resolution.92, 93 Patients should be carefully monitored for the development of bradycardia, heart block, and hypotension while phenytoin is being administered. Oral loading may also be considered (up to 18 mg/kg) because this route of administration decreases the likelihood of serious adverse reactions, i n c l u d i n g b r a d y c a r d i a and heart block. When the drug is given orally, therapeutic levels are usually achieved within six hours. 94 A maintenance dosage of approximately 300 mg/day may be effective in preventing recurrence. One report documented IM phenobarbitol as effective in the management of hiccups. 95 Several au20:5 May 1991

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thors, however, failed to m e n t i o n phenobarbitol in relatively comprehensive lists of drugs used for intractable hiccup management.6, 6s,s6 At least one author cited IV, IM, or oral phenobarbitol as "unreliable" in the treatment of hiccups. 7s C l i n i c a l e x p e r i e n c e w i t h carbamazepam is relatively limited. A case of intractable hiccups believed to be secondary to new-onset multiple sclerosis responded to oral carb a m a z e p a m (200 mg t h r e e t i m e s daily) within 24 hours. Other authors supported a trial of therapy with this drug for the treatment of intractable hiccups. 13,65,86,96 Reasoning that hiccups may be a type of myoclonus involving the diap h r a g m , Jacobson and c o w o r k e r s used long-term therapy with valproic acid to effectively manage five patients with hiccups of a variety of etiologies. 97 Dosing began at 15 mg/ kg/day and was gradually increased at two-week intervals until hiccup resolution was achieved; the t i m e until resolution was not reported. With subsequent tapering of valproic acid, hiccups recurred in three of the five patients. 97 It should be noted that fatalities related to hepatotoxicity in patients receiving valproic acid have recently been recognized, and, consequently, long-term use of this drug for hiccup m a n a g e m e n t may not be appropriate. Another class of anticonvulsants, the benzodiazipines, are believed to not be efficacious in the management of hiccups. In fact, s o m e benzod i a z i p i n e s m a y e v e n i n c i t e hiccups, 58,98,99 a p r o b l e m widely accepted by clinicians using this class of drugs as preoperative medication. Metaclopramide is a dopamine antagonist that increases esophageal sphincter tone, stomach peristalsis, and the rate of gastric e m p t y i n g . Probably more important, metaclopramide is known to have central antidopaminergic activity that inhibits vomiting.99,100 Many authors have found this drug to be effective in the relief of persistent and intractable hiccups. 6,13,43,99-tOt The recommended initial dose is 10 mg IV or IM. If the drug is effective, a maintenance regimen of 10 to 20 mg four times daily is recommended for at least ten days. A muscle relaxant and several sedative hypnotics and analgesics have been suggested for the management 20:5 May 1991

of persistent and intractable hiccups. Orphenadrine has been anecdotally reported to terminate intractable hiccups.tO2,1°3 This drug can be administered parenterally (60 mg IV or IM) or by the oral route (100 rag), and an oral maintenance regimen may be effective in preventing hiccup recurrence. Amitriptyline, an antidepressant with sedative effects, has been recommended by several authors for the treatment of persistent and intractable hiccups.75, los Stalnikowicz et al found oral amitriptyline (10 mg three times daily) effective in the treatment of hiccups in a 17-year-old boy with idiopathic intractable hiccups in which chlorpromazine and metaclopramide had not been effective. 1°4 Several sedatives and analgesics have been suggested for the managem e n t of persistent and intractable hiccups. Chloral hydrate, a relatively safe and time-honored sedative, has been recommended for the management of hiccups, but little information is available to substantiate its use for this purpose. 63 IV pentazocine and morphine have been reported by several authors to be effective, although because of the potential for r e s p i r a t o r y depression w i t h these narcotics when they are given intravenously, their routine use for this purpose cannot be advocated.2a, lo5 Several drugs classified as stimulants have also been used in an attempt to resolve persistent and intractable hiccup episodes. Unfortunately, no controlled studies exist to document the efficacy of the foll o w i n g a g e n t s for t h i s p u r p o s e : ephedrine, lO6 methylphenidate,6,7s a m p h e t a m i n e , 6 5 , 7s a n d n i k e t h amide, lo7 Each of these drugs has been anecdotally reported effective when given by the IV route. Only a m p h e t a m i n e has been found to be occasionally effective for hiccup resolution when given orally; the recommended dosage is 5 to 10 mg three times daily. Because of this drug's addictive potential, its use cannot be routinely recommended for the management of hiccups. Several o t h e r agents of diverse types have been r e c o m m e n d e d for the management of intractable hiccups. Many of these have sequentially been heralded as a long-soughta f t e r p a n a c e a o n l y to find a f t e r greater experience w i t h the agent that it is not noticeably more effecAnnals of Emergency Medicine

tive than drugs already used. These agents include ketamine, edrophoniurn, d e x a m e t h a s o n e , a m a n t a d i n e , nifedipine, and baclofen, lO8-i t 3

SUMMARY Hiccups are a common, and fortunately usually transient, benign malady. Occasionally, however, hiccups fail to resolve spontaneously, resulting in patient fatigue and incapacitation and the need for the affected individual to seek m e d i c a l care for resolution of the problem. The approach to the management of these patients consists of the identification and t r e a t m e n t of serious underlying causes of the episode as well as therapeutic interventions to achieve hiccup resolution. REFERENCES 1. Oxford Latin Dictionary, ed 7. Oxford, Oxford University Press, 1980, p 769.

2. Davis J: An experimental study of hiccup. Brain 1970;93:851-872. 3. Stedman's Medical Dictionary, ed 22. Baltimore, Williams & Wilkins, 1972, p 1153.

4. MeFarling D, Susac J: Hoquet diabolique: Intractable hiccups as a manifestation of multiple sclerosis. Neurology 1979;29: 797-801. 5. Cooney C, Buckley J: Prolonged singuhous as a result of barbiturate toxicity, lr Med J 1987;80:290-291. 6. Nathan M, Leshner R, Keller A: Intractable hiccups. Laryngoscope 1980~90:I612-1618. 7. Baethge B, Lidsky M: Intractable hiccups associated with high dose intravenous methylprednisolone therapy. Ann Intern Med 1986~i04:58-59. 8. Shay S, Myers R, Johnson L: Hiccups associated with reflux esophagitis. Gastroenterology 1984~87:204-207. 9. 8tine R, Tmed 8: Hiccups: An unusual manifestation of a n a b d o m i n a l aortic aneurysm. JACEP 1979~8:368-370. 10. Rosenow E: Diaphragmatic spasms in animals produced with a Streptococcus from epidemic hiccup: Pre p liminary report. JAMA 1921~76:1745-1747. ll. Swann I: Intrauterine hiccup. Br Med f 1978; 2:1497-1498. 12. Brouillette R, Thach B, Abu-Osba Y, et al: Hiccups in infants: Characteristics and effects on ventilation, f Pediatr 198096:219-225. 13. Wagner M, Stapczynski J: Persistent hiccups. Ann Ernerg Med 1982;1i:24-26. 14. Sonadjian J, Cain J: Intractable hiccups: Etiological factors in 220 cases. Postgrad Med 1968;43:72-77. 15. Fisher C: Protracted hiccup A male malady. Trans Am Neurol Assoc 1967;1:128-129. 16. Anthoney T, Anthoney S, Anthoney D: On temporai structure of human hiccups: Ethology and chrono biology, lnt J Chronobio] 1978;5:477-492. 17. Mayo C: Hiccup. Surg Gyneco] Obstet 1932;55: 700-708. 18. Bellingham-Smith E: The significance and treatm e n t of o b s t i n a t e hiccough. I ractitioner. 1938; 140:i66-171. 19. Noble E: Hiccup. Can Med Assoc 1934;3l:38-41. 20. Bailey H: Persistent hiccup. [ ractitioner 1943; 150:1273 1277. 2I. Lewis J: Hiccups: Causes and cures. J Cfin Gastro enterol 1985;7:539-552. 22. Gigot A, Flynn P: Treatment of hiccups. JAMA

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1952;150:760-764. 23. Samuels L: Hiccup: A ten year review of anatomy, etiology, and treatment. Can Med Assoc J 1952;67: 315-322. 24. Travell J: A trigger point for hiccup. [ Ain Osteopath Assoc 1977;77:308-312. 25. Graham D: Esophageal motor abnormality during hiccup. Gastroenterology 1986;90:2039-2044. 26. Hemachuda T, Phanthumchinda K, Indrakoses A, et al: Intractable hiccups [singultus) as presenting manifestation of Japanese encephalitis. J Med Assoc Thai 1984;67:620-623. 27. Shim C: Motor disturbances of the diaphragm. Clin Chest Med 1980;h125-129. 28. C a m p b e l l M: M a l i g n a n t hiccup. A m J Surg 1940;48:449-455. 29. Kappis M: Ein beitrag zur e n i s t e h u n g und bebanlung des singultus. Klin Wochenschr Jahrgang 1924;24:1065-1067. 30. Miller F, Felipe G, Mueller E, et ah Fetal hiccups: An associated fetal heart rate pattern. Obstet Gyneco] 1983;62:253-255. 31. Dunn P: Fetal hiccups )letter). Lancet 1977;2:505. 32. Scarnati R: Intractable hiccup (singultus): Report of a case. [ A m Osteopath Assoc 1979;79:127-129. 33. Obis P: Remedies for hiccups. Nursing 1974;4:88. 34. Cronin R: Psychogenic polydipsia w i t h hyponatremia: Report of eleven cases. A m J Kidney Dis 1987;9:410-416. 35. Gluck M, Pope C: Chronic hiccups and gastroesophageal reflux disease: The acid perfusion test as a provocative maneuver. A n n Intern Med 1986;105: 219-220. 36. Herman J, Nolan D: A bitter cure (letter). N Eng] J Med 1981;305:1654. 37. Lewitt P, Barton N, Posner J: Hiccup with dexa methasone therapy. Ann Neural 1982~12:405-406. 38. Fischer A, McLean W: Intractable hiccups as presenting symptom of brainstem tumor in children. Child Brain 1982;9:60-63. 39. Karian J, Buchheit W: Intractable hiccups: A complication of ventriculoperitoneal shunt: Case report. Neurosurgery 1980;7:283-284. 40. Rosenow E: Further studies on the etiology of epidemic hiccup (singultus) and its relation to encephalitis. Arch Neural Psychiatr 1926;18:712-734. 41. Brain W: Epidemic hiccup and encephalitis le thargica. Br Med J 1923;2:856-857. 42. Byrnes C: Hiccup crisis in tabes dorsalis. Bull Johns Hopkins Hasp 1935;56:264-275. 43. Jones J, Lloyd T, Cannon L: Persistent hiccups as an unusual manifestation of hyponatremia. J Emerg Med 1987;8:283-287. 44. Cardi E: Hiccups associated with hair in the external auditory canal - Successful treatment by manipulation. N Engl J Med 1961;265:286.

52. Lederman R, Breuer A, Hanson M: Peripheral nervous system complications of coronary artery bypass graft surgery. Ann Neural i982;12:297-301. 53. Kevorkian M, Matte G, Kevorkian J, et ah Hiccup and electroventricular stimulation with a pervenous electr, odes. PACE 1982;5:440-441. 54. Fodstat H, Blom S: Phrenic nerve stimulation (diaphragm pacing) in chronic singultus. Neurochir (Stuttg} 1984;27:115-116. 55. Fodstad H: The Swedish experience in phrenic nerve stimulation. PACE 1987;10:246-251. 56. Salem M, Baraka A, Rattenborg C, et ah Treatment of hiccups by,pharyngeal stimulation in anesthetized and conscious subjects. JAMA 1967;202:126-130. 57. Greenblatt D, Shader R: Benzodiazepines in Clinical Practice. New York, Raven Press, 1974, p 203.

1987;6h225-226. 82. Van Heuvan P, Smeets P: Behavioral control of chronic hiccuping associated w i t h gastrointestinal bleeding in a retarded epileptic male. J Behav Ther Exp Psychiate 1981;12:341-345. 83. Bendersky G, Baren M: Hypnosis in the termination of hiccups unresponsive to conventional treatment. Arch Intern Med 1959~104:417-420. 84. Dorcus R, Kirkner F: The control of hiccoughs by hypnotic therapy. J Ciin Exp Hypnosis 1955;3:104-108. 85. Goldenberg I, Ochi R, Almquist A, et al: Cardioversion for intractable hiccups: A frightening cure. N EngI J Med 1987;316:883. 86. Driscoll C: Symptom control in terminal illness. Prim Care 1987;14:353-363.

58. De Mendonca M: Midazolam-induced hiccoughs (letter). Br Dent J 1984;157:49.

87. Davignon A, Laurieux G, Genest J: Chlorpromazine in the treatment of persistent hiccough. Union Med Can 1955;84:282.

59. Boehm D: Guinness I984 Book of World Records. ed 22. New York, Sterling Publishing Co, 1984, p 33.

88. Physicians Desk Reference, ed 43. OradelI, NJ, Medical Economics Publishing Co, 1989, p 2073.

60. Lowenberg S, March H: Persistent hiccoughs as the sole symptom of thoracic aneurysm. J Clin Gastroenterol 1985;13:624-626.

89. Friedgood C, Ripstein C: Chlorpromazine (Thorazine) in the treatment of intractable hiccups. [AMA 1955;157:309-310.

61. Ikram H, Orchard R, Read S: Intractable hiccuping in acute myocardial infarction. Br Med [ 1971;2:504.

90. Man P, Chen C: Severe shock caused by chlorpromazine hypersensitivity. Br J Psychiatr 1973;122:185-187.

62. Kounis N: Persistent hiccuping in acute myocardial infarction - Report of a case. J Irish M e d Assoc 1974;67:644-645.

91. Ives T, Fleming M, Weart C: Treatment of intractable hiccups with intramuscular haloperidol. A m J Psychiatr 1985; 142:1368-I369.

63. S t r o m b e r g B: The hiccup. Ear Nose Throat J 1979;58:354-357.

92. Petroski D, Patei A: Diphenylhydantoin for intractable hiccups (letter}. Lancet 1974;h997.

64. Birkhead R, Friedman J:. Hiccups and vomiting as initial manifestations of multiple sclerosis (letter}. J Neural Neurosurg Psychiatr 1987;50:232-233.

93. Davis J: Diphenylhydantoin for hiccups (letter). Lancet 1974;1:997.

65. Williamson B, Macintyre h Management of intractable hiccup. Br Med J 1977;2:501-503. 66. Laing T, Marariu M, Malik G, et ah Intractable hiccups and a posterior fossa arteriovenous malformatkm: A case report. Henry Ford Hasp Med J 1981;29:145-147. 67. Benzon H, Prasad Y, Barthwell D: The value of fluoroscopy before performing a phrenie nerve block. Anesthesiology 1981;55:469-470. 68. Halbert H: Hiccoughing. Practioner 1951;167: 286-289. 69. Thorne M: Hiccup and heart block. Br Heart J 1969;3l:397-399. 70. Harrington J, DeSanctis R: Hiccup-induced atrioventricular block. Ann Intern Med 1969;70:105-106. 71. Swan H, Simonson L: Hiccups complicating myocardial infarction. N Engl J Med 1952;247:726-728. 72. Carbary L: Hiccups: A passing annoyance or a true problem? J Pract Nurs 1981;31:25-26.

94. Osborn H, Zisfein J, Sparano R: Single-dose oral phenytoin loading. Ann Emerg Med 1987;16:407-412. 95. Butt H, Hamelberg W, Jacoby I: Hiccup: Its possible cause and t r e a t m e n t in anesthesia. Anesth Analg 1961;40:182-185. 96. McFarling D, Susac J: Carbamazepine for hiccoughs (letter). JAMA I974;230:962. 97. Iacobson P, Messenheimer J, Farmer T: Treatment of intractable hiccups with valproic acid. Neurology 1981;31:1458-1460. 98. Winsted D: Hiccups following ingestion of oral ehlordiazepoxide Iletter]. A m J Psychiatr 1976;136:719. 99. Shaughnessy A: Potential uses for metoclopramide. Drug Intel] Clin Pharmaco] 1985;19:723-728. I00. P i n d e r R, B r o g d e n R, S a w y e r P, et al: Metoclopramide: A review of its pharmacological properties and clinical use. Clin Pharmacokinet 1976; 12:81-131. 10l. West T: Drug control of common symptoms in the terminally ill patient. S Aft Med ] 1977;51:415-418.

73. Bhargava R, Datta S, Badgaiya R: A simple technique to stop hiccups (letter). Indian [ Physiol Phar macoI 1985;29:57-58.

102. Gibbs A: Two cases of persistent hiccup treated with orphenadrine citrate. Practitioner 196,3;191:646.

74. Schisel A: Hiccup remedies. N EngI J Med i972; 286:323.

103. Finch W: Rapid control of persistent hiccups by orphenidrine citrate. Med Times 1966;94:485-488.

75. Lamphier T: Methods of management of persistent hiccup (singuhus). Md Med J 1977;11:80-81.

104. Stalnikowicz R, Fich A, Troudart T: Amitriptyline for intractable hiccups (letter}. N Engi J Med 1986; 315:64-65.

45. Bender M, Ockner R: Diseases of the peritoneum, mesentary and diaphragm, in Sleisenger M, Fordtran I {eds): Gastrointestinal Disease: Pathophysio]ogy, Diagnosis, Management, ed 3. Philadelphia, WB Saunders Co, 1983, p 1589-1590.

76. G o l d s m i t h S: A t r e a t m e n t for hiccups (letter). JAMA i983;249:1566.

46. Roth J: Hiccup, in Berk J ted): Gastroet]terology, 4. Philadelphia, WB Saunders Co, 1985, p 195-196.

ed

77. Youguang I: Clinical applications of Point Futu. J Trad Chin Med 1986;6:6-8.

47. Kaufmann H: Hiccups: An occasional sign of esoph• c ageal obstruction. Gastroenterology 1982;82:1443-1445.

78. Bondi N, Bettelli A: Trattamento del singhiozzo con agopuntura ill Soggetti Anestetizzati ed in Soggetti coscienti. Minerva Med 72, 1981.

107. Gilston A: Nikethamide for hiccough (letter}. Anaesthesia 1979~34:1060.

79. Juan G, Calvery P, Talamo C, et ah Effect of carbon dioxide on diaphragmatic function in human beings. N Engl J Med 1984;310:874-879.

108. Shantha T: Ketamine for the treatment of hiccups during and following anesthesia: A preliminary report. Anesthesiology 1973;52:822-824.

80. Satto C, Giuseppe C, Cosmi E: Treatment of hiccups by continuous airway pressure 1CPAP) in anesthetized subjects )letter}. Anesthesiology 1982;57!345.

109. Tavakoli M, Corssenn G: Control of hiccups by k a t a m i n e : A p r e l i m i n a r y report. A M J M e d Sci 1974;3 h229-230.

81. Bobele M: Nonmedical management of intractable hiccups: A brief review of the literature. Psychnl Rep

110. Teodorowicz J, Z i m m y M: The effect of ketamine in patietfts with refractory hiccups in the postoperative

48. Johnson J, Raft M, Barnwell P, et al: Splenic abscess complicating infectious endocarditis. Arch Intern Med 1983;143:906-912. 49. Oster M: Cancer of the pancreas (letter). N EaRl J Med 1980;302:232. 50. Madanagopulan N: Metoclopramide in hiccup. Curr Med Res Opin 1975;3:371-374. 51. Mackay-Dick J: Hiccup (letter). Br Med 1 197[;2:591.

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105. Fry E: Management of intractable hiccup. Br Med J 1977~2: 704. 106. Sohn Y, Conrad L, Katz R: Hiccup and ephedrine. Can Atn~esth Sac J I978;25:431-432.

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period: Preliminary report. Anaesth Resus lntens Ther 1975~3:271-272. 111. Askenasy J, Boiangiu M, Davidovitch S: Persistent hiccup cured by arnantidine (letter). N EngI T M e d

1986~318:771-C.

1986~314:1256.

112. Mukhopadhyay P, Osrnan M, Wajirna T, et al: Nifedipine for intractable hiccups (letter). N EngI J Med

113. Burke A, White A, Brill N: Baclofen for intractable hiccups (letter). N Engl [ Med 1988;319:1354.

ERRATUM Figure 3 in the article, "Introduction to Biostatistics: Part 5, Statistical Inference Techniques for Hypothesis Testing With Nonparametric Data" [September 1990;19:1054-1059], contains two errors.

The equation U = N s x N i + (Ns) (N s + 1) / (2 - Rs) should read U = (Ns x N1)+[(Ns)(Ns+ - 2 1)]

Rs

The equation ~ = (N s x N i ) ( N s + N 1. + 1 ) / 1 2 should read o-u =X/(N s x N1)(N s + N 1 + 1)/12

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