Review article: oesophageal spasm diagnosis and management

Transcription

1 Alimentary Pharmacology & Therapeutics Review article: oesophageal spasm diagnosis and management R. TUTUIAN* & D. O. CASTELL *Division of Gastroenterology Hepatology, University of Zurich, Zurich, Switzerland; Division of Gastroenterology Hepatology, Medical University of South Carolina, Charleston, SC, USA Correspondence to: Dr R. Tutuian, Division of Gastroenterology/Hepatology, University Hospital Zurich, Ramistr. 100, A HOF 109, CH-8091 Zurich, Switzerland. radu.tutuian@usz.ch Publication data Submitted 10 February 2006 First decision 28 February 2006 Resubmitted 7 March 2006 Accepted 7 March 2006 SUMMARY Oesophageal spasm is a common empiric diagnosis clinically applied to patients with unexplained chest pain. In contrast it is an uncommon manometric abnormality found in patients presenting with chest pain and/or dysphagia and diagnosed by 20% simultaneous oesophageal contractions during standardized motility testing. Using Medline we searched for diagnostic criteria and treatment options for oesophageal spasm. While the aetiology of this condition is unclear, studies suggest the culprit being a defect in the nitric oxide pathway. Well-known radiographic patterns have low sensitivities and specificities to identify intermittent simultaneous contractions. Recognizing that simultaneous contractions may result from gastrooesophageal reflux this diagnosis should be investigated or treated first. Studies have documented improvements with proton-pump inhibitors, nitrates, calcium-channel blockers and tricyclic antidepressants or serotonin reuptake inhibitors. Small case series reported benefits after botulinium toxin injections, dilatations and myotomies. Uncertainties persist regarding the optimal management of oesophageal spasm and recommendations are based on controlled studies with small numbers of patients or on case series. Acid suppression, muscle relaxants and visceral analgetics should be tried first. Botulinum toxin injections should be reserved for patients who do not respond. Pneumatic dilatations or myotomies represent rather heroic approaches for non-responding patients. Aliment Pharmacol Ther 23, ª 2006 The Authors 1393 doi: /j x

2 1394 R. TUTUIAN AND D. O. CASTELL INTRODUCTION Oesophageal spasms are frequently suspected to be the cause of retrosternal chest cramps in patients in whom cardiac causes of these complaints have been excluded. This entity can be traced back to William Osler who first described oesophageal spasms in 1892 in hypochondriac patients with unexplained chest pain. 1 The concept of non-cardiac chest pain being caused by oesophageal spasms is suggested by the patient describing a retrosternal cramp or spasm. In fact, most patients with non-cardiac chest pain have normal oesophageal motility. In those with abnormal motility the most common abnormality is the nutcracker oesophagus (peristaltic contractions with an average oesophageal amplitude exceeding 180 mmhg). 2 Furthermore, gastro-oesophageal reflux disease (GERD) is a more common cause of non-cardiac chest pain and it seems likely that oesophageal distension in patients with a hypocontracting oesophagus can be perceived as retrosternal spasm. 3 More recent studies indicate that oesophageal spasm is quite infrequent in patients with chest pain and/or dysphagia, accounting for only about 3% of motility abnormalities seen in these groups of patients. 4 The latest AGA technical review reported by Pandolfino and Kahrilas describes distal oesophageal spasm (DES) as a manometric feature in patients with chest pain and dysphagia and comments about its relatively rare occurrence. 5 The purpose of this paper was to review the pathophysiology, diagnosis and management option of patients with oesophageal spasm. We have searched Medline using the keywords esophageal/oesophageal spasm, treatment, diagnosis, nitrates, calcium channel blocker, botulinium toxin, dilatation and myotomy. PATHOPHYSIOLOGY The currently accepted concept attributes this manometric abnormality to an altered endogenous nitric oxide (NO) synthesis and/or degradation. Chakder et al. evaluated the effects of the NO scavenger human recombinant haemoglobin (rhb) in anaesthetized opposum. 6 Recording intraluminal pressure in the lower oesophageal sphincter (LES) and 1, 5 and 9 cm above the LES before and following the administration of rhb, the authors found that rhb caused significant impairment in swallowing-induced LES relaxation and a significant increase in the speed of oesophageal peristalsis. In some instances swallowing caused simultaneous contractions in the oesophagus following rhb administration. Similar data in the opossum were reported by Conklin et al. in studies monitoring intraluminal pressures in the oesophagus and transmembrane potential differences of circular smooth muscle from the oesophagus. 7 In addition to an increased velocity of oesophageal peristalsis, decreased amplitudes of these contractions and diminished LES relaxation, the authors also found that rhb diminished the inhibitory junction potential and shortened the latency of the off response. Based on these studies in the opossum Murray et al. evaluated the effect of human rhb in nine healthy human male volunteers. 8 Oesophageal manometric studies performed before, during and up to 6 h after the intravenous infusion of rhb found that this NO scavenger increased the velocities of peristaltic contractions to produce simultaneous contractions in six (67%) subjects, lead to spontaneous, simultaneous high-pressure contractions in eight (89%) subjects and even induced lower retrosternal chest pain during swallowing in four (44%) subjects. Xue et al. evaluated the role of NO in the control of oesophageal peristalsis and LES function in cats. 9 Measuring intraluminal pressures at the LES and 2, 4 and 6 cm above the LES (smooth muscle), and 12 and/ or 14 cm above the LES (striated muscle) in anaesthetized cats before and during the intravenous administration of L-NG-nitro-arginine (L-NNA) they observed that L-NNA increased the velocity of swallow-induced peristalsis and decreased the amplitude of peristaltic contractions in the smooth muscle oesophagus, associated with the appearance of repetitive contractions. Konturek et al. evaluated the influence of the NO synthase blocker, NG-monomethyl-L-arginine (L-NMMA) on the oesophageal motility of eight healthy volunteers. 10 Evaluating the oesophageal response to 5 ml water swallows using a three-channel electronic catheter the authors noticed that L-NMMA led to a significant and dose-dependent reduction in the latency period between swallows and the onset of contractions and this phenomenon was most pronounced in the distal oesophagus. The L-NMMA infusion significantly reduced the duration of contractions and increased the velocity of onset propagation but did not change the amplitude of contractions. These animal and human experiments support the hypothesis that NO plays an important role in maintaining oesophageal peristalsis and are consistent with

3 REVIEW: OESOPHAGEAL SPASM 1395 prior observations that nitrates provide some benefit in the treatment of patients with oesophageal 11, 12 spasm. DIAGNOSIS Following Osler s 1 initial description, radiological and manometric features of oesophageal spasms have been published throughout the 20th century. Arguably, the best known and most colourful description include the corkscrew or rosary bead oesophagus (Figure 1) based on esophagograms performed in patients with non-cardiac chest pain. In 1934, Moersh and Camp described the radiological patterns of oesophageal spasm as sudden distortions in the lower half of the oesophagus during a barium swallow with puckering into a series of pockets, giving a beaded appearance. 13 However, radiological protocols do not necessarily use defined swallow volumes and record only a limited number of swallows due to the radiation exposure. Therefore, these findings are neither specific nor sensitive in diagnosing oesophageal spasm, a condition characterized by intermittent simultaneous contractions. Oesophageal spasm is preferably diagnosed by oesophageal manometry. In 1958, Creamer et al. were the first to describe the manometric features of oesophageal spasms as high amplitude, simultaneous and prolonged duration contractions. 14 These manometric findings have been reassessed over the past 40 years based on finding simultaneous contractions in the lower oesophageal smooth muscle region Subsequent studies found that spastic contractions were usually not of high amplitude (i.e. above 180 mmhg) as had been previously suggested. On the other hand, in order to classify a contraction as being simultaneous the contraction amplitude in the distal oesophagus has to be at least 30 mmhg. Contractions with amplitudes <30 mmhg in the distal oesophagus are considered manometric ineffective based on data from healthy volunteers 19 and combined video-fluoromanometric studies. 20 The manometric diagnosis of oesophageal spasm is based on identifying an increased frequency of simultaneous contractions during standardized swallows. During conventional manometry a contraction is considered manometrically simultaneous, if the distal onset velocity >8 cm/s or retrograde onset and the amplitudes in the distal oesophagus exceed 30 mmhg (Figure 2). The current manometric definition of oesophageal spasm requires the presence of at least 20% of swallows having simultaneous contractions in the distal oesophagus. 21 The requirement for rapid onset only in the distal oesophagus is supported by a recent study in 53 patients with DES who underwent both proximal and distal oesophageal manometry. Simultaneous contractions were observed in 37% of swallows in the distal (smooth muscle portion) oesophagus but only in 2% of swallows in the proximal (striated muscle Figure 1. Radiological features in patients with oesophageal spasm ( adult/provider/internalmedicine/giatlas/giimaging/ radiologicalimaging/images/ figure63.html); last accessed 20 December Corkscrew oesophagus in diffuse oesophageal spasm

4 1396 R. TUTUIAN AND D. O. CASTELL Figure 2. Manometric tracing [5, 10 and 15 cm above the lower oesophageal sphincter (LES)] in a patient with oesophageal spasm. Notice the simultaneous onset of contraction in the second swallow and normal peristalsis during the first and third swallow. portion) oesophagus. Based on these observations we prefer using the term distal oesophageal spasm instead of diffuse oesophageal spasm to describe DES. 22 Similar to the presenting symptom of patients with DES, the functional consequences of these simultaneous contractions are variable. Studies from our laboratory using combined multichannel intraluminal impedance and manometry (MII-EM) to evaluate oesophageal peristalsis and bolus transit in 71 patients with DES indicate that approximately half of patients with a manometric criteria of DES have normal bolus transit for both liquid and viscous swallows (i.e. no functional defect). About a quarter of DES patients have abnormal bolus transit for both liquid and viscous (i.e. severe functional defect) and the remaining quarter have abnormal bolus transit for either liquid or viscous (i.e. moderate functional defect). 23 In this study we observed manometric and bolus transit differences in DES patients presenting with chest pain and patients presenting primarily with dysphagia (Figure 3). Patients presenting primarily with chest pain had higher contraction amplitudes and a higher proportion of swallows with normal bolus transit time when compared to patients presenting primarily with dysphagia. Based on these observations one can speculate that DES patients with chest pain, higher amplitude contractions and normal transit should be managed differently than DES patients with dysphagia, lower amplitude contractions and abnormal transit. TREATMENT Treating oesophageal spasm is rarely easy. Based on the heterogeneity of symptoms and bolus transit impairments in patients with oesophageal spasm, the rarity of this condition and results of treatment interventions being reported from studies with small number of patients minimal data are available on the optimal treatment of this disorder. As simultaneous oesophageal contractions can be the result of GERD we recommend, as a first step, either testing or empirically treating patients with a proton-pump inhibitor (PPI). Patients not improving with PPI therapy can be offered treatments aimed at relaxing the oesophageal smooth musculature and/or improving oesophageal peristalsis (Table 1). Proton-pump inhibitors The rationale for a PPI trial or testing for GERD in patients with DES is supported by the study of Crozier

5 REVIEW: OESOPHAGEAL SPASM 1397 Figure 3. Combined multichannel intraluminal impedance and manometry tracings picturing manomtric simultaneous contractions with high contraction amplitude and complete bolus transit (a) and low contraction amplitude and incomplete bolus transit (b second swallow). et al. documenting acid-induced oesophageal spasms as a cause for non-cardiac chest pain. 24 Of a group of 275 patients with non-cardiac chest pain and normal motility the authors identified 90 (33%) patients who had a positive response during combined oesophageal motility and acid perfusion testing. In this group of patients with acid-induced spasm, 90% had excessive dysmotility changes (repetitive waves, multiple peaks, spontaneous or simultaneous contractions) compared with an incidence of 13% in the control group. In a more recent study, Pehlivanov et al. were able to document sustained oesophageal contractions as a response to GER using synchronized pressure, ph and high-frequency intraluminal ultrasound monitoring of the oesophagus. 25 The need to either test or empirically treat GERD is underscored the findings of Campo and Traube. 26 Evaluating 31 patients with DES the authors found no differences in oesophageal contraction amplitude, percentage of repetitive contraction or LES pressure

6 1398 R. TUTUIAN AND D. O. CASTELL Table 1. Suggested therapy for DES Therapy steps Rule out GERD (reflux monitoring or empiric PPI trial) Nitrates Phosphodiesterase inhibitors* Calcium-channel blocker Peppermint oil* Visceral analgetics (TCAs, SSRIs) Anticholinergics Botulinum toxin injection Dilatation Pneumatic dilatation Myotomy * Minimal evidence to date. DES, distal oesophageal spasm; GERD, gastro-oesophageal reflux disease; PPI, proton pump inhibitor; SSRI, serotonin reuptake inhibitor; TCA, tricyclic antidepressants. between a group of patients with idiopathic DES (N ¼ 7; no heartburn; normal endoscopy or acid perfusion test) and a group of patients with reflux-associated DES (N ¼ 10; heartburn; positive endoscopy). Based on these findings the authors concluded that manometric findings per se do not allow a clear separation of idiopathic from reflux-associated DES. There are only few studies specifically addressing the contribution of GERD to chest pain in DES but some data suggest that patients improve under therapy with PPIs. 27 Recognizing that GERD is the most frequent cause of non-cardiac chest pain, simultaneous contractions could be reflux-induced and acid-suppressive therapy with PPIs is generally very well tolerated we recommend the initial step in the management of DES patients either testing for or empiric treating for GERD. Nitrates Based on the pathophysiological mechanisms of DES either short- or long-acting nitrates would be the pharmacological agents of choice to improve oesophageal peristalsis. Orlando and Bozymski were among the first to describe the clinical and manometric effects of nitroglycerine in a patient with oesophageal spasm. 11 Subsequently, Swamy 12 reported on the effect of nitroglycerine and long-acting nitrites in a group of 12 patients with oesophageal spasm. Among the 12 patients with oesophageal spasm seven also had GER and the response to nitroglycerine in this subgroup was unpredictable. In contrast the five patients with spasm and no reflux responded well to treatment with nitroglycerine and this response was maintained on long-acting nitrates from 6 month to 4 years. Although these data support the current understanding of the pathophysiological mechanisms of DES this uncontrolled study included a small number of patients. Unfortunately there are no controlled studies documenting the long-term benefits of nitrates in the treatment of oesophageal spasm. Phosphodiesterase inhibitors Given the smooth muscle relaxant effects of PD-5 inhibitors (sildenafil, vardenafil, tadalafil) this class of medication could be of great interest for patients with oesophageal spasm and non-cardiac chest pain. Although there are no study specifically addressing the benefits of a treatment with PD-5 inhibitors in patients with oesophageal spasm data from studies in patients with non-cardiac chest pain support the concept of a therapeutic trial with such agents in DES patients. Animal studies and studies in healthy volunteers have documented the ability to decrease oesophageal contraction amplitude and the propagation velocity of oesophageal contractions through increasing the availability of NO. 28, 29 Evaluating the effects of sildenafil 50 mg in 11 patients with oesophageal motility disorders found manometric improvement in nine patients but symptomatic improvement only in four patients. Our group has also reported on one patient with hypercontractile oesophageal dysmotility who had a positive sustained response while being treated with PD5-inhibitors. 30 Of note is that the positive manometric and symptomatic response was noted with all three, currently available PD5-inhibitors (i.e. sildenafil, vardenafil, tadalafil). Calcium-channel blockers Nashrallah et al. compared the effects of nifedipine 10 mg and placebo t.d.s. in a 4-week placebo-controlled, crossover study in 20 patients with primary oesophageal motor disorders. 31 This group included 10 patients with hypertensive LES, four patients with DES, three patients with vigorous achalasia, one patient with achalasia and two patients with nutcracker oesophagus. While overall the patients responded better to nifedipine

7 REVIEW: OESOPHAGEAL SPASM 1399 compared with placebo the improvement was most marked in patients with hypertensive LES. Drenth et al. compared the effects of diltiazem to placebo in a 10-week double-blind crossover study in eight patients with DES presenting chest pain and/or dysphagia. 32 Using visual analogue scales to assess the severity of chest pain and dysphagia the authors found that diltiazem lead to a reduction in the dyphagia (four of six patients) and chest pain (six of eight patients) scores. Compared with placebo though, the differences in chest pain and dysphagia scores were statistically not significant most likely due to small number of patients included in this study. Davies et al. also evaluated the effects of nifedipine compared with placebo in treating oesophageal spasms for 6 weeks. 33 Using diary scoring cards to assess symptom response in eight patients the authors found no difference between the nifedipine and placebo treatment periods. Peppermint oil Recognizing the smooth muscle relaxant properties of peppermint oil, Pimentel et al. evaluated the effects of oral administration of this substance on oesophageal function in eight patients with DES. 34 Using an eightchannel water perfused manometry system they evaluated the amplitude and duration of contractions and percentage of manometric simultaneous contractions before and 10 min after the administration of five drops of peppermint oil in 10 ml of water. While there was no reduction in the contraction amplitude and duration of oesophageal contractions, the peppermint oil eliminated simultaneous oesophageal contractions in all patients. In addition to these manometric changes two of the eight patients (25%) reported resolution of the chest pain after the ingestion of peppermint oil. This observation has to be interpreted cautiously as there was no placebo control group in this study with a very small number of patients. Visceral analgesics (tricyclic antidepressants, serotonin reuptake inhibitors) Approaching symptomatic oesophageal dysmotilities from a different perspective, investigators have evaluated the role of tricyclic antidepressants or serotonin reuptake inhibitors (SSRIs) to influence oesophageal perception. 35 Clouse et al. investigated the role of low-dose trazodone ( mg/day) to improve symptoms in patients with symptomatic oesophageal contraction abnormalities in a 6-week double-blind, placebo-controlled trial. 36 At the end of trial period patients receiving trazodone (N ¼ 15) had a significantly greater global improvement of symptoms compared with those receiving placebo (N ¼ 14). In addition, the authors noticed that the active treatment did not change the manometric findings during the study. In a subsequent study, Handa et al. evaluated the role of SSRIs in patients with DES. 37 Compared with a group of 26 healthy volunteers the nine patients with DES had higher anxiety and depression scores. Patients with DES underwent initial treatment with isosorbide dinitrate (ISDN) for 1 month and then received SSRIs for an additional month. The authors noticed symptomatic improvement in one patient during treatment with ISDN and in eight patients during treatment with SSRIs and concluded that antidepressant treatment may be effective in patients with DES. Botulinum toxin injection Storr et al. evaluated the short- and long-term effects of botulinum toxin (BoTox) injection in nine symptomatic patients with oesophageal spasm. 38 Patients were asked to rate their symptoms before, 1 day after and 1, 4 and 6 months after the injection of 100 IU of BoTox at several levels in the oesophagus starting at the gastro-oesophageal junction. Patients reported a decrease in the total symptom scores from a median of 8.0 (IQR: ) before treatment to 2.0 ( ) 1 day after the injection and remained at 2.0 ( ) 1 month after the injection of BoTox. One month after treatment with BoTox the authors reported eight of nine patients being in remission and the remission lasted in all eight patients at 6 months. Subsequently four patients required re-injection at 8, 12, 15 or 24 months after the initial treatment with similarly good results. The authors concluded that BoTox injection represents an effective treatment for symptoms caused by oesophageal spasm and that BoTox injections can be repeated when symptoms relapse. The effect of BoTox in patients with non-cardiac chest pain was reported by Miller et al. 39 The authors grouped together 18 patients with oesophageal spasm, five patients with hypertensive LES, one patient with nutcracker oesophagus and five patients with ineffective oesophageal motility as having non-achalasia, nonreflux-related spastic oesophageal motility disorders.

8 1400 R. TUTUIAN AND D. O. CASTELL Patients were asked to rate the severity of chest pain, dysphagia, regurgitation and heartburn before and 1 month after the injection of 100 IU BoTox at the gastro-oesophageal junction. The clinical evaluation also included the duration of response defined as the time period between the injection and the point in time at which the severity of symptoms returned to the preinjection level. One month after the injection of BoTox 14 of 18 (77%) patients with oesophageal spasm reported a reduction of at least 50% in the chest pain score. In the entire group the mean duration of response for chest pain was 7.3 (range: 1 18) months. Both this and the study by Storr et al. 38 reported favourable responses to the treatment with BoTox, but unfortunately lack a placebo/non-intervention or medical treatment arm. Dilatations (rigid dilators or small diameter balloons) In a series from Guy s Hospital in London, Irving et al. reported on the effects of balloon dilatation in a group of 20 patients with severe symptoms that did not respond to conservative treatment. 40 Oesophageal spasm was documented based on the presence of more than 30% non-peristaltic activity during standard oesophageal manometry. Fourteen of the 20 patients (70%) underwent balloon dilatation reported good clinical improvement and six of 20 patients did not, including one oesophageal perforation after balloon distension. Three of the non-responders underwent full-length myotomy, with relief of symptoms in two patients. These data suggest that oesophageal balloon dilatation could be considered in the treatment of oesophageal spasm but patients need to be clearly informed about the risk of oesophageal perforation. Pneumatic dilatations Ebert et al. reported on the success of pneumatic dilatation in nine patients with severe symptoms of diffuse oesophageal spasm and LES dysfunction that were unresponsive to medical therapy. 41 The initial response was positive in eight of nine patients who reported a marked improvement in dysphagia and regurgitation. In the follow-up manometric examination (performed after an average of 12.4 months after dilatation) the authors found that pneumatic dilatation successfully reduced the mean (S.E.M.) LES pressure from mmhg prior to dilatation to mmhg after dilatation. Pneumatic dilatation did not influence though the manometric pattern of the oesophageal body. Oesophageal myotomy There are several reports on the effect of surgical interventions in patients with oesophageal spasm. Eypasch et al. reported on the follow-up after long oesophageal myotomy with antireflux procedure in 15 patients with severe chest pain and/or dysphagia attributed to oesophageal spasm. 42 Evaluating the severity of dysphagia, chest pain, regurgitation and heartburn before and a mean of 2 years after the operation the authors found an improvement in individual symptoms as well as the overall symptom score. Manometric testing after the myotomy revealed a significant reduction in the amplitude of oesophageal contractions, LES pressure and frequency of simultaneous and triple-peak contraction. In addition to these 15 patients the group evaluated the symptomatic response in four patients who underwent oesophagectomy after having failed multiple previous oesophageal procedures and observed the same favourable outcome. Based on these results the authors concluded that long oesophageal myotomy is a valid treatment alternative in appropriately selected patients with oesophageal spasm. A similar experience was reported by Ellis who performed esophagomyotomy in 42 patients with chest pain attributed to oesophageal spasm and other related disorders. 43 In contrast to the previous study by Ellis 43 restricted the myotomy to the manometrically located diseased portion of the oesophagus. Post-operatively he found an overall improvement rate of 70% at a median follow-up of 5 years and 8 months. More recently Nastos et al. reported the long-term results after myotomy and fundoplication by thoracotomy in the treatment of 16 patients with oesophageal spastic disorders (eight with an accompanying epiphrenic diverticulum). 44 Evaluating symptom severity, manometric and radionuclide emptying studies before and after surgery the authors found symptomatic improvement in all patients, a decrease in amplitude of oesophageal body contractions and LES pressure but no change in oesophageal emptying delay. Comparing patients with epiphrenic diverticuli and patients without a diverticulum the results suggested that patients with spastic disorders plus a diverticulum had better clinical results and improved oesophageal function after surgery when compared to patients with pure spastic disorders.

9 REVIEW: OESOPHAGEAL SPASM 1401 In a nutshell these surgical data suggest that oesophageal myotomy could be considered carefully in patients with symptomatic oesophageal spasms. When considering the surgical option though one has to be aware that these results come from case series performed in highly specialized centres. CONCLUSIONS Oesophageal spasm is a relative rare manometric abnormality, accounting for 3 7% of abnormalities identified in patients referred for oesophageal manometry and can be found in patients presenting with non-cardiac chest pain and/or dysphagia. Oesophageal spasm is a manometric finding based on identifying 20% or more simultaneous contractions in the distal oesophagus. Radiographic patterns of corkscrew or rosary bead oesophagus during barium esophagograms are present in patients with oesophageal spasms even though these findings have a low sensitivity and specificity to identify these intermittent abnormalities. There is an uncertainty regarding the optimal management of patients with oesophageal spasm and therapeutic recommendations are based on studies, which included a limited number of patients and are largely uncontrolled. In patients with oesophageal spasm we recommend first evaluating for or treating gastrooesophageal reflux. In patients with chest pain and no reflux we suggest NO donors or calcium-channel blockers and reserve tricyclic antidepressant or botulinum toxin for non-responding patients. Identifying lower pressures and impaired bolus transit in patients with dysphagia raises the possibility that these patients might benefit from a therapy aimed at increasing the amplitude of oesophageal contractions. The value of such an approach requires further study. We believe that pneumatic dilatation or myotomy represent rather heroic approaches to these patients that should be considered after the risk benefit ratio has been carefully evaluated. ACKNOWLEDGEMENT No external funding was received for this study. REFERENCES 1 Osler W. Oesophagismus. In: Osler W, ed. Principles and Practice of Medicine. New York, NY, USA: D Appleton and Co., 1892: Katz PO, Dalton CB, Richter JE, Wu WC, Castell DO. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years experience with 1161 patients. Ann Intern Med 1987; 106: Meyer GW, Castell DO. Human esophageal response during chest pain induced by swallowing cold liquids. JAMA 1981; 246: Dalton CB, Castell DO, Hewson EG, Wu WC, Richter JE. Diffuse esophageal spasm. A rare motility disorder not characterized by high-amplitude contractions. Dig Dis Sci 1991; 36: Pandolfino JE, Kahrilas PJ. AGA technical review on the clinical use of esophageal manometry. Gastroenterology 2005; 128: Chakder S, Rosenthal GJ, Rattan S. In vivo and in vitro influence of human recombinant hemoglobin on esophageal function. Am J Physiol 1995; 268: G Conklin JL, Murray J, Ledlow A, et al. Effects of recombinant human hemoglobin on motor functions of the opossum esophagus. J Pharmacol Exp Ther 1995; 273: Murray JA, Ledlow A, Launspach J, Evans D, Loveday M, Conklin JL. The effects of recombinant human hemoglobin on esophageal motor functions in humans. Gastroenterology 1995; 109: Xue S, Valdez D, Collman PI, Diamant NE. Effects of nitric oxide synthase blockade on esophageal peristalsis and the lower esophageal sphincter in the cat. Can J Physiol Pharmacol 1996; 74: Konturek JW, Thor P, Lukaszyk A, Gabryelewicz A, Konturek SJ, Domschke W. Endogenous nitric oxide in the control of esophageal motility in humans. J Physiol Pharmacol 1997; 48: Orlando RC, Bozymski EM. Clinical and manometric effects of nitroglycerin in diffuse esophageal spasm. N Engl J Med 1973; 289: Swamy N. Esophageal spasm: clinical and manometric response to nitroglycerine and long acting nitrites. Gastroenterology 1977; 72: Moersch HJ, Camp JD. Diffuse spasm of the lower part of the esophagus. Ann Otol Rhinol Laryngol 1934; 43: Creamer B, Donoghue FE, Code CF. Pattern of esophageal motility in diffuse spasm. Gastroenterology 1958; 34: Gilles M, Nicks R, Skyring A. Clinical, manometric and pathological studies in diffuse oesophageal spasm. Br Med J 1967; 2: DiMarino AJ Jr. Characteristics of lower esophageal sphincter function in symptomatic diffuse esophageal spasm. Gastroenterology 1974; 66: Castell DO. Achalasia and diffuse esophageal spasm. Arch Intern Med 1976; 136: Vantrappen G, Janssens J, Hellemans J, Coremans G. Achalasia, diffuse esophageal spasm and related motility disorders. Gastroenterology 1978; 76: Richter JE, Wu WC, Johns DN, et al. Esophageal manometry in 95 healthy adult volunteers. Dig Dis Sci 1987; 32: Kahrilas PJ, Dodds WJ, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988; 94:

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