Persistent heartburn in a patient on PPISamir Haffar M.D.Associate Professor of GastroenterologyAl-Mouassat University Hospital – Damascus – Syria
Clinical History – 136-year-old woman with 6-year history of heartburnSymptoms occurred from 3 times/day to 3 times/weekSymptoms occasionally awaken her from sleep during nightNo dysphagia, chest pain, epigastric pain, bloating, or vomitingGood appetite, no weight loss, denies smoking or drinking alcoholSocial worker, married, 2 toddlers at homeConsidered her work & her family life to be very stressfulUnremarkable physical examination except for borderline obesity
Clinical History – 2• Seen by her primary care physician: lifestyle modifications, loseweight, less busy work schedule, & H2RA twice daily• No improvement despite 2 months of therapy with H2RAUnable to lose weight or change her work schedule• Three months ago: PPI once daily half an hour before breakfast• PPI help during first 2 weeks, symptoms recurred with less severityShe takes antacids, OTC H2RA, & another PPI before bedtime
Persistent heartburn in a patient on PPI Definition of refractory GERD Putative mechanisms for refractory GERD Diagnostic options for refractory GERD Therapeutic approaches of refractory GERD Recommendations
What constitutes refractory GERD?• PPI one or twice daily Most investigators: bidSome investigators: qd• Duration 8 weeks in EE4 weeks in NERDPatients who failed to obtain satisfactory symptomaticresponse &/or complete esophageal healing after afull course of standard dose PPI (once a day)EE: Ersosive esophagitisNERD: Non Ersosive Reflux diseaseFass R et al. Aliment Pharmacol Ther 2005 ; 22 : 79 – 94.
Refractory GERD in each of the GERD groupsFass R et al. Aliment Pharmacol Ther 2005 ; 22 : 79 – 94.10 – 40% of patients fail to respond symptomatically,either partially or completely, to a standard dose PPI
Symptomatic response to PPI in NERDPPIs once daily for 4 weeksResponse correlated with extent of esophageal acid exposureAliment Pharmacol Ther 2000 ; 14 : 597 – 602.
Healing failure in patients with EEPPI qd for 8 weeksRichter JE et al. Am J Gastroenterol 2001 ; 96 : 3089 – 98.Patients might continue to report GERD symptoms despitecomplete healing of esophageal mucosa (up to 15%)
Underlying mechanisms for persistentheartburn despite treatment with PPIsFass R & Sifrim D. Gut 2009 ; 58 : 295 – 309.10 – 40 % of patients
• Non compliance• Improper dosing time• Reduced PPI bioavailability• Rapid PPI metabolism• PPI resistancePutative mechanisms for failure of PPIRelated to PPIsFass R. Clin Gastroenterol Hepatol 2008 ; 6 : 393 – 400.Unrelated to PPIs• Weakly acidic or alcaline reflux• Bile reflux (DGER)• Esophageal hypersensitivity• Nocturnal reflux• HP infection• Delayed gastric emptying• Eosinophilic esophagitis• Psychological co-morbidity• Others (unrelated to GERD)
Non complianceMost common cause for PPI failure• GERD is a symptom-driven disease• By end of 6 months, 30% of patients still consume PPIs• Factors of compliance Presence or absence of symptomsSeverity of symptomsPersonal preference• Compliance should be assessed in all patients withrefractory GERD prior to ordering any evaluative test
Dosing time of PPIsAliment Pharmacol Ther 2000 ; 14 : 1267 – 1272.21 volunteers taking PPI each morningEither 15 min before breakfast or without food or drinkOn day 7, intragastric pH-metry from 8:00 to 16:00 ( 8-h period)17.2%IQR: 4.6 – 45.542.0%IQR: 31.4 – 48.8P ˆ= 0.01
• Non compliance• Improper dosing time• Reduced PPI bioavailability• Rapid PPI metabolism• PPI resistancePutative mechanisms for failure of PPIRelated to PPIsFass R. Clin Gastroenterol Hepatol 2008 ; 6 : 393 – 400.Unrelated to PPIs• Weakly acidic or alcaline reflux• Bile reflux (DGER)• Esophageal hypersensitivity• Nocturnal reflux• HP infection• Delayed gastric emptying• Eosinophilic esophagitis• Psychological comorbidity• Others (unrelated to GERD)
Esophageal pH monitoring• Catheter esophageal pH monitoringWireless esophageal pH monitoring (Bravo capsule)• Quantitative (DeMeester) & qualitative analysis (SI – SAP)• off PPIs Test if initial diagnosis correcton PPIs Test if symptoms due to residual acid (PPIs bid)• Positive pH Heartburn related to acid refluxNegative pH, positive SI Heartburn related to acid refluxNegative pH, negative SI Heartburn not related to acid reflux
24 h catheter esophageal pH monitoring5 cm above LES
Normal 24 h esophageal pH monitoringQuantitative analysisQualitative analysisBremner CG et al. Esophageal disease & testing. Taylor & Francis Group, 2005.
Composite scoring systemsJohnson & DeMeester is the most commonly usedPercentage of total time pH < 4Percentage of upright time pH < 4Percentage of supine time pH < 4Number of reflux episodesNumber of reflux episodes >5 minLongest reflux episodeDeMeester scoreNormal ≤ 14,72
Mean SD Median Minimum Maximum 95th %Total time at pH < 4 (%) 1.5 1.4 1.2 0 6.0 4.5Upright time at pH< 4 (%) 2.2 2.3 1.6 0 9.3 8.4Supine time at pH< 4 (%) 0.6 1.0 0.1 0 4.0 3.5Number or reflux episodes 19.0 12.8 16.0 2.0 56.0 46.9Number of episodes > 5 min 0.8 1.2 0 0 5.0 3.5Longest episode (min) 6.7 7.9 4.0 0 46.0 19.8Composite score 6.0 4.4 5.0 0.4 18.0 14.7Normal values of DeMeester’s score50 healthy volunteersDeMeester TR et al. Ann Surg 1976 ; 184 : 459 – 470.
Qualitative analysisSymptom–reflux correlation• Symptom index: Positive if ≥ 50%• Symptom sensitivity index: Positive if > 10 %• Symptom association probability Positive if > 95%Determine relationship between heartburn episodes & acidreflux events, regardless if pH test is normal or abnormal
Percentage of total time pH < 4Normal values• Off therapy5 cm above LES20 cm above LES 1 %Periods of meals or acidic beverages excluded• On therapy5 cm above LES20 cm above LES ?* Based on 95% CI obtained in healthy subjects treated with omeprazole 40 mg qdKuo B et al. Am J Gastroenterol 1996 ; 91 : 1532 – 8.4 – 5.5 %1.6 – 4 %*
Abnormal acid exposure time in heartburnDisease Percentage of total time pH < 4Barrett’s esophagus 93 %* ENRD Endoscpic Negative Reflux Disease* *NERD Non Erosive Reflux DiseaseErosive esophagitis 75 % (in one study)ENRD*NERD**Functional heartburn- SI > 50%- SI < 50%50 %100 %0 %Hypersensitive esophagusNon acid reflux or motor event
24 hour pH monitoring is not thegold standard for diagnosis of GERD
Bravo system (Medtronics)Esophageal Probe25 x 6 x 5.5 mmBatterypHelectrodeSuctionchamberRadiotransmitterDelivery systemReceiver100 x 70 x 30 mm - 165 g
Wireless esophageal pH monitoringBravo capsule – 48 hoursGastrointest Endoscopy Clin N Am 2005 ; 15 : 307 – 318.Patients might have normal test on day 1 & abnormal test on day 2Increase sensitivity to detect symptoms correlated with acid refluxMore studies needed in patients with refractory GERD
Bravo normal values50 asymptomatic volunteers1st 24 h 2nd 24 hMean(+ SD)95thpercentileMean(+ SD)95thpercentile% total time at pH < 4 1.79 (2.16 5.89 1.78 (1.78) 5.64% upright time at pH < 4 2.45 (3.14) 7.81 2.54 (2.57) 7.46% supine time at pH < 4 0.37 (1.18) 1.58 0.34 (1.28) 1.29Number of reflux episodes 21.2 (18.5) 55.30 22.3 (19.8) 56.15No of reflux episodes >5 min 0.62 (1.21) 3.55 0.75 (1.15) 3.00Longest reflux episode 3.79 (4.31) 11.23 5.95 (4.52) 17.03DeMeester score 6.02 (4.82) 15.93 5.95 (4.52) 15.48
pH testing in refractory GERDVery few studies• Catheter pH monitoring1PPI qd Limited value (normal test in 70%)PPI bid Non-contributory value (normal test in 96%)• Wireless pH monitoring2 days: Normal test on both days in 65%4 days3: More studies neededHigh failure rate: 25%1 Charbel S et al. . Am J Gastroenterol 2005 ; 100 : 283 – 9.2Hirano I et al. Clin Gastroenterol Hepatol 2005 ; 3 : 1083 – 8.
Multichannel Intraluminal ImpedanceAntegrade bolus movement during swallowingProgression of impedance from proximal to distalGastrointest Endoscopy Clin N Am 2005 ; 15 : 257 – 264.
Multichannel Intraluminal ImpedanceRetrograde bolus movement observed in refluxProgression of impedance from distal to proximalGastrointest Endoscopy Clin N Am 2005 ; 15 : 257 – 264.
Advantages of MII• Direction of bolus Anterograde – retrograde• Content of refluxate Liquid – Gas – Mixed• Height of refluxate Related to volume of refluxate• pH characteristics Acid reflux(combined MII-pH) Weekly acid refluxWeekly alkaline refluxAcid re-reflux
Combined MII-pH probe• Impedance orifices3, 5, 7, 9, 15, & 17 cm from the tip• pH orifice5 cm from the tip• Ө MII-pH probe = Ө pH probeDo not change patient comfortBremner CG et al. Esophageal disease & testing.Taylor & Francis Group, NY, 1st edition, 2005.
“Sleuth” monitor – SandhillMultichannel Intraluminal Impedance with pH sensor“Sleuth” monitor attached to the catheter& worn around a belt during the recording period
• Analysis similar to esophageal pH monitoring- Quantitative analysis- Qualitative analysis: SI – SSI – SAP• Healthy: Total no of reflux: 40 per 24 h1/3 acid & 2/3 weakly acidic or alkaline• Negative study rules out GERD as cause of symptomsEsophageal MII-pH monitoringMost sensitive method for reflux detection
GERD classification by combined MII-pH• Acid refluxReflux with drop of pH from above 4.0 to below 4.0• Superimposed acid reflux (Acid re-reflux)Acid reflux occurs while pH < 4.0• Weakly acidic refluxReflux results in esophageal pH between 4.0 & 7.0• Weakly alkaline refluxReflux with nadir esophageal pH does not drop < 7.0Sifrim D et al. Gut 2004 ; 53 ; 1024 – 1031.
Combined MII-pH of the esophagusFass R & Sifrim D. Gut 2009 ; 58 : 295 – 309.Weakly acidic reflux4 ≤ pH < 7Weakly alkaline refluxpH ≥ 7
MII-pH in refractory GERD• Shift from acidic reflux to weakly acidic refluxRegurgitation become predominant symptom• off PPI Little value when compared with pH (10%)on PPI Improved diagnostic yield by 20%• Positive SI for acid reflux 10%Positive SI for non-acid reflux 37%Mainie I et al. Gut 2006 ; 55 : 1398 – 402.Zerbib F et al. Am J Gastroenterol 2006 ; 101 : 1956 – 63.
Bilitec recorder*Assess bile reflux by using bilirubin as surrogate marker* Medtronic, Minneapolis, MN, USA
Esophageal BilitecMust be accompanied by 24 h esophageal pH• Fiberoptic probe to detect bilirubin (450 nm absorption)• Presented as per cent time bilirubin absorbance > 0.14• Progressive increase in DGOR across spectrum of GERDParticularly high prevalence in patients with Barrett’s• Medtronic stops commercialization of the product
Esophageal pH & Bilitec studyMaximal bile reflux in the esophagus during supine periodBremner CG et al. Esophageal disease & testing. Taylor & Francis Group, 2005.Limited evidence of increase in DGER in refractory GERD
% of time with bilirubin absorbance > 0.14Duodeno-gastro-esophageal refluxVaezi MF et al. Gastroenterology 1996 ; 111 : 1192 – 9.0.4%3.2%14.6%23%46%
Visceral hypersensitivityNot specifically studied in refractory GERD• Most patients have NERD or functional heartburn• Heartburn associated with weakly acidic reflux• Lower perception thresholds for painBalloon esophageal distentionElectrical stimulation• Dilated intercellular spacesPromotes higher activation of sensory nerve endings
Dilated intercellular spaces (DIS)• Higher activation of sensory nerve endings• Nonspecific Asymptomatic subjectsCandida infection of esophagusFood allergyEosinophilic oesophagitisEsophageal cancer• Disappearance of DIS & symptoms resolution after PPI• NERD patients refractory to PPI have persistence of DIS
Dilated intercellular spacesRabbit oesophageal mucosa at electron microscopyFarre R et al. Gut 2008 ; 57 :1366 – 74.Acid-pepsin solution at pH 5.0Acid-pepsin solution at pH 5.0plus deoxycholic acid 2 mmol/l
Nocturnal acid breakthroughCombined esophageal & gastric 24 h pH monitoringGastric pH < 4 for ≥ 60 min despite twice daily PPIGastrointest Endoscopy Clin N Am 2005; 15: 289 - 306.75% of GERD patients & healthy subjects on PPI bidNo correlation between NAB & nocturnal GERD symptoms
Delayed gastric emptying• Few studies evaluates frequency of gastric emptyingin refractory GERD• Rapidly growing number of patients with DM & thoseusing narcotics for pain syndrome might soon makegastroparesis one of the leading causes of PPI failure
Diagnosis of eosinophilic esophagitisRelatively uncommon disorder• Clinical symptoms of esophageal dysfunction:Dysphagia, food impaction, refractory GERD, chest pain• 15 eosinophils in 1 high-power field• Lack of responsiveness to high-dose PPIor normal pH monitoring of distal esophagusFuruta GT et al. Gastroenterology 2007 ; 133 : 1342 – 1363.
Endoscopic images of eosinophilic esophagitisLinear furrows &adherent white exudatesConcentric ringsSmall calibre esophaguswith strictureMucosal laceration fromDiagnostic endoscopy
Diagnostic techniques for refractory heartburn• UGI Endoscopy Low diagnostic yield• pH testing PPI qd: limited valuePPI bid: non-contributory value• MII-pH Best diagnostic tool on PPI• Bilitec 2000 Limited evidence
UGI endoscopyFirst test used in clinical practice for refractory GERD• Normal endoscopy (most frequent)• Esophageal erosions• Pill-induced esophagitis• Infectious esophagitis• Zollinger-Ellison syndrome• Eosinophilic esophagitisVery low diagnostic yield if no alarm symptomsASGE guidelines. Gastrointest Endosc 2007 ; 66 : 219 – 24.
Erosive esophagitis in refractory GERD & untreated patientsPoh CH et al. Gastrointest Endosc 2010 ; 71 : 28 – 34.OR of erosive esophagitis in refractory GERD: 0.11 (95% CI: 0.04-0.30)Eosinophilic esophagitis: 0.9% of refractory GERDCross-sectional study105 refractory GERD – 91 untreated patints
Therapeutic approaches of refractory GERD• Compliance & dosing time• Lifestyle modifications• Proton-Pump Inhibitors (PPI)• H2RA at bedtime• Baclofen• Promotility drugs & bile acid binders• Pain modulators• Endoscopic treatment for GERD• Antireflux surgery• Alternative medicineFirst managementStandard of care
Compliance & proper dosing timeEvaluation of proper compliance and adequate dosingtime should be the first management when assessingpatients with heartburn who are not responding to PPIsbefore instituting any other intervention
Lifestyle modifications• Only weight loss and elevation of the bed head areeffective in improving GERD• Insufficient data to support other lifestyle modificationsKaltenbach T et al. Arch Intern Med 2006 ; 166 : 965 – 71.Recent systematic review of all publicationsIt is reasonable to recommend avoidance of specificlifestyle activities identified by patients or physiciansto trigger GERD-related symptoms
Proton pump inhibitors• Switching to another PPI• Doubling the PPI dose½ hour before breakfast & before dinnerIncrease in overall symptom relief by 25%No evidence for further escalation of PPI doseTwo therapeutic strategies“Standard of care”
H2RAs at bedtime• Retrospective study: 56 pts – PPIs bid + H2RAs at bedtime*72% long term improvement in overall symptoms• Good experience accumulated so far with H2RA for GERDRackoff A et al. Dis Esophagus 2005 ; 18 : 370 – 3.• H2RAs might improve GERD-related symptoms in longterm in substantial number of patients• If clinical tolerance: H2RAs intermittently or on demand
TLESRPrimary mechanism of reflux in health & GERDThree characteristics: Non-swallow induced Prolonged Triggered by fundic distension
Baclofen*TLESR reducers• Mechanisms Reduced reflux episodes by 40%Increased LES basal pressureAccelerated gastric emptying• Doses Up to 20 mg tid• Side effects Central nervous system side effectsSomnolence, confusion, tremblingImportant limiting factor in routine usage• Indications Weakly acidic reflux by MII-pHRegurgitation, or sour/ bitter taste in mouth* Gamma-aminobutyric acid B receptor agonists
Promotility drugs & bile acid bindersPromotility drugs• Attractive option in delayed gastric emptying• No available data in GERD patients who failed PPIsCholestyramine or sucralfate• Unclear if any of the currently available bile acid bindersare sufficiently efficacious to improve symptoms
Visceral pain modulators• No studies in GERD patients with refractory heartburn• Attractive option Most patients from NERD groupLack of weakly or acidic reflux• Tricyclic antidepressants, trazodone, & SSRIs• Used in non-mood-altering doses• Same recommendations for non-cardiac chest pain
Endoscopic treatment for GERDInteresting topic of investigation• Requirements: efficacy, safety & durability• Two promising techniquesRadiofrequency energy (Stretta) Refractory GERDEndoluminal fundoplication Candidate for surgery• Most studies open & uncontrolled with short-term results• Few RCTs with less impressive results than open trialsLouis H et al. Best Pract Res Clin Gastroenterol 2010 ; 24 : 969 – 979.
Stretta procedure• 109 patients refractory to PPI bid• Endoscopic esophagitis or abnormal pH testing• 4-years follow-up• Assessment: GERD HRQL questionnaireHeartburnSatisfactionPercent without PPI• Data on long-term follow-up (4 y): sustained improvementNoar MD et al. Gastrointest Endosc 2007 ; 65 : 367 – 72.
Anti-reflux surgery• Anti-reflux surgery in refractory GERD scarcely studied• Careful selection of patientsPositive symptom-reflux correlation in MII–pH on PPIsExcellent results for laparoscopic Nissen fundoplication• Postsurgical follow-up relatively shortMainie I et a. Br J Surg 2006 ; 93 : 1483 – 7.del Genio G et al. J Gastrointest Surg 2008 ; 12 : 1491 – 6.
Alternative medicineAcupuncture• 30 patients on PPI qdAcupuncture biw vs doubling PPI dose/4weekAssessment: GERD symptoms diary – HRQoL by SF 36Acupuncture more effective than doubling PPI dose• Additional studies needed to demonstrate value ofacupuncture in this clinical situationDickman R et al. Aliment Pharmacol Ther 2007; 26 : 1333 – 44.
Traditional Chinese Medicine acupuncturepoints used in the treatment protocol.Dickman R et al. Aliment Pharmacol Ther 2007; 26 : 1333 – 44.Per.6 NeiguanSt.36 ZusanliCV12 ZhangwanCV17 ShanzhongLiv.3 TaichongSp.9 Yinlingquan
Health-related quality of lifeAssessment by Short Form 36HRQol assessed by SF-36SF-36 dimensions scored on a 0 (poor) to 100 (good) health scale
RecommendationsPatient failed full course of PPI once a day• Excluding poor compliance & dosage timing• Switch to another PPI or doubling the PPI dose2-month course of treatment• Maintenance treatment if asymptomatic on PPI bidSame PPI dose inducing remission – PPI qd considered• Lack of symptom improvement → 2 strategiesBased on MII-pH on treatmentEmpirical therapy
Management strategy based on MII-pHPositive for acid reflux (least common scenario)• Review compliance & dosage timing• H2RA at bedtimePositive for weakly acidic reflux• Baclofen Low dose & slow increase in dose approach• Surgery Carefully selected patientPositive SI in esophageal MII–pHNegative• Pain modulators Tricyclics, trazodone, and SSRISame recommendations for NCCP
Empirical therapy for refractory GERDMII-pH not available to many physiciansPatient’s predominant symptom might guide treatment• Heartburn H2RA at bedtime• Regurgitation or sour taste in mouth BaclofenAnti-reflux surgery• Still exhibits lack of response Pain modulatorsFass R. Clin Gastroenterol Hepatol 2008 ; 6 : 393 – 400.
Conclusion• Compliance & dosing time should be evaluated first in patientswith heartburn not responsive to PPI• In patients who failed PPI once daily, doubling PPI dose orswitching to another PPI are potential therapeutic strategies• UGI endoscopy has very limited value if no alarm symptoms• MII-pH monitoring on PPI provides best diagnostic tool:Acid reflux H2RAWeakly acidic reflux Baclofen – Anti-reflux surgeryNo reflux Pain modulators