medifocus april 2007

Monitoring Glycaemic Status

Gestational Diabetes

Diabetic Dyslipidemia

Insulins in Clinical Practice

Hypertension With Diabetes

Volume: 5 • Issue: 3 & 4 • Septermber 2007

DIABETESKnow more to manage the menace

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RPG & Acute Abdomen

Explained

Vol. 5 Issue 3 & 4 April - Sept 2007

• Owned,Edited,PrintedandPublishedby Dr.VinayAggarwalforandonbehalfof

PushpanjaliMedicalPublicationsPvt.Ltd.,A-14,Pushpanjali,VikasMargExtn.,Delhi-110092

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unsolicitedmanuscriptsunlessaself-addressedstampedenvelopeisenclosed.

• ViewsexpressedinarticlesinPushpanjaliMedi-Focusdonotnecessarilyreflectthoseoftheeditorialboard.

Editor-in-Chief Dr. Vinay Aggarwal

SectionalEditorial Dr. S. K. Wangnoo

EditorialBoardDr. Ashok Grover

Dr. Hari Haran Dr. Sharda JainDr. Parkash Gera Dr. S. Arul RhajDr. Rajiv Gupta Dr. Deepak Pande Dr. Atul Jain Dr. Yogesh Jhamb Dr. Vineet Jain Dr. Neeraj JainDr. B.K. Gupta Mr. S.K. SinghalMr. Atul Gandotra Dr. Madhumita Puri

Photographer Mr. Mukesh Kapoor

DesignandLayout Tabassum

Considerthesefacts…..

Indians are more prone todeveloping diabetes than almostany other population in theworld!

Indiahasthehighesteverreportednumberof20millionpeoplewithdiabetes, which has earned her

thedubioustitleofthe“DiabeticCapital”oftheWorld.

Andthisisnotall….

Indianstendtobecomediabeticatarelativelyyoungerage of 45 years, which is about 10 years earlier thanreportedintheWest.Further,aperson’slifeexpectancyafterdevelopingdiabetesisabout8yearsaftertheonsetofthedisease,astheytendtosuccumbtokidneyaswellasheartdiseasemoreoftenthanothers.

Thereisaneedforaconcertedeffortforallconcernedto learn of the pitfalls that lead to this disorder.Precautionary measures would include measuringthewaist,andnot just thebodyweight - toknowtheprogressofdisease;and toavoid thepaunch,not justobesity.Thus,physio-therapistsand ‘weight-watchers’alike require a better understanding of the causes ofdiabetesandheartdisease.

What is the profile of the potential diabetic? Moderninformationallowsforareasonable‘guess’:Ifapersonisover45yearsofage,hasaprotrudingand‘bigbelly’and has a family background of diabetes, it is almostcertainthatheorshewilldevelopthedisorder.

Mereprescriptionofdrugsandimposingrestrictionsondiet is not the only answer for this problem. Instead,developing an acute understanding the disease in thelocalcontextandurgingtheacceptanceofappropriatelifestylesarenowurgentlymorethaneverrequired.

The present issue of “Medi-Focus” attempts to raisetheseissuesbycoveringawidearrayoftopicsrelatedto diabetes and its complications. Brief reviews ofthe disease processes are given along with the latestrecommendations in treatment. Topics pertainingto all the aspects of diabetes type 1 diabetes, type 2diabetes,hypertension, lipidsandgestationaldiabetesarecoveredinthisissue.

Ihopethiswillbehelpfultophysiciansandinternistsalike and contribute to a better understanding ofdiabetes.

Dr. S. K. Wangnoo

Vol. 5, Issue 3 & 4 April - Sept 2007

EDITOR SPEAKS

CONTENTS

1. Type1Diabetes-Presentation, 5DiagnosisandTreatment

2. OralMedicationstotreattype 92Diabetes

3. ManagementofPostPrandial 11Hyperglycemia

4. TheEvolvingRoleofTheFamily 15 PhysicianAndFamilyMedicine5. InsulinsinClinicalPractice– 17

AnOverview5. MonitoringofGlycaemicstatus 216. GestationalDiabetes 257. DiabeticDyslipidemia 298. TreatmentofHypertensionin 33

AdultPatientswithdiabetes-ADAGuidelinesReview

9. RapidlyProgressive 37Glomerulonephritis

10.ApproachtoAcuteAbdominal 4311.MaintainingQualityinHealthcare 49 Services12.PushpanjaliFamilyphysicians 53 forum(PFPF)13.PushpanjaliHealthCareEvents 54 andInitiatives14.GuidelinesforSubmissionof 59 Manuscripts

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M E D I C A L C E N T R EHeart & Trauma Hospital

LIST Of CONSULTANTS

CONSULTANT RESIDENCE CHAMBER MOBILE DAY/TIMING

MEDICAL DIRECTORDr.VinayAggarwal 22374612 22371818 9811050403

MEDICAL SUPERINTENDENTDr.H.S.Nagi 95120-4125563 9818599722 9.00am-5.00pm(Daily)

PHYSICIANDr.ParkashGera 22375440,22371284 22075641 9810000944 11.30am-1.00pm(Daily)Dr.SangeetaBhargava 42440940,22441900 22094921-22 9810249001 9.00am-10.00am(Daily)

PHYSICIAN & NON INASIVECARDIOLOGISTDr.MukeshAjmera 22374502 9811008306 11.00am-1230pm(Daily)

PHYSICIAN-CHEST SPL.Dr.AshokGrover 22411236,22541854 Fax.22524700 9810121609 4.00pm-5.30pm(Daily)

GYNAECOLOGISTDr.ShardaJain 22238838-22238847 22414049-22453724 9312644808 8.00am-9.00am(Daily)Dr.KanikaGupta 22149718,22169718 9810183236 10.00am-12.00noon (Tue,Wed,Fri) 7.00pm-8.00pm(Mon,Tue,Sat)Dr.BakulArora 22750757,22750551 9810089120 7.00pm-8.00pm(Mon,Fri)Dr.AnitaJain 95120-4112881,264039722582002 9810262229 1.00pm-2.00pm(Daily) Dr.RekhaSarin 65261328 9818088114 9.00am-11.00am (Mon,Thur,Sat)Dr.SunitaLal 9810630691 5.00pm-6.00pm(Mon.Thur)

SURGEONDr.YogeshJhamb 22378281 9811168281 11.30am-1.30pm(Daily)Dr.YogeshAggarwal 22238871 9810081484 6.00pm-8.00pm(Daily)Dr.SameerParuthi 9810061958 OnCall

CHILD SPECIALISTDr.DeepakPande 22243742,42182025 22432218 9810366571 11.30am-1.00pm(Daily)Dr.VineetJain 95120-4112881,2640397 22582002 9810121098 10.00am-12.00noon(Daily)Dr.AlokGupta 65374625 9910227227 9312248808 5.00pm-6.30pm(Daily)

PAEDIATRIC SURGEONDr.AnuragKrishna 24112687,24114887 9810060565 1.00pm-2.00pm(Sat)

ORTHOPAEDIC SURGEONDr.B.K.Malik 22778904 9811703004 6.00pm-8.00pm(Daily)Dr.AshishSao 9312010421 9.30am-12.30pm (Mon,Wed,Fri)Dr.GirishChhabra 95120-2628200,2625200 22507728 9810025926 9.30am-12.30pm (Tue,Thu,Sat)Dr.P.K.Dhar 22244801 9810038879 10.30am-12.00noon(Daily)Dr.DaulatSingh 22120442 22111872 9810244149 OnCallDr.R.K.Sachdeva 22162135 22094892 9811073613 5.00pm-6.00pm(Daily)Dr.AlokSharma 9312070380 6.00pm-8.00pm(Daily)

ANAESTHETISTDr.RajeshDhall 22167122 9810110405 Oncall(Tue,Thu,Fri,Sun)Dr.SwarajGarg 22543003 22548796,22519888 9811441064 Oncall(Mon,Wed)Dr.RakeshAtray 22152245,22157745 9810272563 Oncall(Sat)

ENT SURGEONDr.AtulJain 22376205 22545000 9811120545 12.00noon-1.30pm(Daily)Dr.AnuragJain 22720901 9810249015 8.30pm-9.30pm(Daily)Dr.VyomeshBansal 9310071990 6.00pm-8.00pm (Tue,Thu,Sat)

GASTROENTEROLOGISTDr.NeerajJain 22371024 22545000 9810166989 4.00pm-6.00pm(Daily)

ONCOLOGISTDr.SudersanDe 26252065 9810227340 Oncall(Tue),byappointment

ONCO SURGEON Dr.PraveenJain 22146173 22149256 9810139314 OncallDr.UmangMittal 95121-2668149 9412201474 4.00pm-6.00pm(Wed) 11.00am-12.00noon(Sat)

EYE SPECIALISTDr.L.D.Sota 26016636 9312876694 10.00am-1.00pmDaily (exceptWed) 4.00pm-7.00pm(Wed)Dr.P.C.Bhatia 26515263,26863998 9810064554 Oncall


LIST Of CONSULTANTS

CONSULTANT DAY / TIMINGSPHONE NO

PHYSICIANDr.RubyBansal 9.00am-11.00amR)2614076 (Daily)M)9891376756

CHILD SPECIALISTDr.(Mrs.)VTBoppal9.00pm-10.00amM)9811161590 (Daily)

SURGEONDr.VijayS.Pandey 11.00am-1.00pmR)95120-2628254 (Mon,Thur)M)9818492809

ENDOCRINOLOGISTDr.S.K.Wangnoo 7.00pm-9.00pmR)22618242 (Mon,Wed)

22621357M)9810113922

DENTAL SURGEONDr.JyotiGoyal 10.00am-1.30pmR)986878041 6.00pm-9.00pmDr.GopalGoyal (Daily)M)9868235811

DERMATOLOGISTDr.RituGupta 7.30pm-9.00pmR)22371114 (Wed,Fri)M)9891063467 ENTDr.SaketAggarwal 11.00am-1.00pmM)9811231599 (Mon,Thurs)

PHYSIOTHERAPISTDr.Md.MajidKhan 1.00pm-4.00pmM)9873207660 (Daily)

Dr.SonikaSaraswat 8.00am-3.00pmM)9899649920 (Daily)

Dr.SachinKr.Gupta 4.00am-8.00pmM)9873322564 (Daily)

HOMOEOPATHICDr.DeepakKarla 11.00am-1.00pmM)9313882040 (Thur,Sat)

CONSULTANT RESIDENCE CHAMBER MOBILE DAY/TIMING

URO-SURGEONDr.C.M.Goel 951202630717 951202630365 9811047047 1.00pm-2.00pm(Mon,Thu)

PATHOLOGISTDr.VandanaArora 22246806 9811009938 9.00am-4.00pm(Daily)Dr.ArchanaSood 22096401 9312319887 OnCall

MICROBIOLOGISTDr.NarinderSaini 22376289 22381445 9810252127 8.00am-9.00am(Daily)

RADIOLOGISTDr.MukeshKoshal 22546704 9810062179 12.00noon-1.30pm(Daily)

NEUROLOGISTDr.B.K.Gupta 22371675,22371033 30946399 9811084263 OnCallDr.NirmalaLahoti 22540271,22526601 9810061981 OnCallDr.Aditya 9810556353 9.00am-11.00am (Tue,Thur,Sat)

NEURO SURGEONDr.J.Kumar 9810273684 OnCallDr.VikasGupta 9810661522 7.00-8.00pm(Tue,Fri)

NEPHROLOGISTDr.NeeruAggarwal 95120-2724591 95120-2780736 9810266275 1.00pm-2.00pm(MontoFri) 9.00amto10.00am(Sat)

PSYCHIATRISTDr.RamanJeetJaswal 22526533 9810526533 OncallDr.VikasMohanSharma 22623183 9810412911 6.00-8.00pm(Fri)

PSYCHOSEXUAL DISORDERSDr.(Col.)V.K.Wadia 55469686 26140058 9891192777 6.00pm-8.00pm(Fri)

PSYCHOLOGISTDr.DeepaliBatra 9818425297 4.00pm-6.00pm(Wed,Fri)

CARDIOLOGISTDr.LokeshChandraGupta 9310124059 9810124059 7.00pm-9.00pm (Mon,Wed,Fri)

ENDOCRINOLOGISTDr.S.K.Wangnoo 22618242,22621357 95120-2921446 9810113922 OnCall

DENTISTDr.GeetaPaul 9811415489 9810292498 10.00am-2.00pm(Daily) 5.00pm-8.00pm

PHYSIOTHERAPISTDr.Md.MajidKhan 9873207660 9.00am-1.00pm(Daily)

HOMOEOPATHIC PHYSICIANDr.M.M.Aggarwal 22434770 22094879 22513835

PLASTIC SURGEONDr.R.K.Sandhir 95120-2458588 22592073,22169732 9810033525 OnCallDr.ManojBansal 22155057 22097417,22093107 9810003628 11.00am-1.00pm(Daily)

SKIN SPECIALISTDr.V.K.Upadhyaya 22152084 22091758 9810033882 OncallDr.MukeshGirdhar 95120-2625544 22372484 9810078198 OncallDr.RituGupta 9891063467 10.00am-11.00am (MontoFri)Dr.RitikaGupta 9818560759 Oncall

CHEST SURGEONDr.R.C.Jain 26803436,26808035 9811106203 Oncall

RHEUMATOLOGISTDr.AnishAggarwal 95120-2753546 9810073795 4.00pm-7.00pm(Fri)

OthersDr.PoonamGupta 22095708 22161397 9811744426Dr.S.P.Singh 22152036 9811152254Dr.JyotiAggarwal 22238871 9910081484Dr.DeepakLahoti 9810123067Dr.MadhuAhuja 22516733 22541842 9810067539

fAMILY PHYSICIANSDr.V.K.Malhotra 22157127 9313100602 OnCallDr.AjayAggarwal(B/oMD) 9810130292 OnCallDr.AjayArora 22156672 22510904 9810049714 OnCallDr.VipinJain 22372065 22412008 9811047912 OnCallDr.K.B.Bhatia 22372727 22372728 9811319070 OnCallDr.HariHaran 22549804 22540624 9810197049 OnCallDr.AtulAggarwal 22459608 9811137098Dr.D.R.Rai 9312504480Dr.V.P.S.Chawla 9811305435Dr.SangeetaGupta 9810395657Dr.AshwaniGoyal 22112343 9811112688Dr.A.K.Jain 9871803070Dr.RakeshGupta 22155979,55298198


Archana D. AryaConsultant Pediatric EndocrinologistCentreforChildHealth,SirGangaRamHospitalNewDelhi

Type 1 Diabetes - Presentation, Diagnosis and Treatment

Archana D. Arya

Type 1 Diabetes, also known as “InsulinDependent Diabetes Mellitus” or “JuvenileDiabetes”inthepast,accountsfortwothirdsofchildrenwithdiabetesa.

Presentation B cell destruction due to an autoimmuneprocess results in insulindeficiency in type1diabetes,whichisresponsiblefortheclassicalsymptoms of polyuria, polydipsia and weightloss.Polyuriamaypresentasbedwetting inapreviouslytoilettrainedchild.Polyphagiaisnotpresentoftensinceketosisleadstoanorexiainthesechildren.

Sometimes these classical symptoms maygo unnoticed and the child may presentwith symptoms of ketoacidosis (DKA) suchas pain abdomen and vomiting, and may bemisdiagnosed as gastroenteritis. Associatedsymptoms that may be present in diabeticchildrenarepyogenicskininfections,monilialvaginitisanddysuriainyounggirls.Theseareusuallyassociatedwithpolyuriaandpolydipsiaand are rarely isolated symptoms of type 1diabetes. Dehydration with very wet diapers/persistentmonilialinfectioninthediaperareainbabies shouldarouse suspicionofdiabetes.Rarely transient hyperglycemia may occur inchildren during stressful situations such assevere illnesses or high dose glucocorticoidtherapy. In these instances hyperglycemia isnotsevere,goingtoamaximumof300to400mg/dl.

DiagnosisFasting blood glucose of more than 126 mg/dland a random blood glucose of 200 mg/dl ormoreisdiagnosticofdiabetes.

v Ina leanchildbelow10yearsofagewithhighbloodglucose levelsandketosiswithorwithoutacidosisandnofamilyhistoryofdiabetes,themostlikelydiagnosisistype1diabetes.

v In children who are obese with signs ofinsulin resistance such as acanthosisnigricans, and especially with a familyhistoryoftype2diabetes,thepossibilityoftype2diabetesmustbekeptinmind,evenif theypresentwithketosisandtestsmustbeundertakentodistinguishbetweentype1andtype2diabetes.

Management of Type 1 DiabetesA sick dehydrated child with DKA must beadmittedforcorrectionoffluidandelectrolyte

imbalances as well as intravenous insulintherapy. If the child is metabolically stable atthe timeofdiagnoses,andif facilityofagooddiabeteseducationteamisavailabletoeducatetheparents,andhelp themwithmanagement,treatment can be initiated on an outpatientbasis.

Ifthesefacilitiesarenotavailableitisadvisableto admit the child for initiation of insulintherapy and for the purpose of providingdiabetes education to the family. Duration ofadmissionshouldbeasshortaspossiblesincebettercontrolofhyperglycemiaisachievedoncethechildisperformingroutineactivities.

INSULIN THERAPYInsulin PreparationsTherearevariousinsulinpreparationsavailablein the market. Human insulin has replacedporcine insulin in most parts of the world,although studies suggest that they causeasymptomatic hypoglycemia more often thanthe porcine preparations. Fast acting regularinsulin, ultra fast acting insulin analogs suchaslisproanddetemir,intermediateactingNPHinsulin and peakless basal insulin analogssuch as aspart and glargine can be used formanagement. Recently, inhaled insulin hasbecomeclinicallyavailable inUSA. IthasnotbeenapprovedbytheFDAforuseinchildrenlessthan18yearsofage.

Insulin RegimensYoungerchildrencanbemanagedwithasplitdose regimen of regular or rapid acting withNPH insulin injected before breakfast anddinner.Inolderchildren,itispreferabletouseacombinationofbasalinsulintoprovide24-hourinsulin coverage and regular or rapid actinginsulintocoverthepostmealglucosepeak.

Premixed insulin preparations are usually notpreferredbecauseoftheinabilitytoadjustdosesaccordingtomealplans.Theymaybeusedinpatientswithcomplianceproblems.Continuoussubcutaneousinsulininfusion(CSII)bymeansofinsulinpumpmaybeusedformanagement.Itresultsinimprovedcontrolofhyperglycemiaandmoreflexibilityoflifestyle.Costoftherapyisamajorfactorlimitingitsuseinourcountry.

Insulin DosageInitial requirement of insulin may be up to1u/kg/day. About 65% patients will undergopartial remission (honeymoon period) a few

Vol. 5, Issue 3 & 4 April - Sept 2007�

weeksfollowingdiagnosisduetoresidualBcellfunction,whenthe insulinrequirementmaybe<0.5u/kg/day.ThedurationofthisphasevariesindifferentpatientsandoncetheresidualBcellfunctionislost,mostpreadolescentswillneedabout0.8u/kg/dandadolescentswouldneed1.0u/kg/dofinsulin.Duringpubertytheinsulinrequirementmayincreaseupto1.5-1.8u/kg/dduetotheinsulinresistancecausedbythehormonalmilieu.

Medical Nutrition TherapyThis is an integral part of diabetes management. A balancebetweennutritionandexerciseisasimportantforgoodcontrolas adjusting insulin doses, but is often neglected. Nutritionistconsultationregardingdietisaveryimportantpartofmanagingtype1diabetes.About50-55%of thecaloric intakeshouldbefrom carbohydrates, 30% from fats and about 15-20% fromproteins.Dietshouldbeindividualizedaccordingtothechild’sactivities and metabolic needs. Children on CSII and basalinsulinfollowcarbohydratecountingtodecidetheinsulindoseatsomecenters.

ExerciseDiabetic children should be encouraged to exercise for30-60minutesat-least5timesaweek.Snackshouldbeprovidedand insulin dose adjusted, based on the time and duration ofexercise.

Goals of TherapyThegoaloftherapyistoprovidemetabolicnormalityandphysicalandemotionalhealthtothepatient.Thiscanbeprovidedby:

v Elimination of diabetic symptoms such as polyuria,polydipsia

v Prevention of acute complications like hypoglycemia andDKA

v Ensuringnormalgrowthandsexualmaturationv Earlydetectionofassociateddiseasesv Preventionofhyperlipidemiav Counselingforemotionaldisordersv Preventionofchronicvascularcomplications

Good glycemic control is of prime importance for achievingtheaboveobjectivesandthiscanonlybeachievedbyfrequent,regular monitoring. The Diabetes Control and ComplicationsTrial (DCCT) has shown that there is a marked reduction indiabetes-associatedcomplicationswithfrequentmonitoringandmultipleinsulininjections,butisassociatedwithahighriskofhypoglycemia.Henceintensivetherapyisnotrecommendedforveryyoungchildren.

Goalsof therapyinthemanagementof type1diabetesshouldbe individualized according to the age and socioeconomicbackgroundofthepatient.Foroptimalcontrolitisrecommendedthat the blood glucose (BG) level remains in the range80-120 mg/dl in fasting state and 80-140 mg/dl before meals.In toddlers and young children who have hypoglycemicunawarenessthegoalsshouldnotbeasrigid.ItisrecommendedthattheymaintaintheirfastingBGwithin100-140mg/dlandaBGof100-180mg/dlbeforemeals.

MonitoringAglucometershouldbeused formonitoringBGathome. If itis not affordable, a dextrostix can be used. The strips can bedividedlongitudinallyandcanbeusedtwice.UrineglucoseformonitoringisnotagoodsubstituteforBGmeasurement,sinceitcannotdetecthypoglycemia.Ifitispracticed,thepatientshoulddoublevoidbeforetesting.

Another BG monitoring system known as the continuousglucose monitoring system (CGMS) is now available in India.CGMS continuously measures subcutaneous tissue interstitialglucoselevels,recordingaveragevaluesevery5minuteswithinarangeof40400mg/dl.GlucosevaluesobtainedwiththeCGMShave been shown to correlate with laboratory and glucometermeasurementsofBG.CGMSprovidesanalarmtowarniftheBGistoohighorlow.

BloodGlucoseshouldbemonitoreddaily,beforeeachmealandperiodically at bedtime and 2-3 am, depending on the insulinregimen. In addition, it should be checked if hypoglycemia issuspectedandfrequentlyduringillness.BGreadingsshouldberecordedandthedoseof insulinshouldbemodifiedbasedonthereading.

UrineketonesmustbecheckedifBGisgreaterthan300mg/dl,duringillnessandinthefastingstateifpossible

follow Up Thepatientshouldvisitthedoctorevery3-4months.Heightandweight should be measured at every visit and pubertal statusassessedadolescents.Completephysicalexaminationincludingthyroidglandexaminationandinspectionofinjectionsitesforhypertrophyshouldbedone.Bloodglucose recordsshouldbescrutinizedandappropriatechangesintheinsulindoseshouldbemade.

GlycosylatedHb(HbA1C)shouldbecheckedevery3-4months.Itshouldremainbelow8%atalltimes.Goalscanbespecificforeachindividual.

Lipid profile, 24-hour or a timed collection of urine formicroalbumin and eye examination should be performedannually. Routine surveillance for associated autoimmunedisordersshouldbedoneasfaraspossible.

Suggested Reading:1. SpringerD,DziuraJ,TamborlaneWV,SteffenAT,AhernJH,

VincentMWeinzimerSA.Optimalcontroloftype1diabetesmellitus in youth receiving intensive treatment. J Pediatr.2006Aug;149(2):154-6.

2. Daneman D. Type 1 diabetes mellitus. Lancet. 2006Mar11;367(9513):847-58.

3. HallerMJ,AtkinsonMA,SchatzD.Type1diabetesmellitus:etiology,presentation,andmanagement.PediatrClinNorthAm.2005Dec;52(6):1553-78.

4. Daneman D, Wolfson DH, Becker DJ, Drash AL : Factorsaffecting glycosylated hemoglobin values in children withinsulin-dependentdiabetes.JPediatr99:847853,1981

5. Diabetes Control and Complications Trial ResearchGroup:Theeffectof intensive treatmentofdiabeteson thedevelopment and progression of long term complicationsin insulin-dependent diabetes mellitus. N Engl J Med329:977986,1993

6. Mecklenburg R, Benson J, Becker N, Brazel P, Fredlund P,MetzR,NielsonR,SannerC,SteenrodW:Clinicaluseoftheinsulininfusionpumpin100patientswithtype1diabetes.NEnglJMed307:513518,1982.

7. DaviesAG,Baun JD :Adecadeof insulin infusionpumps.ArchDisChild63:329332,1988

8. TsuiE,BarnieA,RossS,ParkesR,ZinmanB:Intensiveinsulintherapywithinsulinlispro:arandomizedtrialofcontinuoussubcutaneousinsulininfusionversusmultipledailyinsulininjections.DiabetesCare10:17221727,2001


S.K. WangnooSenior ConsultantEndocrinologistApolloCentreforObesityDiabetes&Endocrinology(ACODE)IndraprasthaApolloHospital,NewDelhi

Garima S GuptaRegistrarApolloCentreforObesityDiabetes&Endocrinology(ACODE)IndraprasthaApolloHospital,NewDelhi

Oral Medications to Treat Type 2 Diabetes

S.K. Wangnoo1 and Garima S Gupta2

The epidemic of type 2 diabetes in the latterpartof the20thand in theearly21stcentury,and the recognition that achieving specificglycemic goals can substantially reducemorbidity, has made the effective treatmentof hyperglycemia a top priority. Maintainingglycemic levels as close to the non-diabeticrange as possible has been demonstrated tohaveapowerfulbeneficialimpactondiabetes-specific complications, including retinopathy,nephropathy, and neuropathy in the settingof type 1 diabetes; in type 2 diabetes, moreintensive treatment strategies have likewisebeendemonstratedtoreducecomplications.

The development of new classes of bloodglucose-lowering medications to supplementthe older therapies, such as lifestyle-directedinterventions, insulin, sulfonylureas, andmetformin,hasincreasedthetreatmentoptionsfor type 2 diabetes. Whether used alone or incombinationwithotherbloodglucose-loweringinterventions, the availability of the neweragents has provided an increased numberof choices for practitioners and patients andheightened uncertainty regarding the mostappropriate means of treating this widespreaddisease. Although numerous reviews on themanagement of type 2 diabetes have beenpublished in recent years, practitioners areoften left without a clear pathway of therapytofollow.

Clinicaltrials,suchastheDiabetesControlandComplications Trial (DCCT), the StockholmDiabetes Intervention Study (SDIS) in type1 diabetes and the UK Prospective DiabetesStudy (UKPDS) and Kumamoto Study in type2diabetes,havehelpedestablishtheglycemicgoals of therapy that result in improved long-termoutcomes.

The most recent glycemic goal recommendedbytheAmericanDiabetesAssociation,selectedon the basis of practicality and the projectedreduction in complications over time, is “ingeneral”anA1Clevel<7%.For“theindividualpatient,” the A1C should be “as close tonormal (<6%) as possible without significanthypoglycemia.” The most recent glycemicgoal setby theEuropeanUnion InternationalDiabetes Federation is an A1C level <6.5%.Factors such as life expectancy and risk forhypoglycemia need to be considered forevery patient before intensifying therapeuticregimens.

Choosing specific antihyperglycemic agentsis predicated on their effectiveness in

lowering glucose, extraglycemic effects thatmay reduce long-term complications, safetyprofiles,tolerability,andexpense.

Effectiveness in Lowering GlycemiaApart from their differential effects onglycemia, there are insufficient data at thistimetosupportarecommendationofoneclassofglucose-loweringagents,oronecombinationof medications over others with regardto effects on complications. However, thedifferentclassesdohavevariableeffectivenessin decreasing glycemic levels, and theoverarching principle in selecting a particularintervention will be its ability to achieve andmaintainglycemicgoals.

Amajor factor inselectingaclassofdrugs,oraspecificmedicationwithinaclass,toinitiatetherapy or when changing therapy, is theambientlevelofglycemiccontrol.Whenlevelsof glycemiaarehigh (eg,A1C>8.5%),classeswith greater and more rapid glucose-loweringeffectiveness, or potentially earlier initiationof combination therapy, are recommended;conversely,whenglycemic levelsarecloser tothetargetlevels(e.g.,A1C<7.5%),medicationswith lesser potential to lower glycemia and/ora slower onset of action may be considered.Obviously, the choice of glycemic goals andthe medications used to achieve them mustbe individualized for each patient, balancingthepotentialforloweringA1Candanticipatedlong-term benefit with specific safety issues,as well as other characteristics of regimens,including side effects, tolerability, patientburdenandlong-termadherence,expense,andthe nonglycemic effects of the medications.Finally,type2diabetesisaprogressivediseasewithworseningglycemiaovertime.Therefore,addition of medications is the rule, not theexception,iftreatmentgoalsaretobemetovertime.

MetforminMetformin is the only biguanide availablein most parts of the world. Its major effectis to decrease hepatic glucose output andlower fasting glycemia. Typically, metforminmonotherapy will lower A1C by ~1.5percentagepoints.Itisgenerallywelltolerated,with the most common adverse effects beinggastrointestinal. Lactic acidosis though quiterare (<1 case per 100,000 treated patients),is always a matter of concern because ofits potentially fatal outcome. Metformin


monotherapyisusuallynotaccompaniedbyhypoglycemiaandhasbeenusedsafely,withoutcausinghypoglycemia,inpatientswith pre-diabetic hyperglycemia. The major nonglycemiceffectofmetformin iseitherweightstabilityormodestweightloss, in contrast to many of the other blood glucose-loweringmedications.

SulfonylureasSulfonylureas lower glycemia by enhancing insulin secretionand A1C by ~1.5 percentage points. The major adverse sideeffect is hypoglycemia, but severe episodes, characterized byneedforassistance,coma,orseizure,areinfrequent.However,such episodes are more frequent in the elderly. Episodes canbebothprolongedandlifethreatening,althoughtheseareveryrare.Severalofthenewersulfonylureashavearelativelylowerrisk for hypoglycemia. In addition, weight gain of ~ 2 kg iscommonwiththeinitiationofsulfonylureatherapy.

GlinidesLikethesulfonylureas,theglinidesstimulateinsulinsecretion,although they bind to a different site within the sulfonylureareceptor. They have a shorter circulating half-life than thesulfonylureas and must be administered more frequently. Ofthe two glinides currently available, repaglinide is almost aseffectiveasmetforminorthesulfonylureas,decreasingA1Cby~1.5percentagepoints.Nateglinide issomewhat lesseffectivein lowering A1C than repaglinide when used as monotherapyor in combination therapy. The glinides have a similar riskfor weight gain as the sulfonylureas, but hypoglycemia maybe less frequent, at least with nateglinide, than with somesulfonylureas.

a Glucosidase Inhibitorsa-Glucosidase inhibitors reduce the rate of digestion ofpolysaccharides in the proximal small intestine, primarilylowering postprandial glucose levels without causinghypoglycemia. They are less effective in lowering glycemiathan metformin or the sulfonylureas, reducing A1C by 0.5-0.8 percentage points. Since carbohydrate is absorbed moredistally,malabsorptionandweightlossdonotoccur;however,increased delivery of carbohydrate to the colon commonlyresults in increased gas production and gastrointestinalsymptoms.This is themostcommoncauseofdiscontinuationoftheseclassesofdrugs.

ThiazolidinedionesThiazolidinediones (TZDs or glitazones) are peroxisomeproliferatoractivated receptor ã modulators; they increase thesensitivityofmuscle,fat,andlivertoendogenousandexogenousinsulin (“insulin sensitizers”). The limited data regarding theblood glucose-lowering effectiveness of TZDs when used asmonotherapy have demonstrated a 0.5-1.4% decrease in A1C.The most common adverse effects with TZDs are weight gainand fluid retention. There is an increase in adiposity, largelysubcutaneous,with redistributionof fat fromvisceraldepositsshown in some studies. The fluid retention usually manifestsas peripheral edema, though new or worsened heart failurecanoccur.TheTZDseitherhaveabeneficial orneutral effectonatherogenic lipidprofiles,withpioglitazonehavingamorebeneficialeffectthanrosiglitazone.

Recentcontroversiessurroundingtheuseofrosiglitazonesandanincreasedriskofadversecardiaceventshavefuelledanxiety

in the minds of practitioners about their use in diabetics.However,dataatthispointoftimeisinsufficienttoaddtothiscontroversy and while prescribing these medications, the risktobenefitratioshouldbecarefullyweighed.

Incretin and Incretin MimeticsIncretins are hormones released from the gastrointestinaltract in response to nutrient ingestion that potentiate glucose-stimulated insulin secretion from islet beta cells. Thesearch for incretins was prompted by the observation thatadministrationofanoralglucose load leads toamuchgreaterstimulation of insulin release than a comparable glucoseload given intravenously. This connection between the gutand the pancreatic islets is known as the enteroinsular axisand is deemed responsible for ~50% of postprandial insulinrelease.The2predominantincretinsareglucagon-likepeptide(GLP)-1 and glucose-dependent insulinotropic peptide (GIP).These 2 peptides stimulate insulin secretion, and, unlikeother insulinotropicagents, theydoso inaglucose-dependentmanner. In light of these beneficial actions, GLP-1 and GIPrepresentpotentialtherapeuticagentsforthetreatmentoftype2 diabetes. However, because exogenous GIP is comparativelyless effective than GLP-1 in stimulating insulin secretion intype 2 diabetics, while the insulinotropic action of GLP-1 iswell preserved; much of the current research has focused onenhancingGLP-1actionforthetreatmentoftype2diabetes.

GLP-1 also exerts a number of other biological actions thatcontribute to its ability to lower glucose, including inhibitionof gastric emptying, which reduces meal-associated increasesin glycemic excursion. GLP-1 also inhibits glucagon secretionandsuppresses food intake inbothdiabetic andnondiabetics.Furthermore, GLP-1 has the potential to preserve or enhancebeta-cell function in subjects with type 2 diabetes due to itsability to stimulate beta-cell proliferation and neogenesis andinhibitapoptosis.

However,themajortherapeuticdrawbacktousingnativeGLP-1 is its very short half-life of less than 2 minutes followingexogenousadministration,dueinparttotheproteasedipeptidylpeptidase (DPP)-IV. As a result, preventing the degradation ofnative GLP-1 by inhibiting the activity of the DPP-IV enzymehasemergedasatherapeuticstrategyforenhancingendogenousGLP-1actioninvivo.

DPP IV InhibitorsThe apparent beneficial effects on beta-cell function raisethe possibility that these agents may be able to modify thenaturalhistoryoftype2diabetes.Althoughtheemergingsafetyprofile of the DPP-IV inhibitors appears to be excellent, thelong-term safety of these agents has not yet been ascertained.Similarly, although DPP-IV inhibitors exhibit promising short-term effects on enhancement of beta-cell function, their long-term durability compared with other oral antidiabetic agentsused in the treatment of type 2 diabetes remains unknown.In addition, whether any meaningful differences will emergeamong the different chemical classes of DPP-IV inhibitorscurrently under development cannot as yet be determined.Taken together, the latest available clinical data support theconsiderable early promise associated with the sustainedenhancement of incretin action, making it increasingly likelythatDPP-IVinhibitorsmayprovetobeusefulforthetreatmentof type 2 diabetes. Currently, the DPP-IV inhibitors undervarious phases of research and marketing are Sitagliptin,SaxigliptinandVildagliptin.


S.K. WangnooSenior ConsultantEndocrinologistApolloCentreforObesity,Diabetes&Endocrinology(ACODE)IndraprasthaApolloHospital,NewDelhi

Management of Post Prandial Hyperglycemia

S. K. Wangnoo

Type 2 diabetes is a serious condition that isassociated with a number of life-threateningcomplications, including coronary disease.In addition to being a marker for the onsetof type 2 diabetes, post-prandial glycemia(PPG) appears to be associated with thedevelopment of both the macro vascular andmicro vascular complications of diabetes,independently of HbA1c and FPG levels.Numerous epidemiological studies haveshown elevated postprandial/post-challengeglucose to be independent and significantrisk factors for macro vascular complicationsand increased mortality risk. There is muchevidence to suggest that elevated plasmaglucose levels contribute to the developmentof atherosclerotic lesions. Many studieshave shown that there is a strong correlationbetween elevated plasma glucose levels andthe risk of developing cardiovascular disease.Large, randomized, prospective trials havedemonstratedthatreductionsinhyperglycemiaand management of diabetes-related riskfactors significantly reduce micro vascularand macro vascular complications in patients

witheithertype1ortype2diabetes.Findingsfrom the Diabetes Control and ComplicationsTrial (DCCT), the Kumamoto study, and theUnited Kingdom Prospective Diabetes Study(UKPDS), which demonstrated that therapiesdirected at achieving normal glycemia reducethe development and delay the progression oflong-termmicrovascularcomplications.Thesetrials demonstrated a 30-35% reduction inmicrovascular complicationsper1%absolutereductionofglycosylatedhemoglobin(HbA1c).Furthermore, epidemiological data from theUKPDSalsoshoweda14-16%decreaseinmacrovascular complications for every 1% absolutereduction in glycosylated hemoglobin-with noglycemicthresholdforasubstantivechangeintheriskforanyoftheclinicaloutcomesstudied.Inotherwords,riskreductionextendedintothenormalrangeforHbA1c.Toachievemaximumbenefit from treatment, many researchers andcliniciansnowbelievethatHbA1cvaluesmustbe kept close to 6.5% (International DiabetesFederation, IDF and American College ofEndocrinology,ACE),whichisslightlyabovethenormalrangeinnondiabeticpatients(<6%).

Table:

Epidemiologicalstudiesshowinganassociationbetweenpost-prandialhyperglycemiawithriskofCVDandmortality

HoornStudy 2-h glucose better predictor of mortality thanHbA1c

HonoluluHeart 1-h glucose predicts Program coronary heartdisease

ChicagoHeartStudy 2-h post challenge glucose predicts all-causemortality

DECODE High2-hpostloadbloodglucoseisassociatedwith increased risk of death, independent offastingglucose

Coutinhoetal 2-hglucoseassociatedwithCHD

Whitehall Study, Paris Prospective Study,andHelsinkiPolicemenStudy

2-h post challenge glucose predicts all-causeandCHDmortality

Diabetes PostmealbutnotfastingglucoseisassociatedwithCHD,coronaryheartdisease.

Role of Post-Prandial Hyperglycemia

Recentstudiesdemonstratethathyperglycemiainduces an overproduction of superoxide bythe mitochondrial electron-transport chain.Superoxide overproduction is accompaniedby increased Nitric Oxide (NO) generation,due to endothelial NO synthase (eNOS) andinducibleNOsynthase(iNOS)uncoupledstate,

a phenomenon favoring the formation of thestrong oxidant peroxynitrite, which in turndamages DNA. DNA damage is an obligatorystimulusfortheactivationofthenuclearenzymepoly (ADP-ribose) polymerase. Poly (ADP-ribose) polymerase activation in turn depletesthe intracellular concentration of its substrateNAD+,slowingtherateofglycolysis,electrontransport,andATPformationandproducesan


ADP ribosylation of the GAPDH (glyceraldehyde-3-phosphatedehydrogenase).

Several indirect and direct evidences support the conceptthat acute hyperglycemia works through the production of anoxidative and nitrosative stress. Indirect evidence is obtainedthroughtheuseofantioxidants.Thefactthatantioxidantscanhinder some of the effects acutely induced by hyperglycemia,suchasendothelialdysfunction,activationofcoagulation,andplasmaticincreaseofICAM-1andinterleukins,suggeststhattheactionofacutehyperglycemiaismediatedbytheproductionoffreeradicals.

Directevidenceislinkedtotheestimateoftheeffectsofacutehyperglycemiaonoxidativestressmarkers.Ithasbeenreportedthatduringoralglucosechallenge,areductionoftheantioxidantdefenses isobserved.Theroleofhyperglycemia ishighlightedbythefactthatgivingtwodifferentmeals,whichwillresultintotwodifferent levelsofpostprandialhyperglycemia, thegreaterdropintheantioxidantactivityislinkedwiththehigherlevelsofhyperglycemia.Theevidencethatindiabeticsubjects,LDLsaremorepronetooxidationinthepostprandialphasematchesthesedata.Eveninthissituation,higherlevelsofhyperglycemiaare matched with a greater oxidation of LDLs. Interesting andnewdataareavailableonthepossiblegenerationofnitrosativestress during postprandial hyperglycemia. The simultaneousovergenerationofNOandsuperoxidefavorstheproductionofatoxicreactionproduct,theperoxynitriteanion.Theperoxynitriteanioniscytotoxicbecauseitoxidizessulfydrylgroupsinproteins,initiates lipid peroxidation, and nitrates amino acids such astyrosine,whichaffectsmanysignaltransductionpathways.Theproduction of peroxynitrite can be indirectly inferred by thepresenceofnitrotyrosine,andithasrecentlybeenreportedthatnitrotyrosineisanindependentpredictorofCVD.

However,dyslipidemiaalsoisarecognizedriskfactorforCVDin diabetes, and postprandial hyperlipidemia contributes tothis risk. Innonobese type2diabeticpatientswithmoderate

fastinghypertriglyceridemia,theatherogeniclipoproteinprofileis amplified in thepostprandial state.Suchobservationshaveraised the question of whether postprandial hyperlipidemia,whichrisesconcomitantlywithpostprandialhyperglycemia,isthetrueriskfactor.However,evidencesuggeststhatpostprandialhypertriglyceridemiaandhyperglycemiaindependentlyinduceendothelial dysfunction through oxidative stress. It is nowwellrecognizedthatendothelialdysfunctionisoneofthefirststages, andoneof the earliestmarkers, in thedevelopmentofCVD. Endothelial function is altered early in diabetes. It hasbeen demonstrated that in diabetic subjects, the vasodilatingresponse to stimuli is diminished and that this anomaly isrelated to glycemic control. This effect of hyperglycemia isprobably linked with a reduced production/bioavailability ofNO, since hyperglycemia-induced endothelial dysfunction iscounterbalancedbyarginine.Furthermore,itisveryinterestingthat a rapid decrease of flow-mediated vasodilation has beenshowninthepostprandialphaseintype2diabeticpatientsandthat the decrease correlated inversely with the magnitude ofpostprandialhyperglyemia.

The possible role of hyperglycemia in the activation of bloodcoagulationindicatesthatacuteglycemicvariationsarematchedwithaseriesofalterationsofcoagulationthatarelikelytocauseathrombosis.

MANAGEMENT OPTIONSDiet and ExerciseDietary counseling, regular physical exercise, and weight losshave been recommended for all patients with diabetes. Thetotalamountandnature(composition,portionsize,preparationmethod,consumption,anddigestionrate)ofthecarbohydratesconsumedareallimportantdeterminantsofPPGlevels,andlowcarbohydrate/lowglycemicindexdietscanbluntPPHG,atleastintheshort-term.


With Best Complements From

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Medications

Strategy Therapy

Delayappearanceofglucose LowGIfoods,Glucosidaseinhibitors,GLP,Amylin

IncreaseearlyPPinsulinlevel

Insulinanalogue,Inhaledinsulin

Improvemealrelatedinsulinsecretion

GlucosePotentiators-Replaglinide,GLP-1

Inhibitglucagons

InhibitPPgluconeogenesis

Glucagonantagonists,GLP-1Metformin

Improveinsulinaction InsulinSensitizers

Thecombinationofmedicationstotreatormodifypostprandialhyperglycemia include agents that specifically target PPHG,including a-glucosidase inhibitors, short-acting insulinotropicagents, amylin analogues, glucagon-like peptide-1 (GLP-1)analogues, dipeptidyl peptidase-IV (DPP-IV) inhibitors, andrapid-actinginsulinanalogues.

a-Glucosidaseinhibitorssuchasacarbose,miglitolandvogliboseinhibitintestinaltracta-glucosidasesandpancreatica-amylase.AlthoughmonotherapywiththeseagentsreducesoverallHbA1cvalues less than sulfonylureas or metformin, these are usefulwhen PPHG is difficult to control. Short-acting insulinotropicagents, including repaglinideandnateglinide,dissociate fasterfrom their receptors than the sulfonylureas, mitigating thepotential for delayed hypoglycemia although having a similaroverall incidence of hypoglycemia. Rapid-acting insulinanaloguessuchasinsulinlisprooraspartareabsorbedquicklybuthaveashorterdurationofactionthanthatofregularhumaninsulin. When taken just prior to meals, they target PPHG.Pramlintide,ananalogueoftheglucoregulatorypeptideamylin,whichisdeficientorsuppressedinpatientswithdiabetes,lowers

postprandialglucoseexcursionsandHbA1cvalues.TheGLP-1analogueexenatide,whichhasalongerdurationofactionthanthatofnaturallyoccurringGLP-1,reducesFPGandPPGvalues,decreases appetite, and delays gastric emptying. The DPP-IVinhibitorsitagliptindelaysthedegradationofendogenousGLP-1,lowersHbA1cvalues,andhelpsimproveglycemiccontrol.

ConclusionEvidence accumulates suggesting that postprandial excursionsofbloodglucosemaybeinvolvedinthedevelopmentofdiabetescomplications, particularly (but not only) cardiovascularcomplications.

However, many questions remain unanswered regarding thedefinitionofpostprandialglucoseand,perhapsmostimportantly,whether postprandial hyperglycemia has a unique role in thepathogenesisofdiabeticvascularcomplicationsandshouldbeaspecifictargetoftherapy.

However, this alarmingly suggestive body of evidence for aharmful effect of postprandial hyperglycemia on diabetescomplications has been sufficient to influence guidelinesfrom key professional bodies, including the World HealthOrganization,theAmericanDiabetesAssociation,theAmericanCollegeofEndocrinology,theInternationalDiabetesFederation,theCanadianDiabetesAssociation,and,morerecently,a largetaskforceofEuropeanscientificsocietiesfocusedonCVD.

Therefore,therealquestionseemstobe,asrecentlyunderlinedalsobytheAmericanDiabetesAssociation,“becauseCVDisthemajorcauseofmorbidityandmortalityinpatientswithdiabetes,andin type2diabetes inparticular,understandingthe impacton CVD events of treatment directed at specifically loweringpostprandial glucose is crucial.” To address this fundamentalquestion,futurestudiesmustbespecificallydesignedtoevaluatethisnewissue,whichmaysignificantlychangethetherapeuticapproachtodiabetes.


Reading List 1. Alberti KGMM, Gries FA: Management of non-insulin-

dependentdiabetesmellitusinEurope:aconsensusview.DiabetMed5:275281,1988

2. American College of Endocrinology: American Collegeof Endocrinology consensus statement on guidelines forglycemiccontrol.EndocrPract8:511,2002

3. AmericanDiabetesAssociation:Postprandialbloodglucose(Review).DiabetesCare24:775778,2001

4. AmericanDiabetesAssociation:Standardsofmedicalcareindiabetes(PositionStatement).DiabetesCare27(Suppl.1):S15S35,2004

5. BalkauB,ShipleyM,JarrettRJ,PyöräläK,PyöräläM,ForhanA,EschwègeE:Highbloodglucoseconcentrationisariskfactor for mortality in middle-aged nondiabetic men: 20-yearfollow-upintheWhitehallStudy,theParisProspectiveStudy, and the Helsinki Policemen Study. Diabetes Care21:360367,1998

6. BeckmanJS,KoppenolWH:Nitricoxide,superoxide,andperoxynitrite:thegood,thebad,andugly.AmJPhysiol271:C1424C1437,1996

7. Bonora E, Muggeo M: Postprandial blood glucose as arisk factor for cardiovascular disease in type II diabetes:the epidemiological evidence. Diabetologia 44:2107 2114,2001

8. Brownlee M: Biochemistry and molecular cell biology ofdiabeticcomplications.Nature414:813820,2001

9. CanadianDiabetesAssociationClinicalPracticeGuidelinesExpert Committee: Canadian Diabetes Association2003 clinical practice guidelines for the prevention andmanagementofdiabetesinCanada.CanJDiabetes27(Suppl.2):1163,2003

10. CerielloA,BortolottiN,MotzE,PieriC,MarraM,TonuttiL, Lizzio S, Feletto F, Catone B, Taboga C: Meal-inducedoxidative stress and low-density lipoprotein oxidation indiabetes: the possible role of hyperglycemia. Metabolism48:15031508,1999

11. CerielloA,GiacomelloR,StelG,MotzE,TabogaC,TonuttiL, Pirisi M, Falleti E, Bartoli E: Hyperglycemia-inducedthrombin formation in diabetes: the possible role of theoxidativestress.Diabetes44:924928,1995

12. Ceriello A, Quagliaro L, Catone B, Pascon R, PiazzolaM,BaisB,MarraG,TonuttiL,TabogaC,MotzE:Roleofhyperglycemia in nitrotyrosine postprandial generation.DiabetesCare25:14391443,2002

13. CerielloA,TabogaC,TonuttiL,GiacomelloR,StelG,MotzE, Pirisi M: Post-meal coagulation activation in diabetesmellitus: the effect of acarbose. Diabetologia 39:469 473,1996

14. Ceriello A: Coagulation activation in diabetes mellitus:the role of hyperglycaemia and therapeutic prospects.Diabetologia36:11191125,1993

15. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A,LaaksoM,theSTOP-NIDDMTrailResearchGroup:Acarboseforpreventionoftype2diabetesmellitus:theSTOP-NIDDMrandomisedtrial.Lancet359:20722077,2002

16. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A,LaaksoM,theSTOP-NIDDMTrialResearchGroup:Acarbosetreatment and the risk of cardiovascular disease andhypertensioninpatientswithimpairedglucosetolerance:theSTOP-NIDDMtrial.JAMA290:486494,2003

17. DeBackerG,AmbrosioniE,Borch-JohnsenK,BrotonsC,CifkovaR,DallongevilleJ,EbrahimS,FaergemanO,GrahamI,ManciaG,MangerCatsV,Orth-GomerK,PerkJ,PyoralaK,RodicioJL,SansS,SansoyV,SechtemU,SilberS,ThomsenT,WoodD,theThirdJointTaskForceofEuropeanandOtherSocietiesonCardiovascularDiseasePreventioninClinical

Practice: European guidelines on cardiovascular diseaseprevention in clinical practice. Eur Heart J 24:16011610,2003

18. de Vegt F, Dekker JM, Ruhè HG, Stehouwer CDA, NijpelsGBLM, Heine RJ: Hyperglycaemia is associated with all-causeandcardiovascularmortalityintheHoornpopulation:theHoornStudy.Diabetologia42:926931,1999

19. DonahueRP,AbbottRD,ReedDM,YanoK:Postchallengeglucose concentration and coronary heart disease in menof Japanese ancestry: Honolulu Heart Program. Diabetes36:689692,1987

20. EdelmanSV,WeyerC.Unresolvedchallengeswithinsulintherapyintype1andtype2diabetes:potentialbenefitofreplacingamylin,asecondß-cellhormone.DiabetesTechnolTher2002;4:175-89.

21. GallwitzB.Glucagon-likepeptide-1asa treatmentoptionfortype2diabetesanditsroleinrestoringbeta-cellmass.DiabetesTechnolTher2005;7:651-57.

22. Gerich JE. Clinical significance, pathogenesis, andmanagement of postprandial hyperglycemia. Arch InternMed2003;163:1306-16.

23. Jones RL, Peterson CM: Reduced fibrinogen survival indiabetes mellitus a reversible phenomenon. J Clin Invest63:485493,1979

24. Jones RL: Fibrinopeptide A in diabetes mellitus: relationto levels of blood glucose, fibrinogen disappearance, andhemodynamicchanges.Diabetes34:836841,1985

25. KannelWB,McGeeDL:Diabetesandcardiovasculardiseases:theFraminghamStudy.JAMA241:20352038,1979

26. LaaksoM:Hyperglycemiaandcardiovasculardiseaseintype2diabetes.Diabetes48:937-942,1999

27. LoweLP,LiuK,GreenlandP,MetzgerBE,DyerAR,StamlerJ: Diabetes, asymptomatic hyperglycemia, and 22-yearmortality in black and white men: the Chicago HeartAssociation Detection Project in Industry study. DiabetesCare20:163169,1997.

28. RisticS,ByiersS,FoleyJ,HolmesD.Improvedglycaemiccontrol with dipeptidyl peptidase-4 inhibition in patientswithtype2diabetes:vildagliptin(LAF237)doseresponse.DiabetesObesMetab2005;7:692-98.

29. Stratton IM, Adler AI, Neil HAW, Matthews DR, ManleySE, Cull CA, Hadden D, Turner RC, Holman RR, the UKProspectiveDiabetesStudyGroup:Associationofglycaemiawithmacrovascularandmicrovascularcomplicationsoftype 2 diabetes (UKPDS 35): Prospective observationalstudy.BMJ321:405412,2000

30. Temelkova-KurktschievTS,KoehlerC,SchaperF,LeonhardtW, Henkel H, Hanefeld M: Postchallenge plasma glucoseand glycemic spikes are more strongly associated withatherosclerosis than fasting glucose and HbA1c level.DiabetesCare23:18301834,2000

31. The DECODE Study Group, the European DiabetesEpidemiology Group: Glucose tolerance and mortality:comparison of WHO and American Diabetes Associationdiagnosticcriteria.Lancet354:617621,1999

32. UK Prospective Diabetes Study Group: Intensive blood-glucose controlwith sulphonylureasor insulincomparedwith conventional treatment and riskof complications inpatientswithtype2diabetes(UKPDS33).Lancet352:837853,1998

33. Van Gaal LF, De Leeuw IH. Rationale and options forcombination therapy in the treatment of type 2 diabetes.Diabetologia2003;46(suppl1):M44-M50.

34. World Health Organization: Definition, Diagnosis andClassification of Diabetes Mellitus and Its Complications.Part 1: Diagnosis and Classification of Diabetes Mellitus.Geneva,WorldHealthOrg.1999


Atul GandotraGM-MarketingandBusinessDevelopmentPushpanjaliHealthCare

The Evolving Role of theFamily Physician and Family Medicine

Atul Gandotra

ThefamilyPhysicianisthefirstpointofcontactinamajorityofsituations,andoftenfunctionsas patient’s primary means of entry into thehealthcaresystem.TheretheFamilyPhysicianneedstodevelopaspecialrelationandbondingwiththepatientandtheirfamilymembers.Thisbondalsoacknowledgesthemanyrolesplayedby the doctor as he or she not only treats thepatientbutisareferralpoint,ahealtheducatorand a guide on general health and hygienerelatedneedsofthesociety/community.

Ontheprofessionalfront,thefamilyPhysicianis an advocate in dealing with other medicalprofessionals/Institutes/Hospitalsetcforhispatients.

For a family Physician, family Medicine isunique at it centers round patient - physician

relationship with the patient viewed in thecontextof the family. It is theextentofwhichthisrelationshipisvalued,developed,nurturedand maintained that distinguishes familymedicine fromallother specialtiesand familyphysicianfromallotherspecialists.

The scope of an individual family physician’spractice changes over time, evolving ascompetency in current skills is maintainedand new knowledge is obtained throughcontinuing medical education. this growth inmedicalinformationalsoconfersonthefamilyphysicianaresponsibilityfortheassessmentofnew medical technology and for participationinresolvingethicaldilemmasbroughtaboutbythetechnologicaladvances.

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S. K. WangnooSenior Consultant EndocrinologistApolloCentreforObesity,Diabetes&Endocrinology(ACODE)IndraprasthaApolloHospital,NewDelhi

Tarunika BawaClinical AssistantApolloCentreforObesity,Diabetes&Endocrinology(ACODE)IndraprasthaApolloHospital,NewDelhi

Insulins in Clinical Practice – An Overview

S. K. Wangnoo1 and Tarunika Bawa2

The Diabetes Control and ComplicationsTrial1providedconclusiveevidencethatstrictglycemic control reduces the incidence andprogression of neuropathy, nephropathy, andretinopathy in patients with type 1 diabetes.DatafromtheWisconsinEpidemiologicStudy,theUKProspectiveDiabetesStudy(UKPDS)2,andseveralothertrialshavesuggestedastrongcorrelation between glycemic control andcomplicationsinpatientswithtype2diabetes.In addition, the UKPDS put to reast concernsaboutthepotentialescalationofatherosclerosiswiththeuseofinsulinorsulfonylureas.

Fortunately, as our understanding of theimportanceofstrictglycemiccontrolhascomeinto focus,ourability toachieve thisgoalhasimproved. Much of this newfound ability toobtain a level close to the euglycemic indexin patients with diabetes can be attributed tonovel insulin molecules that scientists havesynthesizedinthepastdecade.

Research in the insulin arena has focused onnew formulations, novel insulin molecules,and various methods of insulin delivery thatmore closely approximate normal physiologicinsulin response than conventionalpreparations. Insulin therapy evolved fromthe use of crude animal extracts availableshortly after the discovery of insulin in 1922by Frederick Banting and Charles Best tonew formulations developed in the 1930s,1940s, and 1950s. More purified productswere developed in the 1960s, followed byrecombinant human insulin in the 1980s andinsulinanalogues in the1990s.Today, insulintherapy holds the promise that non-injectiondeliverymethodswillbecomeavailable in thenear future. The evolution of insulin therapyalready has produced more effective deliverymethodsforbetterglycemiccontrolwithfewersideeffects.

Conventional insulin preparations havepharmacokinetic profiles that do not closelyimitate normal insulin secretory patterns. Bycomparison, the pharmacokinetic profiles oftheinsulinanaloguesareabletocloselymimicthese patterns with an exogenous insulinproduct. The first recombinant DNA humaninsulin analogue, insulin lispro (Humalog),was approved in July 1996 by the US Foodand Drug Administration (FDA). Since then,two additional analogues, insulin glargine(Lantus) and insulin aspart (NovoLog), havebeen approved. Other insulin analogues anddeliverysystemsarebeingevaluated.

Historic Achievements in Insulin Therapy OnJanuary11,1922,14-year-old,65-lbLeonardThompson became the first patient to receiveinsulin3 . His blood glucose level fell slightlywith each 15-mL injection and an abscessdeveloped at the site of one injection. Theextraction process was improved, and insulinwas soon commercially available. The 1923Nobel Prize in Medicine was awarded to SirFredrick Grant Banting and John MacLeod atthe University of Toronto for the discovery ofinsulin.

Thefirstcommercialinsulinpreparation,Iletin,was relatively fast-acting, and administrationduring the middle of the night often wasrequired4 . Because of these limitations, asearch for new insulin formulations withdiffering time-action profiles was launched.The first long-acting insulin, protaminezinc insulin, was introduced in the 1930s.This formulation contained insulin, theprotein protamine, and zinc. NPH insulin, anintermediate-acting formulation containingstoichiometric quantities of protamine andzinc, was introduced in the 1940s. The lenteseries,includingsemilente,lente,andultralentepreparations, was introduced in the 1950s;these formulations containedvarious amountsof zinc. Advances in chromatography in the1960sand1970sledtotheproductionofmorehighlypurifiedinsulins.

In the 1980s, human insulin became the firstpharmaceutical agent to be produced throughrecombinant DNA technology. Limitations inthetime-actionprofilesofconventionalinsulinsprompted the search for insulin analogueswith profiles that more closely approximatednormal physiologic insulin secretory patterns.Todate,morethan300insulinanalogueshavebeen produced4, and three are commerciallyavailable.Becauseofthesearchforalternativedelivery methods, pulmonary, buccal, andperhaps even transdermal insulin deliverysystemsareonthehorizon.

Normal Insulin Secretion Inthepast,oneofthesignificantproblemswithinsulintherapywastheinabilitytomimicnormalinsulinsecretoryresponsewithsubcutaneouslyinjected conventional exogenous insulins.Normal endogenous insulin secretion can beclassifiedasbasalorpostprandial.Basalinsulinsecretion is responsible for the maintenanceof basal glucose homeostasis. Basal insulin


alsogovernstherateofhepaticglucoseproduction,precludingthe overproduction of glucose through gluconeogenesis andglycogenolysisinhealthypersonswithoutdiabetes.

Basalinsulinissecretedatavaryingrateofabout0.5to1U/hrin adults without diabetes5. This secretion maintains serumconcentrations at 5 to 15 microunits/mL (36 to 108 pmol/L)4.Secretion occurs continuously between meals and throughoutthenight.Insulinregimensthatusedintermediate-actingorlong-actinginsulininanattempttomimicthisbasalsecretorypatternhavebeensupersededbythebasalinsulinanalogueglargine.

Postprandial,orstimulated,insulinsecretionoccursinresponsetoamealor snackand results in insulinconcentrationsof60to80microunits/mL(430to574pmol/L)justbeforeamealandupto30minutesafterit.Insulinconcentrationsreturntobasallevelsquickly(within2to4hours)4.Themonomericanalogues,lispro and aspart, more closely approximate this pattern thanregularhumaninsulin.

Problems with Conventional Insulin The goal of exogenous insulin regimens in patients withdiabetes is to provide physiologically correct insulin profiles.However,wheninjectedsubcutaneously,commerciallypreparedconventional insulin formulations have time-action profilesthat do not closely approximatea normal physiologic insulinsecretion

So-called rapid-acting regular human insulin has an onset ofactivityfromahalfhourtoanhourafterinjection,maynotreachpeakconcentrationfor4hours,andhasadurationofactionofupto8hours4.Regularhumaninsulinhasastrongaffinityforself-association.Thus,thehexamericform(eightcloselyboundmolecules) is themostprevalent form in a solutionof regularhumaninsulin.Tobeabsorbed,thehexamermustdissociatetoadimerandfurtherdissociatetoamonomer6.Themonomericformcanthenbeabsorbedintothecapillarybedssurroundingthesubcutaneousreservoir.Therate-limitingstepintheabsorptionofregularinsulinisdissociationtothemonomericform.

Thepharmacokineticandpharmacodynamicprofilesofregularhuman insulin present several problems for the patient. First,regular human insulin is inconvenient to use because thepatientmustcarefullytimetheinsulininjectionto30minutesormorebeforeameal.Second,between-mealhypoglycemiacanbeaproblemwithregularhumaninsulin,becausealthoughitsometimesreachespeakconcentrations2hoursafterinjection,inmanycasesanddependingonthedoseitmaynotpeakfor4to6hoursaftertheinjection,whenglucoselevelsalreadymaybelow.

The so-called intermediate-acting human insulin, NPH andlente, yield peak concentrations 4 to 10 hours after injection.Theeffectivedurationofactionoftheseinsulinis10to20hours.Whenusedasbasal insulin, theseproductspresent twomajorproblems:theyhaveadefinitepeakeffect,andtheirdurationofactionnecessitatesmorethanonedailyinjection.Lastly,humanultralente has an effective duration of 16 to 20 hours. It alsopresentsseveralproblemswhenusedasabasal insulin7 : (1)its onset of action is variable, (2) its peak effect is difficult topredict,and(3)itsdurationofactionisalmostalwayslessthan24hours.

Rapid-acting AnaloguesBecause of the previously mentioned problems withthe pharmacokinetic and pharmacodynamic profiles ofsubcutaneously administered regular human insulin, rapid-

actinginsulinanalogueshavebeensoughtafter.Theidealshort-actinginsulinanalogueormonomericinsulinwouldhaveatime-actionprofilewithanonsetoflessthan1hour,adurationoflessthan4hours,andsimilareffects inallpatients4.Additionally,thehypoglycemicpotencyoftheanaloguewouldbeequaltoorgreater than that of human insulin. Lastly, the ideal analoguewould be non-immunogenic, chemically stable, and mixablewithotherinsulinsandanalogues.Tworapid-actinganalogues,lisproandaspart,areavailableintheUnitedStates.

Insulin LisproThepharmacologiceffectsoflisproarewellreviewed.TheaminoacidcompositionoflisproisidenticaltothatofhumaninsulinexceptthatthepositionsoftheaminoacidsatB28andB29arereversed.Lisprohas a rapidonset of action (15minutes), anditsactionpeaks in30 to60minutesand lastsabout3hours8.It has proved to be an effective and safe postprandial insulinanaloguewithatime-actionprofilethatcloselymimicsnormalpostprandialinsulinresponse.

A more recent insulin formulation contains 75% neutralprotaminelisproand25%lispro(HumalogMix75/25).Mixturesoflisproandintermediate-actinginsulinshaveprovedeffective;however, lispro reacts with isophane insulin over time. Inneutral protamine lispro, the lispro has been cocrystallizedwith protamine to yield an intermediate-acting formulationwith a time-action profile similar to that of isophane insulin.A recent comparative trial9 between Humalog Mix75/25 andhumaninsulin70/30showedthatHumalogMix75/25improvedpostprandialglycemiccontrolwithcomparableoverallcontrol.

Insulin AspartAspartwasapprovedbytheFDAinJune200010.Thisinsulinisidenticaltohumaninsulinexceptforthesubstitutionofasparticacid for proline at position B28. This rapid-acting insulinanaloguecontrolspostprandialglycemicexcursionssimilarlytolispro.

In a study comparing the pharmacokinetics andpharmacodynamics of aspart with regular human insulin11,aspart peaked earlier (52 minutes versus 145 minutes) with ahigher concentration (41 microunits/L versus 18 microunits/L[129pmol/L]),hadashortermeanresidencetime(149minutesversus 217 minutes), and had an earlier peak glycemic effect(94 minutes versus 226 minutes) than regular human insulin.Although some preliminary comparisons of aspart with lisprohave suggested that they are similar, others have reporteddifferences12. Therefore, it is premature to suggest that theseanaloguesareinterchangeable.

Basal Insulin Analogues Theidealbasalinsulinwouldhaveapeaklesseffect,alonghalf-life, once-daily dosing, and little interpatient or intrapatientvariability. The conventional long-acting and intermediate-acting insulins that have been used for basal control havepharmacokinetic profiles that make them difficult to use. Inaddition, they do not mimic normal basal insulin secretion.Finally, after many years of research, a true basal insulin hasbeenintroducedtothemarket:glargine.

Insulin GlargineThishuman insulinanalogue,producedby recombinantDNAtechnologythroughnonpathogenicEscherichiacoli,differsonlyslightlyinstructurefromhumaninsulin13.Glarginehasboth


References1 The effect of intensive treatment of diabetes on the

developmentandprogressionoflong-termcomplicationsininsulin-dependent diabetes mellitus. The Diabetes Controland Complications Trial Research Group. N Engl J Med1993;329(14):977-86

2 Intensive blood-glucose control with sulphonylureas orinsulin compared with conventional treatment and risk ofcomplicationsinpatientswithtype2diabetes(UKPDS33).UK Prospective Diabetes Study (UKPDS) Group. Lancet1998;352(9131):837-53

3 Bliss M. The discovery of insulin. Chicago: University ofChicagoPress,1982:112-3

4 White JR Jr, Campbell RK, Hirsch I. Insulin analogues:new agents for improving glycemic control. Postgrad Med1997;101(2):58-70

5 SetterS,WhiteJ,CampbellRK.Diabetesmellitus.In:HerfindalT,GourleyD,eds.Textbookoftherapeutics:druganddiseasemanagement. 7th ed. Philadelphia: Lippincott Williams &Wilkins,2000:377-406

6 BrangeJ,OwensDR,KangS,etal.Monomericinsulinsandtheir experimental and clinical implications. Diabetes Care1990;13(9):923-54

7 Scholtz HE, et al. (Abstr) Diabetologia 1999;42 (Suppl 1):A235

8 CampbellRK,WhiteJRJr.Insulintherapyintype2diabetes.JAmPharmAssoc(Wash)2002;42(4):602-11

9 Roach P, Yue L, Arora V. Improved postprandial glycemiccontrolwithHumalogMix25,anovelprotamine-basedinsulinlispro formulation. Humalog Mix25 Study Group. DiabetesCare1999;22(8):1258-61

10 Setter SM, Corbett CF, Campbell RK, et al. Insulin aspart:a new rapid-acting insulin analog. Ann Pharmacother2000:34(12):1423-31

11 Home PD, Barriocanal L, Lindholm A. Comparativepharmacokineticsandpharmacodynamicsofthenovelrapid-actinginsulinanalogue,insulinaspart,inhealthyvolunteers.EurJClinPharmacol1999;55(3):199-203

12 ChapmanTM,NobleS,GoaKL.Insulinaspart:areviewofitsuseinthemanagementoftype1and2diabetesmellitus.Drugs2002;62(13):1945-81

13 LevienTL,BakerDE,WhiteJRJr,etal.Insulinglargine:anewbasalinsulin.AnnPharmcother2002;36(6):1019-27

14 Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnalhypoglycemia and better post-dinner glucose control withbedtimeglarginecomparedwithbedtimeNPHinsulinduringinsulincombinationtherapyintype2diabetes.DiabetesCare2000;23(8):1130-6

15 RosenstockJ,RiddleM,DaileyG,etal.Treatmenttotarget:feasibility of achieving control with the addition of basalbedtimeinsulinglargine(Lantus)orNPHinsulinininsulin-naivepatientswithtype2diabetesonoralagents.HOE901/4002StudyGroup.(Abstr)Diabetes2001;50(Suppl2):A129

16 VagueP,SelamJL,SkeieS,etal.Insulindetemirisassociatedwithamorepredictableglycemiccontroland lowerriskofhypoglycemiacomparedtoNPHinsulininsubjectswithtype1diabetes.(Abstr)Diabetes2002;51(Suppl23):A116

17 JacobsonLV,PopescuG,PlumA.Pharmacokineticsofinsulindetemirinpatientswithrenalorhepaticimpairment.(Abstr)Diabetes2002;51(Suppl23):A102

18 Pieber TR, Plank J, Goerzer E, et al. Duration of action,pharmacodynamic profile and between-subject variabilityof insulindetemir in subjectswith type1diabetes. (Abstr)Diabetes2002;51(Suppl23):A214

theadditionof twoargininesat theCterminusof theBchainand thesubstitutionofglycine forasparagineatpositionA21.ThisslightchangeinstructureyieldsamoleculethatissolubleatapHof4buthasarelativelyslowsolubilitywheninjectedinto a neutral pH environment. When glargine is injected,microprecipitates form,andslowly the insulin is resolubilizedand absorbed. This sequence of changes is predictable andprovidesarelativelyconstantlevelofinsulinwithnodiscerniblepeaksoveraperiodof24hours.

Aplethoraoftrialshavedemonstratedtheeffectivenessandsafetyofglargineinpatientswithtype1ortype2diabetes.Somestudieshavesuggestedthatglargineisassociatedwithlesshypoglycemiathan NPH insulin.14,15 These studies concluded that insulinglarginegivenoncedailyisaseffectiveasoneinjectionofNPHinsulin in its effectonglycemiccontrol, andglargine resultedinbetterpredinnerglucoselevelsinonetrial.Thestudiesalsoconcluded that patients who received glargine experienced astatistically significant reduction in nocturnal hypoglycemiacomparedwithpatientswhoreceivedNPHinsulin.

Glargine offers a reasonable alternative to other long-acting orintermediate-acting insulins for introducing insulin therapy topatientswith type2diabeteswhowerepreviously takingoralantidiabetic agents. It also offers a reasonable alternative forpatientswithtype2diabeteswhouseoneortwoinjectionsofNPHinsulinincombinationwitheitheroralagentsorrapid-actinginsulins.Lastly,glargineiseffectiveasabasalinsulinwhenusedwithrapid-actinginsulinsinpatientswithtype1diabetes.

Insulin DetemirDetemir,anotherlong-actinginsulinanalogue,iscurrentlybeinginvestigated.Thiscompoundisasolublebasalinsulinanaloguewith a neutral pH and a unique mechanism for providing asmooth, prolonged time-action profile16 . Detemir apparentlyhas a high affinity for serum albumin, and its binding mayaccountfortheprotractedaction17.

However, on the basis of limited data, it appears that detemirmaynothaveadurationof action toallowonce-dailydosing.One report18 stated that at therapeutically relevantdoses, theanalogue’sdurationofactionisonly20hours.Thiscouldmeanthattoachievearound-the-clockbasalcoverage,twoinjectionsper day would be required. Interestingly, at least one study18hassuggestedthatdetemirhasagreatereffectonhepaticglucoseproductionandalessereffectonperipheralglucoseutilizationthanNPHinsulininpatientswithtype1diabetes.Ifthiseffectissignificantinpatientswithtype2diabetes,detemirmayofferaperquisitenotfoundinotherinsulins.

Conclusion A large body of evidence has proven conclusively thatstrict glycemic control in patients with diabetes reduces theappearance and progression of chronic complications. Strictglycemic control without significant hypoglycemia is themost salient goal of insulin therapy.Toachieve thisobjective,insulin regimens that closely mimic physiologic insulinsecretorypatternsmustbeused.Theolderconventionalinsulinproducts do not have time-action profiles that closely mimicnormalsecretorypatterns;therefore,alloftheseproductshaveproblemsassociatedwiththeiruse.Insulinanalogueswithmoreappropriate pharmacokinetic and pharmacodynamic profiles,bothrapid-acting(postprandial)andlong-acting(basal),arenowavailable.Threeoftheseanalogues-lispro,aspart,andglargine-havebeenwidelystudied,andothersareintheearlystagesofdevelopment.Theseanaloguesofferthephysiciantheabilityto

closelyapproximateendogenousinsulinsecretorypatternswithsubcutaneouslyinjectedexogenousinsulin,improvingglycemiccontrolwithlesshypoglycemia.


Neeru GeraSenior ConsultantEndocrinologistMaxHospitalDelhi.

Monitoring of Glycaemic Status

Neeru Gera

The two large randomized trials DCCTand UKPDS have clearly established therelationship between glycemic control anddiabetic complications. Further, it was alsoestablishedthatthereisnoglycemicthresholdabove normal glycemia for complicationstoset in.

Achievingglycemiccontrolmeansknowingthetargets and accordingly planning the line oftreatment. Glycemic targets are assessed bymeasurementofbloodsugarsandglycosylatedhemoglobin(HbA1c).Assupportedbydifferentstudies one needs to maintain fasting plasmaglucose between 80-100 mg/dl, 2-hour postmeals(allmeals)<140-150andpre-meals90-130 mg/dl and HbA1c < 6.5-7 %. However,thesegeneraltargetsneedtobeindividualizedbasedontheseverityofdiabeticcomplications,frequency of hypoglycemia includinghypoglycemic coma, fertility issues, pre-pregnancy, antenatal, age, co morbid medicalproblems, life expectancy, etc. Specialconsiderationsneedtobegivenwhilemanagingchildren,pregnantwomenandelderly.Further,targets can be subdivided as short term(temporary)andlongterm(theultimate).

Several aspects need to be considered formonitoring likemodeof treatment (dietalone,OHAs,insulin),laboratoryorhomeglucometer,frequency, adjustment of dosages, dietary/exercise schedules and time frame to achievethe targets.Apatienton lifestylemanagementalone needs to achieve and maintain thesame strict targets as a patient on Insulin.The frequency of monitoring may howeverdiffer. On diet alone, it is still reasonable tomonitor blood sugars once in two weeks. OnOHAs, once a week monitoring till targets areachieved, is highly suggested and thereaftercan be less frequent, say, once in 10-14 days.If glycemic control rises beyond the targetlevelsthenmonitoringneedstobeintensified.Patients on insulin must be monitored morefrequently, daily to once in three days andoptimally two to three times a day. Type 1diabetics and pregnant women need to checklevelsthreeormoretimesdaily.Itispreferabletocontrolpremealrandombloodsugar (RBS)before targeting post meals. HbA1c, whichgives average glycemia in preceding two tothree months, should be assessed at first visitandtheneverythreemonths.Oncethepatientshows controlled glycemic status for severalmonths then A1c testing can be reduced toeverysixmonths.

Everypatientdemonstratestheirownglycemicpattern. Hence, it is necessary for the treatingphysician to understand this pattern, decidethe medications and subsequently monitoraccordingly.Further,thephysicianandpatienthave towork togetherasa team.Bothhave tohave a proactive approach, high motivationlevel, patience and an interactive dialogue.The physician must spend time with thepatient and their family to discuss the lineof treatment, practical ways to achieve targetsandthe timeframeof reaching the target.

Education is the key to diabetic management.Special situations need to be addressed. Inaddition to a regular schedule, patients needto be educated about days of sickness, travel,eatingoutetc.Acutesicknessleadstoabrittlestate, prone for both hyper (due to insulinresistance of stress) and hypoglycemia (lowappetite/vomiting etc).Under these conditionsit becomes important to check blood sugarsthree to four times-a-day daily random ratherthan for strict2-hourPPBS.The target shouldstill be to keep all random checks less than180-200 mg/dl. This requires frequent contactwiththedoctorandmodificationofdosagesofinsulin/OHAs.Encouragepatients to eat everytwo to three hours like fruits/biscuits/curd/milk/bread/rice/cereal etc. Any hypoglycemicepisodemandates frequentmonitoringat leastfor that day. After correcting hypoglycemia, arecheckofbloodsugarsafterhalfanhourandagain two to three hours later must be done.This is to ensure that the acute episode hasbeencorrectedwithno furtherrecurrence.

During traveling days, patients need to beencouraged to check blood sugars but as pertheir convenience. The most practical timeis to check fasting sugar before dinner, ifpossible. Patients on insulin must check dailyandthoseonOHAatleasttwiceaweek.Whentraveling for longer periods, dosages need tobe adjusted without waiting to return. Thus,before traveling the patient must be educatedaboutselfadjustmentof insulin/OHAdoses.

Eating out may also lead to fluctuating bloodsugars if the meal is very different fromthe ones eaten usually. Patients should beencouraged to consult a dietitian to learnabout exchange diets minimize fluctuations.Blood sugars must be tested two hours afterthat meal or immediately after reachinghome.Fasting sugar must alsobe checked thefollowing morning. Based on this informationfuture adjustment in medication dosages


can be easily made. It is easier to titrate doses if a patientis on insulin. Insulin doses must be adjusted beforehand inanticipation of the fluctuation it may induce; blood sugarsmustbecheckedin themanneroutlinedabove.

As already highlighted, monitoring can be routinely carriedout from a lab or self glucometer. Since blood sugars need tobemonitoredatdifferenttimesofdayandatregularintervals,patients should be encouraged to own a personal glucometer.However,certainprecautionsneedtobetakenwhenoperatingit.Theglucometermustbecalibratedwiththecontrolsolutionandvenousplasmaglucose,assesstechniqueandmaintenance.Meterreadingscanvaryfromlabby+/-15%infastingstate.Despite limitations SMBGs help in revealing the glycemictrend. The key to management of diabetes is to know one’sown glycemic profile, since further therapy is based on thisbasic information.

It is imperative to extend the outcome of research studiesto practical use. Physicians need to know the implications

of intensive glycemic control, how to achieve them in themost practical way and then the way forward. One mustindividualize the targets. Mere achievement of targets is notenough;therealpracticalchallengeistomaintainthemoveralongerperiodof time.Goodcommunication,a teamapproach,self motivation and periodic assessment of patient’s healthstatuswill result inastutediabeticmanagement.

References

1. AmericanDiabetesAssociationPositionStatement:StandardsofmedicalcareinDiabetesDiabetesCare30,S4-S41,2007

2. American Diabetes Association: Position Statement:Implications of the United Kingdom Prospective DiabetesStudy.DiabetesCare25:S28-S32,2002


Garima S GuptaRegistrarApolloCentreforObesity,Diabetes&Endocrinology(ACODE)IndraprasthaApolloHospital,NewDelhi


Gestational Diabetes

Garima S Gupta1and Tarunika Bawa2

Pregnancy induces progressive change inmaternal carbohydrate metabolism. Aspregnancy advances insulin resistance anddiabetogenic stressdue toplacentalhormones(HPL,Progesterone, andEstrogen)necessitatescompensatory increase in insulin secretion.When this compensation is inadequategestationaldiabetes(GDM)develops.Pregnancythat occurs in a woman who already hasdiabetesistermedPregestationalDiabetes.Boththeseconditionsareassociatedwith increasedmaternal and fetal morbidity but rarely withmortality.

GDM is defined as any degree of glucoseintolerancewithonsetorfirstrecognitionduringpregnancy. This definition applies whetherinsulin or only diet modification is used fortreatmentandwhetherornotconditionpersistsafter pregnancy. The prevalence of GDM was2% in 19821 (IGT-2%)2 which increased to7.63% in 19913 (IGT 8.2%)4 and doubled to16.55%in20025(IGT-14.5%)6.

Who is At-Risk for GDM? The expert committee on diagnosis andclassification of diabetes has recommendedthatscreeningmaynotbenecessaryinwomenwhofulfillthecriteriagivenbelow7.

v Age<25years

v Weightnormalbeforepregnancy

v Member of an ethnic group with lowerprevalenceofGDM

v Noknowndiabeticsinfirstdegreerelatives

v Nohistoryofabnormalglucosetolerance

v Nohistoriesofpoorobstetricoutcome.

But in the Indian context, recognition ofglucose intolerance during pregnancy isperhaps more relevant as Indian woman havean 11-fold increase in the risk of developingGDM as compared to White Caucasianwomen8.

Asglucose is toxic to thedevelopingfetus,allpregnant women ideally should be screenedfor glucose intolerance. However, screening ismandatoryinhigh-riskpatientswhichincludethosewith:

v Age>25years

v Familyhistoryofdiabetes

v Obesity(pre-pregnancyweight(BMI>25)

v Badobstetrichistory

v Glucoseinsecondfastingurinesample.

The optimum period to screen for GDM inpregnancyisbetween24-28weeksbywhichtimeitmanifestsin75%ofwomanwhowilldevelopGDM.IfthereissuspicionofundiagnosedDMorpreextentDM,thenscreeningmaybedoneduringthefirstvisititself9.

Maternal Complication in GDM v Overtdiabetes

v Pre-eclampsia

v Abortions

v Traumaticdelivery

v Pretermlabor

v Toxemia

v RecurrentUTI

fetal Complication v Congenitalmalformation

v Birthasphyxia

v Macrosomia,hypoglycaemia

v Cardiomyopathy

v RDS

v Hypercalcemia

v Hyperbilirubinemia

v Polycythemia.

v Longtermeffects-Obesity,IGT,Diabetes.

ADA Recommendation: 2-step Approach7

An initial screening by measuring plasmaglucose 1 hr after 50 g of oral glucose load(Glucose challenge test) and perform adiagnostic OGT on that subset of womenexceedingtheglucosethresholdvaluesonGCTistheapproachofchoice.

Carpenter and Coustan Diagnostic Criteria (ADA has adopted this criteria) 10

100gOGTT 75gOGTT

Fasting 95mg/dl 95mg/dl

1hr 180 180

2hr 155 155

3hr 140

2 or > venous plasma concentration must bemetorexceededforpositivediagnosis.

WHO Criteria11

WHO recommends using a 75 gm OGTT(2 hours) with a threshold plasma glucose


concentrationof>140mgperdlat2hourssimilartothatofIGToutsidepregnancy.

This criterion is simple and cost effective and is practiced inmanycenters.

Monitoring Glycemic Control Thetightglycemiccontrolexpectedduringpregnancywarrantsintensivemonitoring.Urineglucosemonitoringisnotaccurateduetoalteredrenalthresholdduringpregnancy.Henceglucosemonitoring is the best method using instant blood glucosereflectance meters. HbA1c will indicate retrospective control,patients’ compliance and past performance. It is however notveryuseful forday-to-daymanagementofgestationaldiabetes.Frucostamine estimation would indicate glycemic control forpast2-3weeks.

fetal EvaluationMid Pregnancy

(1620weeks)todetectfetalanomalies

MSAFP

USG

FetalEcho

Late Pregnancy

(28weekstilldeliverytoassessfetalwellbeing)

Maternalassessmentoffetalactivity

Nonstresstest

Contractionstresstest

Fetalbiophysicalprofile

Ultrasonography

Lecithin-to-Sphingomyelin(L/S)ratio,lungprofile.

Management The important predictor of fetal outcome is to ensure thatglycemic control is attained immediately before and duringpregnancy. The plasma glucose level of the normal pregnantwomanis<90and120mg%respectivelyduringfastingandnon-fastingstates12.Hence,thebestfetaloutcomecanbeexpectedbymaintainingthemeanbloodglucoselevelofapproximately105mg%inpregnantwoman.

1) Medical Nutrition Therapy (MNT)

Theexpectedweightgainduringpregnancyis300-400gmperweek.Totalweightgainis10-12kgbyterm;hencemeanplanaimsateuglycemiaandprovidingadequatecalories tosustainnutritional levels for the mother and fetus by avoiding excessweight gain and post prandial glycemia. Calories requirementdepends on age, activity, pre-pregnancy weight and stage ofpregnancy.Ideallyanincrementof300kcalperdayabovethebasalrequirementisneeded13.Non-caloricsweetenersmaybeusedinmoderation.

2) Exercise13,14,15

The woman with pregnancy can use arm ergometery orundertake walks. Such a program results in lower levels ofglycemia. Exercise improves both hepatic glucose output andperipheralglucoseutilizationinoverweightpregnantdiabetics.DietandexercisemayobviatetheneedforinsulintreatmentinGDM.

3) ADA Recommendation - Insulin

If MNT fails to maintain the goal (fasting and pre-mealblood sugar 50-80 mg per dl and post prandial blood sugar<120mg per dl) then insulin may have to be used.16 Due todecrease in insulin sensitivity, the insulin requirement goesupespeciallyduring latterhalfofpregnancy.Therequirementmayrangefrom0.7unitsperkgperdayinfirst trimester to1unitper kgper day in3rd trimester. It is ideal to use Humaninsulin. Most experts now recommend lispro and Aspartinsulin foruse inpregnancy.

This recommendation follows the results of the largestrandomized controlled trials involving 322 pregnant womenwith type 1 DM over a period of >4 years. The trial revealedthat insulin Aspart significantly improves post prandialglycemic control in first and third trimester compared tothe improvement observed with human insulin. The risk ofmajor hypoglycemia was 28% lower for insulin Aspart thanhuman insulin17. The use of glargine in pregnancy is stillunresolved.

4) OHA’s in Pregnant Diabetics

The most important issues with the use of oral hypoglycemicagents (OHA) in pregnancy are placental transfer, resultanttetratogenecity, and congential anomalies18. Sulphonylureasinduce fetal hyperinsulinism and resulting macrosomia andneonatalhypoglycemia.FirmrecommendationsforuseofOHAinpregnancyare limitedbypaucityof level1evidence.

Towner et al in 199519 concluded that major neonatalmalformations were associated with high maternal HbA1Clevel at initial presentation. A retrospective study on 584women by Jacobson20 in 2005 comparing Glyburide withinsulin in 316 and 268 patients respectively observed nosignificantdifferenceinbirthweight,macrosomiaandcesareandelivery.HoweverneonatesborntomothersonGlyburidehadprolongedhyperbilirubinemiaandlongerNICUstay.

Metformincrossesplacentapartiallyinhumans21anddoesnotaltertheplacentalmetabolismofglucoseinmice22.Metforminhasbeenusedinpregnantdiabeticsduringfirsttrimesterwithfavorableoutcome23,butthesestudieshadsmallsamplesizesand were not well controlled21. It has been widely used fortreatment of insulin resistance associated with infertility andpolycysticovariansyndrome.

Alpha Glucosidase inhibitors and thiozolideneones haveconflicting results in safety of their usage in pregnancy.According to ADA (2006) Metformin, Acarbose and Glyburideare category B drugs and all other OHA’s are category Cdrugs24.OHA’sshouldgenerallybediscontinuedunlessexpertclinicalexplanationsorconsensus isavailable.

A study by Karlson and Kjellmen25 showed that perinatalmortality is proportional to maternal blood glucose levelduring last2weeksofpregnancy.

MBG Perinatal mortality

>150mg% 24%

100-150 15%

<100 4%

In GDM, the requirement of insulin will fall precipitouslyand no insulin may be required after expulsion of placenta.Gestational diabetic women require follow up and glucosetolerance test (GTT) after 6 weeks and thereafter at the 6th


month,andannuallytodeterminewhethertheglucosetolerancehasreturntonormal.Around25%ofwomandevelopedDMinlateryears.

These pregnancies must be classified as high risk andare to be taken special care of by a team consisting ofdiabetologist, obstetrician and neonatologist. A short termintensive care not only results in safe motherhood butalsogivesalongtermpayoffinprimarypreventionofobesity,IGTand diabetes in offspring as “Prevention starts before birth”.

Research Gaps v Determinewhichrecommendationproducebetterpregnancy

andlongtermoutcome.

v Examineutilizationofdifferentguidelinesamongprovidertypes.

v Examine barriers to compliance among woman withgestationaldiabetes.

v Researchwaystosupportandoptimizecompliance.

v Researchwaystosupportandoptimizecompliance.

References

1. AgarwalS,GuptaAN.Gestationdiabetes.JAssocPhysiciansIndia1982;30:203

2. RamachandranA,JaliMV,MohanWetaI.HighprevalenceofdiabetesinanurbanpopulationinsouthIndia.BMJ1988;297(6648):587-90.

3. Narendra J, Munichoodappa C. Prevalence of glucoseintoleranceduringpregnancy.IntJDiabDevCountries1991:11:2-4.

4. RamachandranA,SnehalathaC,DharmarajD,etal.Prevalenceof glucose intolerance in Asian Indians. Diabetes Care 1992;151348-55.

5. Seshiah V, Balaji V, Balaji MS et aI. Gestational diabetesmellitusVinIndia.JAssocPhysiciansIndia2004;52:707-11.

6. RamachandranA,SnehalathaC,KapurA,etal.ForthediabetesEpidemiologyStudyGroupinIndia(DESI).HighprevalenceofdiabetesandimpairedglucosetoleranceinIndia.

7. ADA.Clinicalpracticerecommendations2002.DiabetesCare.2002;25(Suppl1)

8. Domhost A, Paterson Cichols JS, Wadsworth J, Chiu DC,Elkeles RS. High prevalence of GDM in women from ethnicminoritygroups.DiabeticMed1992;9(9):820-2.

9. SeshiahV,CynthiaAlexandelajiV,etal.Glycemiccontrolfromearly weeks of gestation and pregnancy outcome. Diabetes2006;55(suppl1):A604).

10. ADA Clinical Practice Recommendations. Diabetes Care2006;29(supplement1):S28

11. WH0 study group prevention of diabetes mellitus - Geneva.WorldHealthOrg.1994.(Techreportseries844).

12. Jovanovic-PetersonL.TheDiagnosisandmanagementofgestationaldiabetesmellitus.ClinDiabetes1995;13:32.

13. PetersonLJ,PetersonCM.Pregnancy in thediabeticwoman.EndocrineandMetabClinNorthAmerica1992;21:433-54.

14. Kitzmiller JL,GavinLA,GinGO,etal.PreconceptualcareofdiabeticglycaemiccontrolpreventscongenitalIN’anomalies.JAMA1991;265:560-80.

15. ClappJF,RokeyR,TreadwayJL,etal.ExerciseinEdpregnancy.MedSciSportsExerc1992;24:5294:

16. Jovanovic L, Bevier WC, Peterson CM. The Santa Barbara@County Health Care Services Program: Birth weightchange I Q concomitant with screening for and treatment ofglucose - intoleranceofpregnancy:Apotential cost-effectiveintervention.AmJPerinatoI1997;14:221-8

17. HodM,VisserG,DammP,etal.Safetyandperinataloutcomein pregnancy: A randomized trial comparing insulin Aspartwith human insulin in 322 subjects with type 1 diabetes.AmericanDiabetesAssociation.Poster1805-P.Diabetes2006,JuneSupplement

18. PneeceR,JovanovicL.Newandfuturediabetestherapies:aretheysafeduringpregnancy.JMatrnFetalNeontalMed2002;12(6):365-75.

19. TownerD,KiosSL,LeungB,etal.Congenitalmalformationsin pregnancies complicated by Type- 2 DM. Diabetes Care1995;18:1446-51

20. GavinF,JacobsonMD,GladysA,etal.Comparisonofglyburideand insulin for the management of gestational diabetes in alargemanagedcareorganization.AmJObstetGynaecol2005;193:118-24.

21. Briggs CG, Freeman RK, Yaffe SJ. Drugs in pregnancy tolactation.5thed.WilliamsandWilkins,1998.

22. DennoKM,SadlerTW.Effects of thebiguanide classof oralhypoglycemicagentonmouseembryogenic.Teratology1994;49:389.

23. Elliot B, Langer 0, Schenker S, Johnson RF. Comparativeplacental transfer of OHA’s in humans. A model of humanplacentaldrugtransfer.AmJObstetGynaecol1994;171:653-60.

24. Coetzee EJ, Jackson WPU. Oral hypoglycemis in the firsttrimesterandfetaloutcome.SAfrMedJ1984;65:635-7

25. Karlsson K, Kjellmer I. The outcome of diabetic pregnanciesinrelationshiptothemother’sbloodsugarlevel.AmJObstetGynaecol1972;112:213-20.

Healthiscertainlymorevaluablethanmoney,becauseitisbyhealththatmoneyisprocured;

butthousandsandmillionsareofsmallavailtoalleviatethetorturesofthegouttorepair

thebrokenorgansofsense,orresuscitatethepowersofdigestion.Povertyisindeed,anevil

fromwhichwenaturallyfly;butletusnotrunfromoneenemytoanother,nortakeshelter

inthearmsofsickness.

Johnson




Diabetic Dyslipidemia


IntroductionType 2 diabetes is associated with a two- tofour-fold excess risk of coronary heart disease(CHD)accordingtoATPIII/NANHES.Althoughthe degree of glycemia in diabetic patients isstrongly related to the risk of micro vascularcomplications (retinopathy and renal disease),the relation of glycemia to macro vasculardiseaseintype2diabetesismoremodest.Thefindingofincreasedcardiovascularriskfactorsbeforetheonsetoftype2diabetesalsosuggeststhataggressivescreeningfordiabetescombinedwithimprovedglycemiccontrolalonewillnotbe likely to completely eliminate excess riskof CHD in type 2 diabetic patients. Clearly, amultifactorial approach to prevention of CHDintype2diabeteswillbenecessary.

The most common pattern of dyslipidemia intype2diabeticpatientsiselevatedtriglyceridelevels and decreased HDL cholesterol levels.The concentration of LDL cholesterol in type2 diabetic patients is usually not significantlydifferent from nondiabetic individuals;however, LDL particles are smaller and moreatherogenic in type 2 diabetics. Diabeticpatientsmayhave elevated levels ofnon-HDLcholesterol(LDLplusVLDL).

Asinnondiabeticindividuals,lipidlevelsmaybe affected by factors unrelated to glycemiaor insulin resistance, such as renal disease,hypothyroidism, and the frequent occurrenceofgeneticallydeterminedlipoproteindisorders(eg, familial combined hyperlipidemia andfamilial hypertriglyceridemia). Furthermore,useofalcoholandestrogenmayalsocontributetohypertriglyceridemia.

Trials in Diabetic DyslipidemiaNo clinical trial has been done on the effectsof lipid-lowering agents on subsequent CHDspecifically in diabetic subjects. However, anumber of clinical trials have included smallnumbers of adult type 2 diabetic subjects. Inthe Scandinavian Simvastatin Survival Study(4S) trial, simvastatin (HMG CoA reductaseinhibitor or “statin”) significantly reducedCHD incidence and totalmortality (borderlinesignificantly) in diabetic subjects with highLDL cholesterol and with previous clinicalCHD. In theCholesterol andRecurrentEvents(CARE) study, pravastatin reduced CHDincidencesignificantlyindiabeticsubjectswithaverage LDL levels and with previous clinicalCHD. In theHelsinkiHeartStudy,gemfibrozil(fibric acid derivative) was associated with

a reduction in CHD in diabetic subjectswithout prior CHD (although this result wasnot statistically significant). In the VeteransAffairs High-Density Lipoprotein CholesterolIntervention Trial (VA-HIT), gemfibrozilwas associated with a 24% decrease incardiovasculareventsindiabeticsubjectswithpriorcardiovasculardisease.

Lifestyle interventions and Glycemic ControlWeight loss and increased physical activityleads to decreased triglyceride and increasedHDL cholesterol levels and also to modestlowering of LDL cholesterol levels. Diabeticpatients who are overweight should be givena prescription for Medical Nutrition Therapy(MNT)andforincreasedphysicalactivity.Theproportion of saturated fat in the meal planshould be reduced. Some (but not all) studiessuggest that a high-monounsaturated fat dietmayhavebettermetaboliceffectsthanahigh-carbohydratediet,althoughotherexpertshavesuggested that such a dietary modificationmay make weight loss more difficult in obesediabeticpatients.

Recommendations of the American HeartAssociation for patients with CHD havesuggested that the maximal Medical NutritionTherapy (MNT) typically reduces LDLcholesterol 15-25 mg/dl. Thus, if the LDLcholesterol exceeds the goal by >25 mg/dl, the physician may decide to institutepharmacological therapy at the same timeas behavioral therapy for high-risk patients(i.e., diabetic patients with aprior myocardialinfarction and/or other CHD risk factors).In other patients, behavioral interventionsmay be evaluated at 6-week intervals, withconsideration of pharmacological therapybetween3and6months.

Interventions to improve glycemia usuallylower triglyceride levels. In general, glucose-lowering agents do not change or haveonly a modest effect on raising HDL levels.However, the HDL composition may changein a direction thought to be antiatherogenic.ThiazolidinedionesmayincreaseHDLandLDLlevels,butthelong-termeffectofsuchchangesis not known. LDL cholesterol may decreasemodestly(upto10-15%)withtheachievementof optimal glycemic control. Since improvedglycemic control may also lower triglyceridelevels, it might also cause a favorable changeinLDLcomposition.


Treatment GoalsThe categories of CHD risk by lipoprotein levels in type 2diabeticpatientsareshownintable1.Duetofrequentchangesin glycemic control in diabetic patients and their effects onlevels of lipoprotein, levels of LDL, HDL, total cholesterol,and triglyceride should be measured every year in adultpatients. If values fall in lower-risk levels, assessmentmayberepeatedevery2years.Inchildrenwithdiabetes,considerationshould be given to measuring lipoproteins after age 2 years,as suggested by the National Cholesterol Education Program(NCEP) Report of the Expert Panel on Blood Cholesterol inChildrenandAdolescents.

Table 1: CHD risk by lipoprotein levels in type 2 diabeticpatients

Risk LDL–C HDL-C Triglycerides

High >130 <40 >400

Borderline 100-129 40-59 150-399

Low <100 >60 <150

For HDL-C, values are 10 mg% more in females, all values are in mg%

Optimal LDL cholesterol levels for adults with diabetes are<100mg/dl,optimalHDLcholesterollevelsare>40mg/dl,anddesirable triglyceride levels are <150 mg/dl. (In women who,atleastwhennondiabetic,tendtohavehigherHDLcholesterollevels than men, it may be desirable to have even higherHDL cholesterol levels [>50 mg/dl]). However, raising HDLcholesterollevelspharmacologicallyindiabeticpatientsisverydifficultsincethemosteffectiveagentraisingHDLcholesaterollevels is nicotinic acid, which has to be used with caution inpatientswithdiabetes.FibratescanraiseHDLcholesterollevelssignificantlywithoutaffectingglycemiccontrol.

TherecommendationsfortreatmentofelevatedLDLcholesterolgenerally followtheguidelinesofboth theNCEPandarecentADA consensus development conference with the followingcaveats that pharmacological therapy should be initiated afterbehavioral interventions are used. However, in patients withclinical cardiovascular disease or very high LDL cholesterollevels (i.e., 200 mg/dL), pharmacological therapy should beinitiatedatthesametimethatbehavioraltherapyisstarted.

Table 2: TreatmentdecisionsbasedonLDLcholesterollevelinadultswithdiabetes.

Medical Nutrition Therapy

Drug Therapy

InitiationLevel

LDLGoal InitiationLevel

LDLGoal

WithCHD,PVDorCVD

>100 <100 >100 <100

W i t h o u tCHD,PVDorCVD

>100 <100 >130 <100

Data are given in milligrams per decilitre

Inthecontextof theNCEPreport, it issuggestedthatdiabeticsubjects with clinical CHD and an LDL cholesterol level of=100 mg/dl after MNT and glucose interventions be treatedwithpharmacologicalagents.Fordiabeticpatientswithoutpre-existing CHD, the current ADA recommendations for starting

pharmacological therapyareanLDLcholesterol levelof=130mg/dl and a goal of <100 mg/dl for LDL cholesterol. Since alarge proportion of diabetic patients die before they reachthe hospital, a preventive strategy based solely on secondarypreventionwouldnotbeableto“save”largenumbersofthesediabetic patients. In patients with LDL between 100 mg/dland 129 mg/dl, a variety of treatment strategies are available,includingmoreaggressiveMNTandpharmacologicaltreatmentwith a statin . In addition, if the HDL is <40 mg/dl, a fibricacid such as fenofibrate might be used in patients with LDLbetween100and129mg/dl.

InagreementwiththeearlierADAconsensuspanel, increasedtriglyceride levels are recognized as a target for intervention.SincerecommendedLDLlevelsareconsideredtobe<100mg/dlandsincemanydiabeticpatientshaveincreasedtriglyceridelevels, a large proportion of diabetic patients will haveelevated levels of both LDL cholesterol and triglycerides. Assuch, there is likely to be an increase of diabetic patients onpharmacological therapyand thusan increase inexpenditureson pharmacological therapy. However, the clinical trial datasuggest that reduction of LDL cholesterol is associated withreduction in CHD and perhaps over-all mortality. Economicanalyses, basedon the4S study, suggest thatpharmacologicaltherapy may be cost-effective once indirect costs of CHD aretakenintoaccount.

The initial therapy for hypertriglyceridemia is behaviormodification with weight loss, increased physical activity,and moderation of alcohol consumption (moderate meansmoderate!). In thecaseofseverehypertriglyceridemia (=1,000mg/dl), severe dietary fat restriction (<10% of calories; inaddition to pharmacological therapy) is necessary to reducetheriskofpancreatitis. Improvedglycemiccontrol (whichhasbeen facilitated by the introduction of new glucose-loweringagents and more frequent use of combination therapy) is alsovery effective for reducing triglyceride levels and should beaggressively used before the introduction of fibric acids. Afterthe achievement of optimal glycemic control (or at least afterthe achievement of as much improvement as likely to bepossible), the physician may consider adding a fibric acid.The decision to start pharmacological therapy/ treatment isdependent on the clinician’s judgment between triglyceridelevels of 200 mg/dl and 400 mg/dl. Above 400 mg/dl, strongconsiderationshouldbegiventopharmacologicaltreatmentoftriglyceridemia.

In contrast, improved glycemic control will only modestlyreduce LDL cholesterol levels, and therefore in diabeticpatients with both high LDL cholesterol and high glucoselevels, one might simultaneously initiate glucose loweringand statin therapy. In some studies, higher-dose statins aremoderatelyeffectiveinreducingtriglyceridelevelsinmarkedlyhypertriglyceridemic subjects (triglyceride =300 mg/dl). Thecritical issue is that gemfibrozil should not be initiated alonein diabetic patients who have undesirable levels of bothtriglycerideandLDLcholesterol.FenofibratemayhavegreaterLDL-lowering effects and may be useful in diabetic patientswith combined hyperlipidemia. Although HDL cholesterol,as noted above, is a powerful predictor of CHD in diabeticpatients, it is difficult to raise HDL cholesterol levels withoutpharmacological intervention. Nicotinic acid, which shouldbe used with caution in diabetic patients, and fibrates caneffectivelyincreaseHDLcholesterollevels.

In some cases, combined lipid therapy may be initiated. Thecombinationof statinswithnicotinicacidandespeciallywith


gemfibrozil or fenofibrate has been associated with increasedrisk of myositis, although the risk of clinical myositis (asopposed to elevated creatinine phosphokinase levels) appearsto be low. However, the risk of myositis may be increasedwith the combination of gemfibrozil and cerivastatin (nolonger marketed now) or in patients with renal disease. Thecombinationofstatinswithnicotinicacidisextremelyeffectiveinmodifyingdiabeticdyslipidemia(withthelargestincreasesinHDLcholesterollevels),butthecombinationmaysignificantlyworsenhyperglycemia.Thus,thiscombinationshouldbeusedwith extreme caution: use low doses of nicotinic acid (=2 gofnicotinicacidperday)with frequentmonitoringofglucoselevels.Flushing,acommonsideeffectofstartingnicotinicacid,can be reduced by either taking it with meals or combiningwithaspirin.Lipid

Lowering AgentsA brief summary of the actions of available agents for lipidlowering in patients with diabetes is shown in table 4 below.

Generally,oneortwoagentsareavailableineachclasswiththeexceptionof thestatins, forwhichtherearemany.Thechoiceof statin should depend principally on the LDL reductionneeded to achieve the target (<100 mg/dl, on the initial LDLlevel,andonthejudgmentofthetreatingphysician.

Type 1 diabetic patients who are in good control tendto have normal (and sometimes better than normal)levels of lipoprotein. Their composition of lipoproteinsmay be abnormal, but the effects of these compositionalabnormalities in relation to CHD are unknown. There isrelatively little observational data on lipoproteins and CHD,and there are no clinical trials relating lipoproteins to CHD.It seems reasonable that if type 1 diabetic patients have LDLcholesterol levels that are above the goals recommended fortype 2 diabetic patients, they should be aggressively treated.Improved glycemic control may be even more important intype 1 diabetic patients than in type 2 diabetic patients forreduction of CHD (eg, Wisconsin Epidemiologic Study ofDiabeticRetinopathy[WESDR]).

Table 3:PrioritiesinManagementofDiabeticDyslipidemia

I. LDLcholesterollowering

Firstchoice HMGCoAreductaseinhibitor(statin)

Secondchoice Bileacidbindingresin(resin)orfenofibrateII. HDLcholesterolraising

Behavioralinterventionssuchasweightloss,increasedphysicalactivity,andsmokingcessationmaybeuseful,Difficultexceptwithnicotinicacid,whichshouldbeusedwithcaution,orfibrates

III. Triglyceridelowering

Glycemiccontrolfirstpriority

Fibricacidderivative(gemfibrozil,fenofibrate)

StatinsaremoderatelyeffectiveathighdoseinhypertriglyceridemicsubjectswhoalsohavehighLDL-C

IV. Combinedhyperlipidemia

Firstchoice Improvedglycemiccontrolplushigh-dosestatin

Secondchoice Improvedglycemiccontrolplusstatinplusfibricacidderivative(gemfibrozil,fenofibrate)

Thirdchoice Improved glycemic control plus resin plus fibricacidderivative(gemfibrozil,fenofibrate)

Improved glycemic control plus statin plusnicotinicacid(glycemiccontrolmustbemonitoredcarefully)


Table 4: Actionsofavailableagentsforloweringlipids

Risk LDL HDL Triglycerides Trials

first Line Drugs

HMG CoA reductase inhibitor

Triglyceride lowering

fibric Acid derivative

LDL lowering

Bile acid resins

LDL and triglyceride lowering

Nicotinic Acid

4S(simvastatin)

CARE(pravastatin)

Helsinki(gemfibrozil)

none

none

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Treatment of Hypertension in Adult Patients with Diabetes - ADA Guidelines Review


Hypertension (defined as a blood pressure³140/90 mmHg) is an extremely commonco-morbid condition in diabetes, affecting ~20-60%ofpatientswithdiabetes,dependingonobesity, ethnicity, and age. In type 2 diabetes,hypertension is often present as a part of themetabolic syndrome of insulin resistance alsoincludingcentralobesityanddyslipidemia. Intype 1 diabetes, hypertension may reflect theonset of diabetic nephropathy. Hypertensionsubstantially increases the risk of both macrovascular and micro vascular complications,including stroke, coronary artery disease,and peripheral vascular disease, retinopathy,nephropathy, and possibly neuropathy. Inrecentyears,adequatedatafromwell-designedrandomized clinical trials have demonstratedthe effectiveness of aggressive treatment ofhypertensioninreducingbothtypesofdiabetescomplications.

Diabetes increases the risk of coronary eventstwofold in men and fourfold in women. Partof this increase is due to the frequency ofassociated cardiovascular risk factors suchas hypertension, dyslipidemia, and clottingabnormalities. Inobservationalstudies,peoplewith both diabetes and hypertension haveapproximately twice theriskofcardiovasculardisease as non diabetic people withhypertension. Hypertensive diabetic patientsare also at increased risk for diabetes-specificcomplications including retinopathy andnephropathy. In the U.K. Prospective DiabetesStudy (UKPDS) epidemiological study, each10 mmHg decrease in mean systolic bloodpressure was associated with reductions inrisk of 12% for any complication related todiabetes, 15% for deaths related to diabetes,11% for myocardial infarction, and 13% formicrovascular complications. No threshold ofriskwasobservedforanyendpoint.

The UKPDS and the Hypertension OptimalTreatment (HOT) trial both demonstratedimproved outcomes, especially in preventingstroke, in patients assigned to lower bloodpressure targets. Optimal outcomes in theHOT study were achieved in the group witha target diastolic blood pressure of ²80 mmHg(achieved 82.6 mmHg). Randomized clinicaltrials demonstrate the benefit of targetinga diastolic blood pressure of 80 mmHg.Epidemiological analyses show that bloodpressures ³120/70 mmHg are associated withincreased cardiovascular event rates andmortality in persons with diabetes. Therefore,

atargetbloodpressuregoalof<130/80mmHgis reasonable if it can be safely achieved.Thereisnothresholdvalueforbloodpressure,and risk continues to decrease well into thenormalrange.

Dietary management with moderate sodiumrestriction has been effective in reducingblood pressure in individuals with essentialhypertension. Several controlled studies havelookedattherelationshipbetweenweightlossandbloodpressurereduction.Weightreductioncan reduce blood pressure independent ofsodium intake and also can improve bloodglucose and lipid levels. The loss of onekilogram in body weight has resulted indecreasesinmeanarterialbloodpressureof~1mmHg.The role of very lowcaloriediets andpharmacologic agents that induce weight lossinthemanagementofhypertensionindiabeticpatientshasnotbeenadequatelystudied.Someappetitesuppressantsmayinduceincreasesinblood pressure levels, so these must be usedwith care. Given the present evidence, weightreduction should be considered an effectivemeasure in the initial management of mild-to-moderate hypertension, and these resultscouldprobablybeextrapolated to thediabetichypertensivepopulation.

Sodium restriction has not been tested inthe diabetic population in controlled clinicaltrials. However, results from controlledtrials in essential hypertension have showna reduction in systolic blood pressure of ~5 mmHg and diastolic blood pressure of 2-3 mmHg with moderate sodium restriction(from a daily intake of 200 mmol [4,600 mg]to 100 mmol [2,300 mg] of sodium per day).Adoseresponseeffecthasbeenobservedwithsodium restriction. Even when pharmacologicagentsareused,thereisoftenabetterresponsewhen there isconcomitantsalt restrictiondueto the aforementioned volume component ofthehypertensionthatisalmostalwayspresent.The efficacy of these measures in diabeticindividualsisnotknown.

Moderately intense physical activity, suchas 30-45 minutes of brisk walking most daysof the week, has been shown to lower bloodpressure and is recommended. The AmericanDiabetes Association Consensus DevelopmentConference on the Diagnosis of CoronaryHeart Disease in People with Diabetes hasrecommended that diabetic patients who are35 years of age or older and are planning tobeginavigorousexerciseprogramshouldhave


exercisestresstestingorotherappropriatenoninvasivetesting.Stress testing is not generally necessary for asymptomaticpatients beginning moderate exercise such as walking.Smoking cessation and moderation of alcohol intake are alsorecommendedandareclearlyappropriate forallpatientswithdiabetes.

There are a number of trials demonstrating the superiority ofdrug therapy versus placebo in reducing outcomes includingcardiovascular events and microvascular complications ofretinopathy and progression of nephropathy. These studiesused different drug classes, including angiotensin-convertingenzyme(ACE)inhibitors,angiotensinreceptorblockers(ARBs),diuretics, and ß-blockers, as the initial step in therapy. All oftheseagentsweresuperiortoplacebo;however,itmustbenotedthatmanypatientsrequiredthreeormoredrugstoachievethespecified target levels of blood pressure control. Overall thereisstrongevidencethatpharmacologic therapyofhypertensionin patients with diabetes is effective in producing substantialdecreasesincardiovascularandmicrovasculardiseases.

Therearelimiteddatafromtrialscomparingdifferentclassesofdrugsinpatientswithdiabetesandhypertension.TheUKPDS-HypertensioninDiabetesStudyshowednosignificantdifferenceinoutcomesfortreatmentbasedonanACEinhibitorcomparedwithaß-blocker.Therewereslightlymorewithdrawalsduetoside effects and there was more weight gain in the ß-blockergroup. In post myocardial infarction patients, ß-blockers havebeen shown to reduce mortality. There are numerous studiesdocumenting the effectiveness of ACE inhibitors and ARBsin retarding the development and progression of diabeticnephropathy. ACE inhibitors have a favourable effect oncardiovascular outcomes, as demonstrated in the MICRO-HOPE study. This cardiovascular effect may be mediated bymechanismsotherthanbloodpressurereduction.Itispossiblethatotherdrugclassesmaybehavesimilarly.

Somestudieshaveshownanexcessofselectedcardiaceventsin patients treated with dihydropyridine calcium channelblockers (DCCBs) compared with ACE inhibitors. Ongoingtrials including the Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial (ALLHAT) studyshouldhelp to resolve this issue.DCCBs in combinationwithACEinhibitors,ß-blockers,anddiuretics,asintheHOTstudyand the Systolic Hypertension in Europe (Syst-Eur) Trial, didnot appear to be associated with increased cardiovascularmorbidity. However, ACE inhibitors and ß-blockers appearto be superior to DCCBs in reducing myocardial infarctionand heart failure. Therefore, DCCBs appear to be appropriateagents in addition to, but not instead of, ACE inhibitors andß-blockers. Non-DCCBs (i.e., verapamil and diltiazem) mayreduce coronary events. In short-term studies, non-DCCBshavereducedalbuminexcretion.

Therearenolong-termstudiesof theeffectof -blockers, loopdiuretics, or centrally acting adrenergic blockers on long-termcomplications of diabetes. The a -blocker arm of the ALLHATstudy was stopped by the data and safety monitoringcommittee because of an increase in cases of new-onsetheart failure in patients assigned to the a -blocker. While thiscould merely represent unmasking of heart failure in patientspreviously treated with an ACE inhibitor or a diuretic, itseems reasonable to use these as second-line agents whenpreferred classes have been ineffective or when other specificindications, such as benign prostatic hypertrophy (BPH), arepresent.

There is a strong epidemiological connection betweenhypertension in diabetes and adverse outcomes of diabetes.Clinical trials demonstrate the efficacy of drug therapyversus placebo in reducing these outcomes and in setting anaggressive blood pressure-lowering target of <130/80 mmHg.It is very clear that many people will require three or moredrugs to achieve the recommended target. Achievement ofthe target blood pressure goal with a regimen that does notproduce burdensome side effects and is at reasonable cost tothe patient is probably more important than the specific drugstrategy.

Because many studies demonstrate the benefits of ACEinhibitors on multiple adverse outcomes in patients withdiabetes, including both macro vascular and microvascularcomplications, in patients with either mild or more severehypertension and in both type 1 and type 2 diabetes, theestablished practice of choosing an ACE inhibitor as thefirst-line agent in most patients with diabetes is reasonable.In patients with microalbuminemia or clinical nephropathy,both ACE inhibitors (type 1 and type 2 patients) and ARBs(type 2 patients) are considered first-line therapy for thepreventionofandprogressionofnephropathy.However,otherstrategies including diuretic and ß-blocker-based therapy arealso supported by evidence. Because of lingering concernsabout the lower effectiveness of DCCBs (compared withACE inhibitors, ARBs, ß-blockers, or diuretics) in decreasingcoronary events andheart failure and in reducingprogressionof renal disease in diabetes, these agents should be used assecond-line drugs for patients who cannot tolerate the otherpreferred classes or who require additional agents to achievethe targetbloodpressure.Otherclasses, including a-blockers,may be used under specific indications (such as symptomsof BPH for a-blockers) or other agents have failed to controlthe blood pressure or have unacceptable side effects. Bloodpressure, orthostatic changes, renal function, and serumpotassiumshouldbemonitoredatappropriate intervals.

Treatment decisions should be individualized based on theclinical characteristicsof thepatient, includingco-morbiditiesaswellastolerability,personalpreferences,andcost.

Goal (mmHg) <130 <80

Behaviouraltherapyalone(maximum3months)thenaddpharmacologictreatment

130-139 80-89

Behaviouraltherapy+pharmacologictreatment

>140 >90

v Blood pressure should be measured at every routinediabetes visit. Patients found to have systolic bloodpressure 130 mmHg or diastolic blood pressure 80mmHg should have blood pressure confirmed on aseparateday.

v Orthostatic measurement of blood pressure shouldbe performed to assess for the presence of autonomicneuropathy.

Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg

v Patientswithasystolicbloodpressureof130-139mmHgoradiastolicbloodpressureof80-89mmHgshouldbegivenlifestyle/behavioraltherapyaloneforamaximumof3monthsandthen,iftargetsarenotachieved,shouldalsobetreatedpharmacologically.


v Patientswithhypertension(systolicbloodpressure140mmHg or diastolic blood pressure 90 mmHg) shouldreceivedrug therapy in addition to lifestyle/behavioraltherapy.

v Initialdrugtherapymaybewithanydrugclasscurrentlyindicated for the treatment of hypertension. However,some drug classes (ACE inhibitors, ß-blockers, anddiuretics)havebeenrepeatedlyshowntobeparticularlybeneficialinreducingCVDeventsduringthetreatmentof uncomplicated hypertension and are thereforepreferredagentsforinitialtherapy.IfACEinhibitorsarenottolerated,ARBsmaybeused.Additionaldrugsmaybechosenfromtheseclassesoranotherdrugclass.

v If ACE inhibitors or ARBs are used, monitor renalfunctionandserumpotassiumlevels.

v In patients with type 1 diabetes, with or withouthypertension, with any degree of albuminuria, ACEinhibitorshavebeenshowntodelaytheprogressionofnephropathy.

v In patients with type 2 diabetes, hypertension andmicroalbuminuria,ACEinhibitorsandARBshavebeenshowntodelaytheprogressiontomacroalbuminuria.

v In those with type 2 diabetes, hypertension, macroalbuminuria (>300 mg/day), nephropathy, or renalinsufficiency, an ARB should be strongly considered.If one class is not tolerated, the other should besubstituted.

v In patients over age 55 years, with hypertension orwithout hypertension but with another cardiovascular

risk factor (history of cardiovascular disease,dyslipidemia, micro albuminuria, smoking), an ACEinhibitor (ifnot contraindicated) shouldbeconsideredtoreducetheriskofcardiovascularevents.

v In patients with a recent myocardial infarction, ß-blockers, in addition, should be considered to reducemortality.

v Patients with diabetes should be treated to a systolicbloodpressure<130mmHg.

v Inpatientswithmicroalbuminuriaorovertnephropathy,inwhomACEinhibitorsorARBsarenotwelltolerated,anon-DCCBorß-blockershouldbeconsidered.

v If ACE inhibitors or ARBs are used, monitor renalfunctionandserumpotassiumlevels.

v Inelderlyhypertensivepatients,bloodpressureshouldbeloweredgraduallytoavoidcomplications.

v Patients not achieving target blood pressure on threedrugs, including a diuretic, and patients with asignificantrenaldiseaseshouldbereferredtoaspecialistexperiencedinthecareofpatientswithhypertension.

References1. Arauz-Pacheco C, Parrott MA, Raskin P: The treatment of

hypertension in adult patients with diabetes (TechnicalReview).DiabetesCare25:134–147,2002

2. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M,Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J: Preservingrenal function in adults with hypertension and diabetes: aconsensusapproach.AmJKidDis36:646–661,2000


Sameer GulatiJunior ConsultantSt.StephensHospitalNewDelhi

N. P. Singh ProfessorDepartmentofMedicineandHeadofNephrologyDivision,MaulanaAzadMedicalCollegeandAssociatedLokNayakHospital,Delhi

B. Mohan RathiResearch AssociateDepartmentofMedicine,MaulanaAzadMedicalCollegeandassociatedLokNayakHospital,NewDelhi.CollegeandAssociatedLokNayakHospital,Delhi

Rapidly Progressive Glomerulonephritis

Sameer Gulati1, N P Singh2 and B. Mohan Rathi3

Definition: Rapidly progressive glomerulone-phritis (RPGN)/crescentic glomerulonephritisis a disease of the kidney that results ina rapid decrease in the glomerular filtrationrate of at least 50% over a short period(a few days to 3 months). 1 The mainpathological finding is fibrinoid necrosis(>90% of biopsy specimens); and extensivecrescent formation is present in at least50% of glomeruli. RPGN is accompaniedby oliguria or anuria and with features ofglomerulonephritis including dysmorphiceryhrocyturia, erythrocytic cylinduria andglomerular proteinuria. Renal diseases otherthan Crescentic Glomerulonephritis causingsigns and symptoms of Rapidly ProgressiveGlomerulonephritis have been referred to asPseudoRPGN.

Table 1: Pseudo RPGN without glomerulone-phritis

Acuteinterstialnephritis

Thromboembolicrenaldisease

AcutetubularNecrosis

Renalarteryobstruction

SclerodermarenalRenalCrisis

Renalveinthrombosis

MalignantHypertension

Hemolyticuremicsyndrome

LightchainNephropathy

Thromboticthromboctopenicpurpura

Classification:Thereisnouniformclassificationof RPGN. The following classification iscommonlyaccepted:

TypeI: Anti-GBM disease withoutPulmonaryHemorrhage

TypeII: Immune Complex AssociatedDisease (without Anti GBM orANCA)

TypeIII: PauciImmune(withANCA)

TypeIV: Mixed Pattern (with Anti GBMandANCA)

TypeV: Pauci Immune (without ANCAorAntiGBM)

ForpracticalpurposesRPGNhasbeenredefinedinto two categories, ANCA positive or ANCAnegative.

Table 2: ANCApositiveRPGN

Vasculitis Associated with medications:

Microscopicpolyangitis

Hydralizine

Wegner’sgranulomatosis

Aminoguanidine

ChurgStrauss Allopurinol

AntiGBM PropylthiouracilMinocycline

ChronicliverdiseasewithIgAnephritis

Sjogren’ssyndrome

HIVinfection Silicosis

HenochSchonleinpurpura

Systemiclupuserythromatosis

Monoclonalgammopathylightchaindisease.

Polymyositis

Rheumatoidarthritis

Otheracuteorchronicinfection

Pathogenesis of Crescent formation: Crescentformation appears to represent a nonspecificresponse to severe injury to the glomerularcapillary wall. Rents are induced in theglomerular capillary wall, resulting in themovement of plasma products into Bowman’sspace with subsequent fibrin formation, theinflux of macrophages and T cells, and therelease of proinflammatory cytokines, such asinterleukin-1andtumornecrosisfactor-alpha.

Clinical features: The presenting complaintsin RPGN may be similar to those in severepostinfectious glomerulonephritis: the acuteonset of macroscopic hematuria, decreasedurine output, and edema. More commonly,however, RPGN has an insidious onsetwith the initial symptoms being fatigueor edema. The rate of progression of renalfailure is variable ranging from few hoursto many months. Hypertension is relativelyuncommon except in patients with diffuseendocapillary glomerulonephritis, chronicglomerulonephritis or severe fluid overload.Clinical presentation and intensity of RPGNdepends upon histological lesion underlyingpathogenicprocessandenvironmental geneticinfluences. The most common prodrome of


Table 3: ANCAnegativeRPGN

Post Infectious

Viral Miscellaneous

HepatitisCInfluenza

HIV LegionellaMycoplasma

SyphilisLeprosy

EndocapillaryProliferation Subacutebacterialendocarditis

SuppurativeInfections Shuntnephritis

Non Infectious

Systemic Nonsystemic

Vasculitis Associated with treatment

PolyarteritisnodosaMicroscopicpolyangiitisHenochSchonleinpurpuraChurgStrausssyndromeBehcet’ssyndromeRelapsingpolychondritis

AllopurinolPropylthiouracilRifampicinEnalaprilPenicillamineHydralazine

Non vasculitis Membrano proliferative

MalignancyCryoglobulinemiaSystemiclupusErythromatosisAlportsyndromeC3nephriticfactorSilicosis

IgG-IgAnephropathyMembranousnephropathyIdiopathicEndocapillaryproliferationWithoutendocapillaryproliferationIdiopathicSarcoidosis

Non Infectious

Systemic Nonsystemic

RheumatoidarthritisDermatomyositisSjogren’ssyndromeReiter’ssyndrome

AntiGBMAntibodiesonGBMGoodpasture’ssyndromeGoodpasture’sdiseaseMembranousnephropathy

ANCA-associatedvasculitis is flu like symptomscharacterizedby malaise, fever, arthralgias, myalgias, anorexia, andweight loss. This occurs in more than 90% of patientsand can occur within days to months of the onset ofnephritis or other manifestations of vasculitis. Followingthe prodrome, the most common complaints are abdominalpain, painful cutaneous nodules or ulcerations, and amigratory polyarthropathy. When pulmonary or upperairway involvement is present, patients complain of sinusitissymptoms, cough, and hemoptysis.

Physical: Hypertension can be present but is not common.Unless specific findings are present, such as those listedbelow, the physical examination results are usually normal.

Urinalysis:With rareexceptions, thesediment shouldcontainred cells that are dysmorphic, red cell casts, positive dipstickproteinuria and leucocytes, including leucocyte cast attimes, consistent with renal injury. Staining for eosinophilsshould be done because interstitial nephritis and severalother entities present in this fashion.2 The urine analysis

also reflects response to therapy with reactivation of urinesediment providing a mirror of reactivation of the disease,frequently before clinical manifestations.

Table 4: Clinical manifestation of affected organs or systems

System Clinical Manifestations

Skin Leukocytoclastic vasculitismostly in lower limbs

Nail fold infarcts

Granulomatous cutaneousnodules in WG, ChurgStrauss syndrome

Painful erythrematousnodules, focal necrosis,ulceration and livedoreticularis due tonecrotizing arteritis

Nervous system Involvement of meningealvessels

Seizures

Most commonmanifestation of ANCAassociated disease isMononeuritis multiplex

Musculoskeletal Symmetrical, migratoryarthritis involving smalljoints

Pain and elevation intissue enzyme levels

Gastrointestinal Intussusception, pancreatitisand occult bleeding due toischemic ulceration

Renal Most common finding incovert renal disease ismicroscopic hematuria

Respiratory Sinusitis, otitis media, ulcersin the nasal mucosa, andsubglottic stenosis in upperrespiratory tract

Pulmonary hemorrhages andhemoptysis

Ocular Iritis, uveitis, andconjunctivitis

Serological testing:Variousserologicaltestsandavarietyofautoantibodiesfordifferentsystemicdiseaseshavebeenadvocatedas shown in the table, but one should not forget hepatitisprofile and HIV testing. The reasons for this include the highassociationbetweenvariousrenaldiseasesandthepresenceofeither Hepatitis B or C, the potential risk of infection to thephysician and clear differences in approach to therapy. HIVtestingisalsoadvocatedbecauseafewpatientswithRPGNcanpresentinthisway.

Chest X ray and stool quaiac: These shouldbe routinepartsofevaluationofthepatientwithRPGN,becausemalignancyissignificantcauseofRPGNandincreaseswithaging.


Erythrocyte Sedimentation Rate (ESR): This old test remainsanessential and inexpensiveparameter to follow for evidenceof disease activity. If it is not elevated at presentation, thenRPGNismuchlesslikely,andifitdecreaseswiththerapy,thenthisreassuresthattheinflammatoryprocessisregressing.

Table 5 : LaboratoryinvestigationsinRPGN

Specific

AntiGBMantibodies

ANCA

AntidSDNAantibodies

AntiSmantibody

C3nephriticfactor

ASOT

AntiGBMdisease

Systemicvasculitis

SLE

SLE

MCGNtypeII,sometimesSLE

Poststreptococcalglomerulonephritis(titersmayalsoincreasewithhyper-globulinemiaandSLE)

AntiDNA’ase Poststreptococcalglomerulonephritis(titersmayalsoincreasewithhyper-globulinemiaandSLE)

Non Specific

Complement:

LowC4,NormalC3

Mixedessentialcryglobulinemia(MEC),SLE

LowC4,C3

LowC3,NormalC4

SLE,MCGNI,MEC

MCGNII,Postinfectiousglomerulonephritis,sometimesSLE

RaisedC3,C4

CryglobulinsMEC,(andothersincludeSLE,Postinfectiousglomerulonephritisusuallyatlowerlevels)

Immunoglobulins:

RaisedIgG,IgM

SLE,SystemicVasculitis,PostinfectiousGN

RaisedIgE

RaisedIgA

ChurgStrausssyndrome

IgAnephropathy,HenochSchonleinpurpura

Paraprotein(IgM)

Rhfactor

CRP

MEC,myeloma

Mostglomerulonephritis,particularlysystemicvasculitis,butusuallynotSLE.

IncreasedAlkaline

Phosphatase

Systemicvasculitis

Non Specific

Hematology,ThrombocytosisEosinophilia

Lymphopenia,Thrombocytopenia

Neutrophilia,SystemicvasculitisChurgStrausssyndrome

SLE

Positive Bacteriological Cultures

Infectionrelateddiseaseparticularlyendocarditis

Renal Biopsy: Renal biopsy differentiates between RPGN andPseudo RPGN and thus the consequent changes in lines ofmanagement.Itisdonetoassessthedegreeofglomerulosclerosisandinterstitialfibrosisasitishighlycorrelatedwithprognosis.It also provides a histological index of response in terms ofcrescentspresent.

Treatment: Early diagnosis with renal biopsy and serologictesting and early initiation of appropriate therapy is essentialto minimize the degree of irreversible renal injury. Empirictherapy may be begun in patients with severe disease,particularly if either renal biopsy or interpretation of thebiopsy will be delayed. Pulse steroids are followed by highdose alternate day steroids. Oral prednisone is initiated at 2mg/kg and then tapered according to protocol.3 If segmentalglomerulosclerosis is present on renal biopsy or the ANCA ispositiveoralcyclophosphamide(2mg/kgdaily-maybetaperedwithadecreaseindosefordecreasedrenalfunction,lowwhitecount or low platelets) is added to the regimen 5 Patients areencouragedtomaintainahighintakeoffluidstodecreasebladder

Table 6: Therapeuticmodalitiesofthefuture.

Anticytokine/receptoragents

Interleukin-1receptorantagonist

SolubleIL-1receptor

SolubleCR-1

SolubleTNF-áreceptorprotein

CTLA4-Ig

Immunosuppressive

Deoxyspergualin

Anti-adhesinproteinantibodies

Peptidesandmutated/substitutedpeptides

Immunosorbantcolumns/Goodpasture’sepitope

ALG(Antilyphocyteglobulin)

Miscellaneous

Trapidil,antiplatelet

Antigenbasedhetropolymers

toxicity. With this regimen, approximately 80% of patientswithnon-anti-GBMshowanimprovement,and75%ofdialysisdependentpatientscomeoffdialysis.6Patientsarefollowedonthis regimen closely with physical examination, biochemicalstudiesandESRwithcarefulurinalysiswithstepwisetaperingasclinicallyindicated.Treatmentofchoiceinanti-GBMdiseaseis plasmapheresis combined with prednisone combined withprednisone and cyclophosphamide. RPGN patients who arerefractory to prednisone and cyclophosphamide, intraveneousgamma globulin has been used with success on the rationalethat anti-idiotypic antibodies play a role in the diseaseprocess. 7 Monoclonal antibodies directed at lymphocytesurfacedeterminantshavealsobeenusedinrefractorycases.8Therapeuticmodalitiesofthefutureareoutlinedbelow:

Inthosepatientswithpseudo-RPGNoranonglomerularcauseof the clinical syndrome of RPGN, the appropriate diagnosisneedstobemadeandappropriatetherapyinstituted.Diagnosticand therapeutic approach to patients presenting with clinicalRPGNisoutlinedinthetablebelow.

Prognosis: The untreated course of RPGN can be devastating,with most patients progressing to ESRD or death within avery shortperiodof time.However if an infectiousetiology isinvolved the course can be much more benign and treatment


of theunderlyingprocesscanleadtoresolutionof thediseaseprocess.Poorprognostic factorshave includeda largenumberof crescents, circumferential crescents, severe tubulointerstialdisease,extensiveglomerularandinterstialscarring,oligonuria,requirement for dialysis and a serum creatinine level higherthan 6 mg/dl.1,3 Patients with anti-GBM disease and 50% ormore crescents with a serum creatinine of 6 mg/dl or greaterhaveessentiallynoexpectationofresponseunlesstheyarealsoANCA positive.3 These ‘double positive’ patients may requiredialysisbut30%to50%ofcasesrecoverfromdialysis,unheardofwithpureanti-GBMdisease.4Additionallythissubgroupofpatientshavemoresystemicmanifestationsandmorefrequentrelapsesoftheirclinicaldisease,whichrarelyoccurswithpureanti-GBMdisease.There is inversecorrelationbetweenANCAand anti-GBM titers with clinical disease i.e. patients tend tohavehighANCAtitersandlowanti-GBMtiters.

Summary:

l RPGNresultsinrapiddecreaseinGFRofatleast50%overa short period. The main pathological finding is fibrinoidnecrosis in > 90% of biopsy specimens and extensivecrescentformationinatleast50%ofbiopsyspecimens

l Patients present with the acute onset of macroscopichematuria, decreased urine output, and edema. Morecommonly,however,RPGNhasaninsidiousonsetwiththeinitialsymptomsbeingfatigueoredema.

l Renal biopsy is done to differentiate between RPGN andPseudo RPGN, besides helping in prognostification andprovidingahistologicalindexofresponse.

l Poor prognostic factors have included a large number ofcrescents,circumferentialcrescents,severetubulointerstialdisease, extensive glomerular and interstial scarring,oligonuria,requirementfordialysisandaserumcreatininelevelhigherthan6mg/dl.

l Patients are further classified on the basis of ANCApositivity.

l The therapy of most patients with RPGN involves pulsemethylprednisolonefollowedbydailyoralprednisone,oralor intravenous cyclophosphamide, and in some settings,plasmapheresis.

l Early diagnosis with renal biopsy and serologic testingand early initiation of appropriate therapy is essential tominimize the degree of irreversible renal injury. Empirictherapy may be begun in patients with severe disease,particularly if either renal biopsy or interpretation of thebiopsywillbedelayed.

References

1. Couser WG: Rapidly progressive glomerulonephritis:classification, pathogenetic mechanisms and therapy. Am Jkidneydis11:449-64,1988.

2. LockwoodCM:Anti-neutrophilcytoplasmicauto-antibodies:thenephrologist’sperspective.JAmSocNephrolXVIII:171-4,1991.

3. Bolton WK: Treatment of crescenteric glomerulonephritis.Nephrology1:257-68,1995.

4. ShortAK,EsnoultVL,LockwoodCM:ANCAandanti-GBMantibodiesinRPGN.AdvExpMedBiol336:441-44,1993.

5. BoltonWK,WilkowskiMJ:Treatmentandprognosisofrenalandsystemicvasculitis.Contribnephrol94:72-80,1991.

6. Bolton WK, Sturgill BC: Methyl-prednisolone therapy foracute crescenteric rapidly progressive glomerulonephritis.AmJNephrol9:368-75,1989.

7. Jayne DR, Davies MJ, Fox CJ et al: Treament of systemicvasculitiswithpooledintravenousimmunoglobulin.Lancet337:1137-39,1991.


Sudeep KhannaConsultantGastroenterologistDepartmentofGastroenterologyPushpawatiSinghaniaResearchInstututeforLiverRenalandDigestiveDiseaseNewDelhi

Arun KumarSenior ConsultantGastroenterologistDepartmentofGastroenterologistPushpawatiSinghaniaResearchInstututeforLiverRenalandDigestiveDiseaseNewDelhi

Approach to Acute Abdomen

Sudeep Khanna1 and Arun Kumar2

Acute abdominal pain refers to previouslyundiagnosed pain that arises suddenly and isoflessthan7days(usuallylessthan48hours)duration. The causes of acute abdominal painare numerous and include intraperitonealas well as extraperitoneal disorders (fig 1).The clinician should be able to tentativelydifferentiate among causes which need urgentsurgical intervention from causes which needtobemanagednon-surgically.It isessential torememberthatalmosttwothirdsofthepatientswho present with acute abdominal pain havedisordersforwhichsurgicalinterventionisnotrequired.

Historically, diagnosis of the causes of acuteabdominal pain has been based largely onpattern recognition, in which an attempt ismade to match new cases to the classicalpresentations. No doubt, knowledge of theseclassic presentations is basic to successfuldiagnosis,butitiscrucialtorememberthatatleastone-thirdofpatientswithacuteabdominalpainexhibitatypicalfeaturesthatrenderpatternrecognitionunreliable.

Clinical EvaluationHistory

A patient listening to the patient’s complaintis the mainstay of history taking. The historytakingmustincludethemodeofonset,duration,frequency, character, location, chronology,radiation,andintensityof thepain,aswellasthe presence or absence of any aggravating oralleviating factors and associated symptoms.Patientsshouldbeallowedtorelatethehistoryintheirownwords,andexaminersshouldnotsuggest specific symptoms, except as a lastresort.Anyquestionsthatmustbeaskedshould

be open-ended - for example, “What happenswhenyoueat?”ratherthan“Doeseatingmakethepainworse?”Leadingquestions shouldbeavoided.Whenaleadingquestionmustbeasked,it shouldbeposed firstasanegativequestion(ie,onethatcallsforananswerinthenegative),since a negative answer to a question is morelikely tobehonestandaccurate.Forexample,if peritoneal inflammation is suspected, thequestionaskedshouldbe“Doescoughingmakethe pain better?” rather than “Does coughingmake the pain worse?” Usually a carefullytakenhistoryismorevaluablethananysinglelaboratory or x-ray finding and will help thecliniciantoforegounnecessaryinvestigations.

The severity of the underlying disease can beassessed by the mode of onset of abdominalpain. A sudden onset pain suggests an intra-abdominal catastrophe, such as a rupturedabdominalaorticaneurysm(AAA),aperforatedviscus,orarupturedectopicpregnancy.Rapidlyprogressivepainthatbecomesintenselycenteredinawell-definedareawithinaperiodofafewminutestoanhourortwosuggestsaconditionsuchasacutecholecystitisorpancreatitis.Painthat has a gradual onset over several hours,usuallybeginningasslightorvaguediscomfortand slowly progressing to steady and morelocalizedpain;suggestsasubacuteprocessandis characteristic of peritoneal inflammation.Numerousdisordersmaybeassociatedwiththismode of onset, including acute appendicitis,diverticulitis, pelvic inflammatory disease(PID),andintestinalobstruction.

Pain can be either intermittent or continuous.Intermittent or cramp-like pain (colic) is painthatoccurs forashortperiod(a fewminutes),followed by longer periods (a few minutes toone-half hour) of complete remission duringwhichthereisnopainatall.Intermittentpainischaracteristicofobstructionofahollowviscusandresultsfromvigorousperistalsisinthewalloftheviscusproximaltothesiteofobstruction.Thispainisperceivedasdeepintheabdomenandispoorlylocalized.Thepatientisrestless,may writhe about incessantly in an effort tofind a comfortable position, and often pressesontheabdominalwallinanattempttoalleviatethepain.Theintermittentpainassociatedwithintestinal obstruction (typically described asgripping and mounting) is usually severe butbearable, the pain associated with obstructionof small conduits (eg, the biliary tract, theureters, and the uterine tubes) often becomesunbearable. Obstruction of the gallbladderorbileductsgives rise toa typeofpainoften


referred to as biliary colic; however, this term is a misnomer,in that biliary pain is usually constant because of the lack ofa strong muscular coat in the biliary tree and the absence ofregularperistalsis.Continuousorconstantpain ispain that ispresentforhoursordayswithoutanyperiodofcompleterelief;it ismorecommonthan intermittentpain.Continuouspain isusuallyindicativeofperitonealinflammationorischemia.

Certain typesofpainaregenerallyheld tobecharacteristicofcertain diseases – for example, the general burning pain of aperforatedgastriculcer,thetearingpainofadissectinganeurysm,andthegrippingpainofintestinalobstruction.Rememberthatthe character of the pain is not always a reliable clue to itscause.

The location of abdominal pain is only a rough guide todiagnosis.Neverthelessinmostdisorders,thepaintendstooccurin characteristic locations, such as the right upper quadrant(cholecystitis), the right lower quadrant (appendicitis), theepigastrium (pancreatitis), or the left lower quadrant (sigmoiddiverticulitis). It is important to determine the location of thepainatonsetbecausethismaydifferfromthelocationatthetimeofpresentation(so-calledshiftingpain).Thismayalsogiveclueto the diagnosis. For example, the classic pain of appendicitisbeginsintheperiumbilicalregionandsettlesintherightlowerquadrant.Asimilar shift in locationcanoccurwhenescapinggastroduodenalcontentsfromaperforatedulcerpoolintherightlowerquadrant.Alsoinpatientswithpancreatitisthepainmaystartfromepigastriumandgetlocalizedtotheback.Radiationofthepainshouldbetakenintoaccount.Forexample,biliarypainisreferredtotherightsubscapulararea,andtheboringpainofpancreatitistypicallyradiatesstraightthroughtotheback.

Theintensityorseverityofthepainisrelatedtothemagnitudeoftheunderlyinginsult.Thereappearstobeasignificantindividualdifferencetotheperceptionofpainandthisshouldbeborneinmind by the clinician. Pain that is intense enough to awakenthepatientfromsleepusuallyindicatesasignificantunderlyingorganiccause.Pastepisodesofpainand factors thataggravateor relieve the pain often provide useful diagnostic clues. Forexample,paincausedbyperitonitistendstobeexacerbatedbymotion,deepbreathing,coughing,orsneezing,andpatientswithperitonitistendtoliequietlyinbedandavoidanymovement.The typical pain of acute pancreatitis is exacerbated by lyingdownandrelievedbysittingup.Painthatisrelievedbyeatingortakingantacidssuggestsduodenalulcerdisease,whereasdiffuseabdominalpain thatappears30minutes to1houraftermealssuggestsintestinalangina.

Associated gastrointestinal symptoms, such as nausea,vomiting,anorexia,diarrhea,andconstipation,oftenaccompanyabdominalpain;however,thesesymptomsarenonspecificandthereforemaynotbeofgreatvalueinthedifferentialdiagnosis.Vomitinginparticulariscommon:whensufficientlystimulatedbypainimpulsestravelingviasecondaryvisceralafferentfibers,the medullary vomiting centers activate efferent fibers andcause reflex vomiting. Once again, the chronology of eventsis important, in that pain often precedes vomiting in patientswith conditions necessitating operation, whereas the oppositeisusuallythecaseinpatientswithmedicalconditions.Thisisparticularlytrueforpatientswithacuteappendicitis,inwhompainalmostalwaysprecedesvomitingbyseveralhours.Diarrheais characteristic of gastroenteritis but may also accompanyincomplete intestinalobstruction.Moresignificant isahistoryofobstipation,becauseifitcanbedefinitelyestablishedthatapatientwithacuteabdominalpainhasnotpassedgasorstoolfor 24 to 48 hours, it is certain that some degree of intestinal

obstruction ispresent.Otherassociatedsymptomsthatshouldbenotedincludejaundice,melena,hematochezia,hematemesis,andhematuria.These symptomsaremuchmore specific thanthe ones just discussed and can be extremely valuable in thedifferentialdiagnosis.Presenceoffeversuggestsaninflammatoryprocess; however, it is usually low grade and often absentaltogether, particularly in elderly and immunocompromisedpatients.Thecombinationofahighfeverwithchillsandrigorsindicatesbacteremia,andconcomitantchangesinmentalstatus(eg, agitation, disorientation, and lethargy) suggest impendingsepticshock.

Eliciting history of trauma, even if the patient thinks it to betrivial, is mandatory. With female patients, it is essential toobtainadetailedgynecologichistorythatincludesthetimingofsymptomswithinthemenstrualcycle,thedateofthelastmenses,previousandcurrentuseofcontraception,anyabnormalvaginalbleedingordischarge,anobstetrichistory,andanyriskfactorsforectopicpregnancy(eg,PID,useofanintrauterinedevice,orpreviousectopicortubalsurgery).

A complete history of previous medical conditions must beobtainedbecauseassociateddiseasesofthecardiac,pulmonary,andrenalsystemsmaygiverisetoacuteabdominalsymptomsand may also significantly affect the morbidity and mortalityassociated with surgical intervention. Weight changes, pastillnesses, recent travel, environmental exposure to toxinsor infectious agents, and medications used should also beinvestigated.Ahistoryofpreviousabdominaloperationsshouldbeobtained.Acarefulfamilyhistoryisimportantfordetectionof hereditary disorders that may cause acute abdominal pain.Adetailedsocialhistoryshouldalsobeobtainedthatincludestobacco,alcohol,orillicitdruguseaswellasasexualhistory.

Tentative Differential DiagnosisInmajorityofcases,atentativedifferentialdiagnosisshouldbeformed and then physical examination should be carried out.Themostcommondiagnosisinpatientswithacuteabdominalpain isnonspecificabdominalpain (NSAP) whichperse isaretrospectivediagnosisofexclusion inwhichnocause for thepaincanbeidentified.Nonspecificabdominalpainaccountsformorethan34%ofallpatientsseen.Themostcommonsurgicaldiagnosisisacuteappendicitis,followedbyacutecholecystitis,smallbowelobstruction,andgynecologicdisorders.Relativelyfewpatientshaveperforatedpepticulcer,afindingthatconfirmsthe recentdownward trend in the incidenceof thiscondition.Oneshouldkeepinmindthattheprevalenceofdiseasesislikelytovaryamongvariousagegroups.

Physical ExaminationTheamountofinformationthatcanbeobtainedfromphysicalexamination is directly proportional to the gentleness andthoroughnessoftheexaminer.Thephysicalexaminationbeginswith a brief but thorough evaluation of the patient’s generalappearance and ability to answer questions. The degree ofobviouspainshouldbeestimated.Thepatient’spositioninbedshouldbenoted:asanexample,apatientwholiesmotionlesswith flexed hips and knees is more likely to have generalizedperitonitis,whereasarestlesspatientwhowrithesaboutinbedis more likely to have colicky pain, which suggests differentdiagnoses.Theareaofmaximalpainshouldbeidentifiedbeforethephysicalexaminationisbegun.Theexaminercaneasilydothisbysimplyaskingthepatienttocoughandthentopointwithonefingertotheareaofmaximalpain.Thisallowstheexaminertoavoidtheareaintheearlystagesof theexaminationandto


confirmitatalaterstagewithoutcausingthepatientunnecessarydiscomfortinthemeantime.

A complete physical examination should be performed andextra-abdominal causes of pain and signs of systemic illnessshould be sought before attention is directed to the patient’sabdomen.Systemicsignsofshock,suchasdiaphoresis,pallor,hypothermia, tachypnea, tachycardia with orthostasis, andfrankhypotension,usuallyaccompanyarapidlyprogressiveoradvancedintra-abdominalconditionand,intheabsenceofextra-abdominal causes is an indication for immediate laparotomy.Theabsenceofanyalterationinvitalsigns,however,doesnotnecessarilyexcludeaseriousintra-abdominalprocess.

Patientliesinsupineposition.Theexaminationshouldincludeinspection,auscultation,percussion,andpalpationofallareasoftheabdomen,theflanks,andthegroin(includingallherniaorifices)inadditiontorectalandgenitalexaminations(and,infemale patients, a full gynecologic examination). A systematicapproachiscrucial:anexaminerwhomethodicallyfollowsasetpatternofabdominalexaminationeverytimewillberewardedmorefrequentlythanonewhoimproviseshaphazardlywitheachpatient.Remember, auscultation is tobedoneafter inspectionaspalpation is likely to stimulate the intestinesandgive falseimpressionaboutbowelsounds.

Thefirststepintheabdominalexaminationiscarefulinspectionof the anterior and posterior abdominal walls, the flanks,the perineum, and the genitalia for previous surgical scars(possible adhesions), hernias (incarceration or strangulation),distention (intestinal obstruction), obvious masses (distendedgall bladder, abscesses, or tumors), ecchymosis (trauma,pancreatitis)orabrasions(trauma),striae(pregnancyorascites),evertedumbilicus(increasedintra-abdominalpressure),visiblepulsations(aneurysm),visibleperistalsis(obstruction),limitationofmovementoftheabdominalwallwithventilatorymovements(peritonitis),orengorgedveins(portalhypertension).

Thenextstepintheabdominalexaminationisauscultation.Ingeneraltheabsenceofbowelsoundsindicatesaparalyticileus;hyperactiveorhypoactivebowelsoundsoftenarevariationsofnormalactivity;andhigh-pitchedbowelsoundswithsplashes,tinkles(echoingasinalargecavern),orrushes(prolonged,loudgurgles)indicatemechanicalbowelobstruction.

Thethirdstepispercussiontosearchforanyareasofdullness,fluid collections, sections of gas-filled bowel, or pockets offreeairundertheabdominalwall.Tympanymaybepresentinpatients with bowel obstruction or hollow viscus perforation.Percussion can be useful as a way of estimating organsizeandofdeterminingthepresenceofascites(signaledbyafluidwaveorshiftingdullness).Itismostuseful,however,asameansofdemonstratingperitonealirritation(reboundtenderness).Thecustomarytechniqueistodigthefingersdeepintothepatient’sabdomen and then let go abruptly. This technique is a time-honoredone,butitispainfulandoftenmisleadstheexaminerintoassumingthatanacuteprocessispresentwhennoneexists.Gentle percussion over the four quadrants of the abdomen ismuchbettertoleratedbythepatient;inaddition,itismuchmoreaccurateindemonstratingreboundtenderness.

The last step, palpation, is the most informative aspect of thephysical examination. Palpation of the abdomen must bedoneverygently toavoidcausingadditionalpainearly in theexamination.Itshouldbeginasfaraspossiblefromtheareaofmaximal pain and then should gradually advance toward thisarea, which should be the last to be palpated. The examinershould place the entire hand on the patient’s abdomen withthe fingers together and extended, applying pressure with the

pulps(notthetips)ofthefingersbyflexingthewristsandthemetacarpophalangealjoints.Itisessentialtodeterminewhethertrue involuntary muscle guarding (muscle spasm) is present.Thisdetermination ismadebymeansofgentlepalpationovertheabdominalwallwhilethepatienttakesalong,deepbreath.If guarding is voluntary, the underlying muscle immediatelyrelaxes under the gentle pressure of the palpating hand. If,however,thepatienthastrueinvoluntaryguarding,themuscleremainsinspasm(ie,tautandrigid)throughouttherespiratorycycle(so-calledboardlikeabdomen).Trueinvoluntaryguardingis indicative of localized or generalized peritonitis. It must berememberedthatmusclerigidityisrelative:forexample,muscleguardingmaybe lesspronouncedorabsent indebilitatedandelderly patients who have poor abdominal musculature. Inaddition,theevaluationofmuscleguardingisdependentonthepatient’scooperation.

Palpationisalsousefulfordeterminingtheextentandseverityof the patient’s tenderness. Diffuse tenderness indicatesgeneralized peritoneal inflammation. Mild diffuse tendernesswithout guarding usually indicates gastroenteritis or someother inflammatory intestinal process without peritonealinflammation. Localized tenderness suggests an early stage ofdiseasewithlimitedperitonealinflammation.

Careful palpation can elicit several specific signs - such asthe Rovsing sign (associated with acute appendicitis) and theMurphysign(acutecholecystitis)-thatareindicativeoflocalizedperitoneal inflammation. Similarly, specific maneuvers canelicit signsof localizedperitoneal irritation, suchas thepsoassign (associated with retrocecal appendicitis), the obturatorsign (pelvic appendicitis), and the Kehr sign (diaphragmaticirritation). One very important maneuver is the Carnett test,inwhichthepatientelevateshisorherheadoff thebed,thustensingtheabdominalmuscles.Tendernesstopalpationpersistswhenthepainiscausedbyabdominalwallconditions(eg,rectalsheathhematoma)butdecreasesordisappearswhenthepainiscausedbyintraperitonealconditions(theCarnettsign).

Rectal,genital,and(inwomen)pelvicexaminationsareanessentialpartoftheevaluationinallpatientswithacuteabdominalpain.Therectalexaminationshouldincludeevaluationofsphinctertone,tenderness(localizedversusdiffuse),andprostatesizeandtenderness,aswellasasearchforthepresenceofhemorrhoids,masses,fecalimpaction,foreignbodies,andgrossoroccultblood.Thegenitalexaminationshouldsearchforadenopathy,masses,discoloration, edema, andcrepitus.Thepelvic examination inwomenshouldcheckforvaginaldischargeorbleeding,cervicaldischargeorbleeding,cervicalmobilityandtenderness,uterinetenderness, uterine size, and adnexal tenderness or masses.Although a carefully performed pelvic examination can beinvaluable in differentiating non-surgical conditions (eg, PID)from conditions necessitating prompt operation (eg, acuteappendicitis),thepossibilitythatasurgicalconditionispresentshould not be prematurely dismissed solely on the basis of afindingoftendernessonpelvicorrectalexamination.

Basic Investigative StudiesInvestigativestudiesdonotsubstituteforclinicalhistorytakingandgoodphysicalexamination.Theyareusefultoconfirmthediagnosisandmanagingthepatient.

Laboratory Tests

A complete blood count, blood chemistries, and a urinalysisare routinely obtained unless the patient is extremelyhemodynamicallyunstable.Thehematocritisimportantinthatitallowsthedetectionofsignificantchangesinplasmavolume


(eg,dehydrationcausedbyvomiting,diarrhea,orfluidlossintothe peritoneum or the intestinal lumen), preexisting anemia,orbleeding.Anelevatedwhitebloodcellcountisindicativeofan inflammatory process and is a particularly helpful findingif associated with a marked left shift; however, the presenceorabsenceofleukocytosisshouldneverbethesingledecidingfactorastowhetherthepatientshouldundergoanoperation.Alowwhitebloodcellcountmaybeafeatureofviralinfections,gastroenteritis,orNSAP.

Serum electrolyte, blood urea nitrogen, and creatinineconcentrationsareusefulindeterminingthenatureandextentoffluidlosses.Bloodglucoseandotherbloodchemistriesmayalsobehelpful.Liverfunctiontestsaremandatorywhenabdominalpainissuspectedtobehepatobiliaryinorigin.Similarly,amylaseand lipase determinations are mandatory when pancreatitis issuspected,althoughitmustberememberedthatamylaselevelsmaybelowornormalinpatientswithpancreatitisandmaybemarkedlyelevatedinpatientswithotherconditions(eg,intestinalobstruction,mesentericthrombosis,andperforatedulcer).

Urinalysis may reveal red blood cells (suggestive of renal orureteral calculi), white blood cells (urinary tract infection orinflammatoryprocessesadjacenttotheureters,suchasretrocecalappendicitis),increasedspecificgravity(dehydration),glucose,ketones (diabetes), or bilirubin (hepatitis). A pregnancy testshould be considered in any woman of childbearing age withacuteabdominalpain.

Imaging

In patients with acute abdominal pain, initial radiologicevaluationincludesplainfilmsoftheabdomeninthesupineandstandingpositionsandchestradiographs.Ifthepatientisunabletostand,aleftlateraldecubitusradiographshouldbeobtained.Theplainradiographsmayhelpconfirmdiagnosessuggestedbythe history and the physical examination, such as pneumonia(signaled by pulmonary infiltrates); intestinal obstruction (air-fluid levels and dilated loops of bowel); intestinal perforation(pneumoperitoneum);biliary,renal,orureteralcalculi(abnormalcalcifications);appendicitis(fecalith);incarceratedhernia(bowelprotruding beyond the confines of the peritoneal cavity);mesentericinfarction(airintheportalvein);chronicpancreatitis(pancreaticcalcifications);acutepancreatitis(theso-calledcoloncutoff sign);visceral aneurysms (calcified rim); retroperitonealhematoma or abscess (obliteration of the psoas shadow); andischemiccolitis(so-calledthumbprintingonthecolonicwall).

USGandCECTcanhelpconfirmthediagnosisorattimespickup diagnosis that might not have been thought of clinically.Remember, USG is an operator dependent process and if theultrasonologistreportsanormalUSGwhentheclinicalsuspicionofanintra-abdominalpathologyishigh,getaCECTdone.

An electrocardiogram is mandatory in elderly patients andin patients with a history of atherosclerotic heart disease.Abdominalpainmaybeamanifestationofmyocardialdisease,andthephysiologicstressofacuteabdominalpaincanincreasemyocardial oxygen demands and induce ischemia in patientswithcoronaryarterydisease.

ManagementAfter a working diagnosis has been established the course ofmanagementfollowsfourbasicpathwaysdependingonwhetherthepatient(1)isinneedofimmediatelaparotomy,(2)isbelievedtohaveanunderlyingsurgicalcondition, (3)hasanuncertaindiagnosis,or(4)isbelievedtohaveanunderlyingnon-surgicalcondition.

It must be emphasized that the patient must be constantlyreevaluated (preferably by the same examiner) even after theworkingdiagnosishasbeenestablished.Ifthepatientdoesnotrespondtotreatmentasexpected,theworkingdiagnosismustbereassessedandthepossibilitythatanotherconditionexistsmustbeimmediatelyentertainedandinvestigatedbyreturningtothedifferentialdiagnosislist.

Acute Abdominal CrisisA systematic approach to patients with acute abdominal painis essential because in some patients, action must be takenimmediately and there is not enough time for an exhaustiveevaluation. As outlined (see above), such an approach shouldinclude a brief initial assessment, a complete clinical history,a thorough physical examination, and basic laboratory andradiologic studies. These steps can usually be completed inless than 1 hour and should be insisted on in the evaluationofmostpatients.

Indications for Immediate Laparotomy

Among the most common of the abdominal catastrophes thatnecessitateimmediateoperationarerupturedAAAsorvisceralaneurysms, ruptured ectopic pregnancies, and spontaneoushepaticorsplenicruptures.Therelativerarityofsuchconditionsnotwithstanding, it must always be remembered that patientswithacuteabdominalpainmayhaveaprogressiveunderlyingintra-abdominal disorder causing the acute pain and thatunnecessary delay in diagnosis and treatment can adverselyaffectoutcome,oftenwithcatastrophicconsequences.

When immediate operation is not called for, the physicianmustdecidewhetherurgentornon-urgentbutearlyoperationis necessary, whether additional tests are required before adecisioncanbemade,whetherthepatientshouldbeadmittedtothehospitalforcarefulobservation,orwhethernon-surgicaltreatmentisindicated.

Suspected Surgical AbdomenIndications for Urgent Laparotomy or Laparoscopy

Onceadefinitivediagnosishasbeenmade,itiseasytodecidewhether a patient should undergo operation. On occasion,however,apatientmustbeoperatedonbeforeaprecisediagnosisis reached.Urgent laparotomy impliesoperationwithin1 to2hours of the patient’s arrival; thus, there is usually sufficienttime for adequate resuscitation, with proper rehydration andrestoration of vital organ function, before the procedure.Involuntaryguardingorrigidityduringthephysicalexamination,particularly if spreading, is a strong indication for urgentlaparotomy.Otherindicationsincludeincreasingseverelocalizedtenderness,progressivetensedistention,physicalsignsofsepsis(eg, high fever, tachycardia, hypotension, and mental-statuschanges), and physical signs of ischemia (eg, fever andtachycardia). Basic laboratory and radiologic indications forurgent laparotomy include pneumoperitoneum, massive orprogressiveintestinaldistention,signsofsepsis(eg,markedorrisingleukocytosis,increasingglucoseintolerance,andacidosis),and signs of continued hemorrhage (eg, a falling hematocrit).Additional findings that constitute indications for urgentlaparotomy include free extravasation of radiologic contrastmaterial,mesentericocclusiononangiography,endoscopicallyuncontrollable bleeding, and positive results from peritoneallavage(ie,thepresenceofblood,pus,bile,urine,orgastrointestinalcontents). Acute appendicitis, perforated hollow viscera, andstrangulated hernias are examples of common conditions thatnecessitateurgentlaparotomy.


Diagnostic and therapeutic laproscopy has come of age.Laproscopic cholecystectomy, appendectomy, treatment forperforated peptic ulcer,strangulated hernias has resulted inshorter operating times, less postoperative pain, fewer chestcomplications,shorterpostoperativehospitalstays,andearlierreturntonormaldailyactivitiesthantheformer.

Hospitalization and Active Observation

After the initial assessment has been completed, narcoticanalgesiaforpainreliefshouldnotbewithheld.Inappropriatelytitrated doses, analgesics neither obscure important physicalfindingsnormasktheirsubsequentdevelopment.Infact,somephysicalsignsmaybemoreeasilyidentifiedafteradequatepainrelief. Severe pain that persists in spite of adequate doses ofnarcotics suggests a serious condition that is likely to call foroperativeintervention.

Activeobservationallows theclinician to identifymostof thepatients whose acute abdominal pain is caused by NSAP orvariousspecificnon-surgicalconditions.Itmustbeemphasizedthat active observation means something more than simplyadmittingthepatienttothehospital:itimpliesanactiveprocessof thoughtful, discriminating, and meticulous reevaluationof the patient (preferably by the same examiner) at intervalsranging from minutes to a few hours, to be complemented byappropriatelytimedadditionalinvestigativestudies.

Additional investigativestudiesbeyondthebasiconesalreadymentioned should be obtained only if the results are likely toalterorimprovepatientmanagementsignificantly.Furthermore,the invasiveness, morbidity, and cost-effectiveness of eachadditional test must be carefully weighed. More liberal use ofsupplemental studies is justified in those patients in whomthe history and physical findings tend to be less reliable(eg, the very young, the elderly, the critically ill, or theimmunocompromised).

Supplementalstudiesthatmaybeconsideredincludecomputedtomography, ultrasonography, diagnostic peritoneal lavage,radionuclide imaging, angiography, magnetic resonanceimaging,gastrointestinalendoscopy,anddiagnosticlaparoscopy.Diagnostic laparoscopy has been recommended when surgicaldisease is suspected but its probability is not high enough towarrant open laparotomy. It is particularly valuable in youngwomen of childbearing age, in whom gynecologic disordersfrequently mimic acute appendicitis. Diagnostic laparoscopyhas also been shown to be useful in the assessment of acuteabdominalpaininICUpatientsandpatientswithAIDS.

Indications for Early or Elective Laparotomy or Laparoscopy

Early laparotomyor laparoscopy(within24to48hoursof theinitialevaluation)isreservedforpatientswhoseconditionsarenot likely tobecome life threatening ifoperation isdelayed topermit furtherresuscitationoradditional investigativestudies.Itisoftenpossibletoperformearlylaparotomyorlaparoscopyinpatientswithuncomplicatedacutecholecystitisordiverticulitisand those with nonstrangulated incarcerated hernias, therebypreventing the increasedpatient risk thatalwaysaccompaniesunplanned emergency operations as well as avoiding thelogistical impediments to unscheduled surgical procedures inthemiddleofthenightoronweekendsorholidays.Similarly,patientswithsimpleuncomplicatedintestinalobstructionsoftenbenefit from several hours of nasogastric tube decompressionandfluidandelectrolyteresuscitation.

Elective laparotomy or laparoscopy is reserved for patientswhose condition is highly likely to respond to conservativemedical management or highly unlikely to become life

threatening during prolonged periods (several days or evenweeks)ofdiagnosticevaluation.

Uncertain DiagnosisHospitalizationandActiveObservation

If the diagnosis is unclear, the clinician needs to decidewhether hospitalization and active observation are necessaryor whether outpatient evaluation is an option. All patientswithacuteabdominalpainandevidenceof extracellular fluiddeficits,electrolyteimbalances,orsepsismustbehospitalized.Furthermore,anypatientwithunexplainedabdominalsymptomswhoseconditionhasnotimprovedwithin24hoursoftheinitialevaluationshouldbehospitalized.

Supplemental studiesareoften required for furtherevaluationandcompleteworkupofpatientswithuncertaindiagnosesandfortheexclusionofmanymedicalconditionsthatdonotcallforoperation.Whenthediagnosis isnotobvious fromthehistoryandthephysicalexamination,apparentontheplainradiographs,or suggested by the basic laboratory studies, ultrasonographyand CT, both of which are now widely available, should beconsidered.CTismoreusefulintheearlyevaluationofpatientswithacuteabdominalpainbecauseitisnotoperatordependent,isnothamperedbythepresenceofoverlyinggas(whichtransmitssoundwavespoorlyand interfereswithultrasonography),andcanbeperformedrapidly(acompletescanoftheabdomenandpelvistakeslessthan15minutes).

Suspected Non-surgical AbdomenThere are numerous disorders that cause acute abdominalpain but do not call for surgical intervention. These non-surgicalconditionsareoftenextremelydifficulttodifferentiatefrom surgical conditions that present with almostindistinguishable characteristics. For example, the acuteabdominal pain of lead poisoning or acute porphyria isdifficulttodifferentiatefromtheintermittentpainofintestinalobstruction, in thatmarkedhyperperistalsis is thehallmarkofboth. The pain of acute hypolipoproteinemia may beaccompanied by pancreatitis, which, if not recognized, canlead to unnecessary laparotomy. Similarly, acute andprostrating abdominal pain accompanied by rigidity of theabdominalwallandalowhematocritmayleadtounnecessaryurgent laparotomy in patients with sickle cell anemia crises.Tofurthercomplicatetheclinicalpicture,cholelithiasisisalsooften foundinpatientswithsicklecellanemia.

Inadditiontonumerousextraperitonealdisorders,non-surgicalcauses of acute abdominal pain include a wide variety ofintraperitoneal disorders, such as acute gastroenteritis (fromenteric bacterial, viral, parasitic, or fungal infection), acutegastritis, acute duodenitis, hepatitis, mesenteric adenitis,salpingitis, Fitz-Hugh-Curtis syndrome, mittelschmerz,ovariancyst,endometritis,endometriosis, threatenedabortion,spontaneous bacterial peritonitis, and tuberculous peritonitis.AcuteabdominalpaininimmunosuppressedpatientsorpatientswithAIDSisnowencounteredwithincreasingfrequencyandcanbecausedbyanumberofunusualconditions(eg,cytomegalovirusenterocolitis, opportunistic infections, lymphoma, and Kaposisarcoma)aswellasbythemoreusualones.

further ReadingR. Scott James: Acute Abdomen. In: Textbook of Surgery: Thebiological basis of modern surgical practice. Ed. Courtney M.Townsend,Jr.Sixteenthedition,2001.HarcourtAsiaPte.Ltd.


Dr Vijay AgarwalExecutive Director PushpanjaliCrosslayHospital

Maintaining Quality in Healthcare Services

Dr. Vijay Agarwal

With the emerging changes in the access tohealth care information and the consequentincrease in consumer expectations, the needtoformalizethedefinitionof“Qualityofcare”isstrongly felt.

Adefinitionofquality,developedin1990,hasbeenwidelyacceptedandisstillrobusttoday:“Qualityof care is thedegree towhichhealthservices for individuals and populationsincrease the likelihood of desired healthoutcomes and are consistent with currentprofessionalknowledge.”

Several ideas in the definition deserve elaboration:

Health services refer to a wide array ofservices that affect health, including those forphysical and mental illnesses. It includesservices aimed at preventing disease andpromoting health and well-being as well asacute, long-term, rehabilitative, and palliativecare. Furthermore, the definition applies tomany types of health care practitioners (eg,physicians, nurses, various other health careprofessionals) and to all settingsof care (fromhospitals and nursing homes to physicians’offices, community sites, and even privatehomes).

Individuals and populations draw attentionto the different perspectives that need to beaddressed. On one hand, we are concernedwith thequalityofcare that individualhealthplans and clinicians deliver to individuals inspecific episodes of care. On the other hand,wemustdirectattentionto thequalityofcareacross the entire system. In particular, wemust ask whether all parts of the populationhave access to needed and appropriateservices and whether their health status isimproving.

Desired health outcomes refers to healthoutcomes that patients desire and highlightsthecrucial linkbetweenhowcare isprovidedand its effects on health, as well as the needto ensure that patients and their families arewell informed about alternative health careinterventions and their expected outcomes. Itunderscores the importance of being mindfulof people’s ability to function as well aspossible in their daily lives in addition toattending to more narrowly defined medicaloutcomes of disease. It also includes aconsiderationofpatientandfamilysatisfactionwithhealthcareservices.

Increases the likelihoodofbeneficialoutcomesreminds us that quality is not identical topositive outcomes. Poor outcomes occurdespite the best possible health care becausedisease often defeats our best efforts.Conversely,patientsmaydowelldespitepoorquality care because humans are resilient.Assessing quality thus requires attention tobothprocessesandoutcomesofcare.

Current professional knowledge emphasizesthathealthcareprofessionalsmuststayabreastof the dynamic knowledge base in theirprofessions and use that knowledgeappropriately.

This definition points to the need to createreliable and valid measures with which toassess the quality of health care over a widerange of diagnostic and therapeutic servicesand for a broad array of health and medicalproblems.Astheacceptanceofthesemeasureshas increased, so has the audience for them.With this wider attention has come the needtobroadenthedomainofmeasures to includeoutcomes as well as processes of care and tospeak to the concerns of consumers bydeveloping outcome measures that go beyondimmediate morbidity and mortality to includevariouskindsof functionalstatus.

In general, either processes or outcomes maybe valid measures of quality. For an outcometo be a valid measure, it must be closelyrelated to processes of care that can bemodified toaffect theoutcome.

Why QualityPoorqualitycareleadstosickerpatients,moredisabilities,highercosts,andlowerconfidencein the health care industry. Furthermore,consumers of healthcare services have certainrights and expectations regarding the qualityof health services they receive, and theirperspective is very important since satisfiedclientsaremorelikelytocomplyandcontinueusing thehealthcareservices.

In the provision of “Quality services”

Qualitycanbedefinedinafewwords-Doingthe right thing, right away, and not doing thewrong things.

1. Quality Assurance is to ensure thatactivities are carried out as perstandardsand tomonitorand improveperformance so that the care providedis as effective, efficient, timely and assafeaspossible.


2. Accreditation is an assessment used by health careorganizations to accurately assess their level ofperformanceinrelationtoestablishedstandardsandtoimplementways tocontinually improve.

Guidelines for Establishing a Quality Assurance Program

3. Ensuring quality care is the primary goal. To achievethisgoal, thehospitalshould:

4. Define the qualifications of physicians performing theprocedures and the facilities that are required for safediagnosticandinterventionalprocedures.

5. Identify important aspects of care, defining acceptablestandards for each of these areas, and designing asystemtomonitorandevaluate thecaregiven.

6. The program must be based on objective criteria thatcan define quality care and these criteria must beapplied to all individuals with the defined privilegeswithinan institution.

Essential Steps in Monitoring and Evaluation

Thereare tenstepsneededindesigningaprogram.Thereare:

7. AssignresponsibilityfortheMonitoringandEvaluation(M&E)Programe.g.ForCoronaryAngiographyaseniorRadiologist who is knowledgeable but who does notperform the procedure should monitor and report totheheadof thedepartment/relevantauthority.

8. Delineate the scope of the care provided e.g.Visualization of all Coronary vessels and theirramifications in theangiogram.

9. Identify important aspects of care e.g. successfulcannulation,satisfactoryresultsandnocomplications.

10. Identify indicators related to the important aspects ofcare e.g. unsuccessful cannulation, unsatisfactoryresultsandcomplications.

11.Establish the thresholds for evaluation related to theindicators e.g. unexplained indicators as determinedfromprocedureandclinicalnotes.

12.Collectandorganizedata.

13.Evaluate care when thresholds are reached e.g.Scrutinize theadverseoutcome.

14.Take action to resolve identified problems e.g. If thesame physician has recurrent problem considerremedialaction.

15.Determine whether care or service has improved anddocument improvement.

16.Communicate relevant information to the facility-wideQualityAssuranceProgram.

Theprogrammaybeusedasout-linedormodifiedtomeettheneeds of the individual institution. While it monitors severalareas of practice, other areas may be added using the sameformat.Thecomplicationandtechnicalsuccessratesarebasedon literaturedata.

Whose responsibility?TheChairmanoftheDepartmentisresponsiblefortheQualityAssurance Program for the entire department. He/she will

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evaluate care and report the results to the department at themonthly meeting. Each practitioner has the responsibility toensure that all thecaregivenbyhim/her isproperly recordedand that any complications are reported. The nurse isresponsible formaintaining therecordsandcomplications.

Data CollectionThe data source will consist of the logs of the patients. Thiscase log will include the patient’s name, hospital number,physician,date indication,andthespecificdiagnosis.

A separate complication log will be maintained, and willcontain thepatientdataandabrief summaryof thedetailsofthecomplication.

All records and case logs will be monitored as part of thedepartment’sconfidentialpeerreviewfile.

EvaluationAll complications will be presented by the staff physicianresponsible and the circumstances of the event will bediscussed at the monthly Quality Assurance Meeting. Inaddition, every six months the cumulative data will bepresented at the department meeting. Complications thatexceed the thresholds will be discussed, both for individualstaff and thedepartment as awhole.The complicationsof allphysicians in the department will be monitored in the samemanner. Similarly, when the thresholds for efficacy andappropriates are not met, a review will be done (see nextsection).

Action to Improve CareWhen complications are presented at the monthly meeting,theywillbeclassifiedasavoidableorunavoidablebythestaff.Meansofpreventing repeatedavoidable complicationswillbediscussedandagreementwillbereached.

The review done each six months will be divided into thethree areas of greatest concern: appropriateness, efficacy andsafety. When appropriateness thresholds are exceeded, eitherbyanindividualorbythedepartmentasawhole,thespecificcases will be discussed. The indications may need to bebroadened as a result of the review of new evidence.Alternatively,reemphasisoftheconsensusviewforproceduralindicationswilloccur.

When efficacy or safety thresholds are exceeded, the reviewwill focus on the specific cases, the general expertise of thepractitioners involved, the overall patient population served,and the equipment related issues. A specific plan of actionwillbeformulated.Thismayinvolvealternationof thresholdsbecause of the patient population, further continuing medicaleducationcoursesforsomepractitionersorvoluntarylimitationofprivileges.Theplanwillbeimplementedbythechiefofthedepartment,andhe/shewillmonitor the resultsof theactionstaken.

Where there is repeated or gross failure of an individual tomeet the standards outlined by the department, and there isnot sufficient improvement after the above actions, followingthehospital’smedicalstaffbylawsandprocedures,involuntarylimitationsofprivilegesmaybeconsidered.

follow-up of Actions TakenThe Problem area will be reviewed at subsequent meetings,after action has been taken. The chief of the department will

report each 6 months until the thresholds are no longerexceeded.Thisreportwillberecordedinthedepartment’sQAmeetingminutes.

ReportingAs defined in the institutional quality assurance plan, theresults of the department meetings will be reported to theHospital Quality Assurance Committee. The specific actionstakenwillbe included,aswill the resultsofpreviousactions.If there are any specific recommendations for altering thehospital privileges of any of the medical staff, based on theaccumulateddata, thesewillbepresented.

Tenets of ChangeTotal Quality Management (TQM) can be successful only ifthere isbuy-in fromthose inapositionof leadership.Leadersmust be educated in the concepts of TQM and make thateducation available to everyone in the organization. Leadersmust be aware that their roles will change and that theirprimary responsibility will be to become the mentors andfacilitators of change. This change in role will allow them toprovide the long range planning and goal setting necessary tosuccess.

Participants must realize that everyone is responsible forquality and that their input, ideas, and recognition of systemsuccesses and deficiencies is critical. Leaders must empowerthose participants working with the processes to makechanges.

The interdisciplinary nature of the system encourages closerelationships with hospitals, physicians, fire departments,police departments, dispatch centers, and other serviceproviders. It is imperative that challenges and change beviewed through the eyes of a ‘system’, which employs theinputofallof theplayers involved.

invites case studies, original, and review articles on different specialties

Please sumit your contributions by email

at

[email protected], [email protected]

or

by post at the address given below

Pushpanjali Medical Publications Pvt. Ltd. A-14, Pushpanjali, Vikas Marg Extn.,

Delhi-110092Ph: 22162818, 42427641, 22372852-58 Extn. 1602

Fax no. 011-22372851


V. K. MalhotraHead,DepartmentofFamilyMedicinePushpanjaliMedicalCentre

Pushpanjali Family Physicians Forum (PFPF)

V. K. Malhotra

PushpanjaliFamilyPhysiciansForumcontinuesto add quality strength by virtue of frequentsessions by experts with family physicianswho are eager to upgrade and update theirinformation base on related progress in thefieldofmedicalsciences.

AsessionwithDrVijayAgarwalwaswelcomeas he spoke on Quality Redefined as far asMedical Services are concerned. According toDrVijay,weareintheeraofdealingwithwellinformedandeducatedcustomerswhohaveacertain level of expectations from theMedicalfraternity and to meet such requirement/expectations, a family physician is supposedto provide services that are holistic innature and address the overall patient needs(psychological and physiological) rather hisdiseaseonly.

Dr Malay Nandi, Consultant MedicalOncologist with Fortis Hospital during hispresentation on Cancer and related problemswasoftheopinionthatfamilyphysicianmustplay the role of a guide and counselor withhis patients in advocatingthe precautions essentialto avoid cancer. In viewof increasing incidenceof Head & Neck cancersDr. Nandi wanted familyphysicianstostartacrusadein spreding the message torefrain from tobacco andtobacco products usage.He gave a brief on varioussymptoms that differenttypes of cancer maytrigger and knowing thesymptoms at an early stagecan be of immense help tothe sufferer and treatingOncologist.

A team of senior Anesthetists & Intensivist,Dr Alok Basu Roy, Dr Atul Gupta andDr Pardeep Sharma conducted a workshop onCPR. Dr Basu made a presentatioan on CPR,highlighting various methodologies involvedinCPRandtheintricaciesinvolveddependingon patient condition calling for attendingphysician to take certain precautions with aview to benefit the patient in as little timeas possible, however Dr Basu made it a mustthat help of dedicated facility to deal withpatient is the first thing a physician mustcall for before he / she starts even attendingthe patient. Dr Atul Gupta and Dr PardeepSharma gave a demonstration on CPR byusing the dummy (Resscae Anne). The CPRworkshop continued for good 2 hrs and wasappreciated by all family physicians in onevoice.

Intimate discussions between Dr. Vijay Agarwal and family physicians

Dr. Nandi taking his session with family physicians

(R to L) Dr. Atul Gupta, Dr. Pradeep Sharma and Dr. Alok Basu Roy busy discussing CPR


Pushpanjali Health Care Events and Initiatives

April 8, 2007 – Pushpanjali Health Care organising “Vision Pushpanjali” at indiaHabitat CentreOn the afternoon of 8th April, 2007 “VisionPushpanjali” was organized at India HabitatCentre as a welcome to honorable Dr VijayAgarwal(Formery,DirectorMaxHospital)whohas come on the Board of Crosslay Remedies

Limited, a Pushpanjali Group Company asExecutive Director. Gracing the occasion,Dr Vijay introduced himself by making apresentation on Quality Medical Practicesleading to services that are holistic in natureand address overall patient needs. Dr Vijayspoke on Medical Quality Assurance in linewith international standards and guidelines,essential to the functioning of a Health carefacility. He gave an extensive presentation onpre-requisites to NABH accreditation and theimportance of such accreditations in view ofdelivering services on par with the best andto the satisfaction of service users.

On the occasion, Dr Vinay Aggarwalre-emphasized the importance of qualityhealthcare and appreciated Dr Vijay’s effortin letting the audience know about the same.

He also welcomed Dr Vijay on the Boardof Directors of Crosslay Remedies Limitedengaged in the erection of 400 bedded multisuper specialty Pushpanjali Crosslay Hospitaland hoped that with Dr Vijay’s joining, theteam would be better placed in deliveringa world class facility on schedule and withsystems that were of high quality and userfriendly to both service providers and serviceconsumers.

May 1, 2007 – Crosslay Remedies Ltd. open School and Dispensery for children and the workers at the upcoming project, Pushpanjali Crosslay HospitalCarrying out the mission to serve society,Pushpanjali started a play school for thechildren of construction workers at the site

of upcoming Pushpanjali Crosslay Hospital.There are more than 40 children who havebeen provided with uniform, writing materialand are offered day meal. Two teachershave been deployed to run the school whilenone other than Dr. P D Garg has taken theresponsibility to manage the progress of thish u m b l eini t ia t ive .A freedispensaryhas alsobeen set upat the sitewith DrAjayAggarwal at thehelmof affairs.The twonoble initiatives have brought a ray of hopeamong the construction workers and theyare extremely happy to be taken care of ---perhaps for the first time in their live.

May 13, 2007 – Crosslay Remedies Ltd. celebrate Mother’s Day over breakfast at the site of Pushpanjali Crosslay HospitalMothers Day on 13 May was celebrated instyle over Breakfast at the site of Pushpanjali

Dr. Vijay Agarwal making his presentation

Audience all ears to the presentation

Children enjoying the positive change in their routine

Dr. Ajay Aggarwal attending a patient

Dr. Satya Gupta, R. Sahni and Dr. P.D. Garg (L to R) discussing the project PCH


Crosslay Hospital. Attended by over 60 medical consultantsand Pushpanjali team members. Talking on the occasion, DrVinay expressed his gratitude to two mothers present at the

site, one who gave him birth (Shrimati Satya) and one whogave him firm footing in medical field (Dr Satya). Dr Vinay’sgesture was well applauded and appreciated.

May- June 2007 – Pushpanjali organised basic training programe on Computer operations for Consultants

In pursuit of continued improvement in human talent andmanpower, on the initiative of Dr Vinay Aggarwal, more than

30 consultants of Pushpanjali Hospitals undertook, in batchesof 5-6, a five-day crash course on basic computer operations.

All the consultants were very happy to be offered such anopportunity and their enthusiasm in learning the teachingduring each of the session was to be seen to be believed.

June 10, 2007 – Press Conference on Aesthetic Surgery with Dr. Dinesh BhargavaAesthetic surgery is fast emerging on the medical horizon ofIndia, every other day the press carries out one or the othernews about various procedures either in demand or beingperformed. Pushpanjali has decided to set up a “Centre ofExcellence” in Aesthetic surgery at the upcoming PushpanjaliCrosslay Hospital. As reported in our last issue, a three-day

workshop on Aesthetic surgery was organized by PushpanjaliHospitals and on the success of same, there has been a lot ofinterest expressed by media community to know more aboutour initiatives. In pursuant of the demand, on 10th june,2007 a press conference with Dr Dinesh Bhargav, an eminent

Aesthetic Surgeon from USA who is setting up the centre ofexcellence and settling down with Pushpanjali was organizedat IMA Convention Centre. The press conference was wellattended by over 20 senior reporters.

July 7-8, 2007 – Ist interactive ECG Workshop using touch pad technology Pushpanjali Hospitals together with National Heart Instituteand IMA-East Delhi Branch under the leadership of

Dr.VinayAggarwal(Chairman&ManagingDirector,PushpanjaliHospitals), Dr O P Yadava (CEO & Chief Cardiothoracic

Dr. Vinay talking about the height while Dr. Satya Jain and Dr. P.. D. Garg appreciate the details

Trainer highlighting the nuances of computer operations

A Computer class in progress

Dr. N. Saini (L) and Dr. Dinesh Bhargav (R) listening to Dr. Vijay Agarwal

A Press Reporter being welcomed to the Press conference

A presentation in progress


Surgeon, NHI), Dr Atul Gupta (President, IMA-East DelhiBranch) and Dr Anil Motta (Organizing Secretary) organizeda first of its kind two-day workshop on Electrocardiography

on 7-8 July, 2007 at IMA Convention Centre, New Delhi. Themost redeeming features of the workshop were a) Exclusivescientific programme designed by Dr O P Yadava, b) Eminent

faculty, c) Touch pad technology, d) Very well attended byover 200 delegates, e) Extremely interactive and f) Very wellorganized.

There was overwhelming appreciation of the content andstyle of the workshop by a majority of attending delegates.A large number of pharma corporates and organizationsfrom associated industry including multi national banksparticipated in the event. Overall the workshop was a grandsuccess and served the purpose it was organized for.

August 22, 2007 – Press Conference on Medical Emergencies workshop There is a pressing need to keep doctors updated with theemerging trends and technological advancements so that theycan efficiently handle emergency cases.

“Therefore, themedical fraternityhas tobeaccordingly tunedand updated. The coming update on medical emergenciessimply aims at keeping the medical fraternity in tune withlatest advances in managing such cases,” Dr Vijay Agarwal,Director and Advisor, Strategy & Planning, Pushpanjali Groupof Hospitals said at the press conference.

“In India, continuous medical education is still not astructured activity. We are just making humble contributions

to fill that void,” Dr Rajiv Gupta, the city’s leading physicianand Vice- Chairman of the workshop said.

Speaking on the occasion, Dr Atul Gupta, President, EastDelhi Branch of IMA, said that the experts in the workshopwould discuss different dimensions of medical emergenciesthrough case-based studies.

“The two-day workshop is a joint initiative of PushpanjaliGroupofHospitalsandEastDelhiBranchofIMA,”Dr.ArvindNarayan, Hony. Secretary IMA East Delhi Branch informed atthe press conference.

Pushpanjali Medical Publications stall during trade exhibition at the workshop

Dr. Vinay and Dr. Yadava welcoming the chief guest Dr. Padmavati

A panoramic view of the audience enjoying the deliberations

Dr. O.P. Yadava fine tuning a presenation while Dr. Vinay Aggarwal and Dr. Anil Motta look on

Dr. Vijay Agarwal addressing the reporters

Delegates participating in the proceedings


August 25- 26, 2007 – “Medical Emergencies” An Interactive Case Based Update

Pushpanjali Medical Publications, Pushpanjali Health CareCompany organized a two-day Interactive Case Based UpdateonMedicalEmergencies togetherwith IMA-EastDelhiBranchon 25-26 August, 2007 at IMA Convention Centre, NewDelhi.

ChiefGuest,DrAjayKumar,PresidentIMA,gracedthereleaseof books and inaugurationof the conference. Speakingon theoccasion, Dr Ajay extended his heartfelt congratulations to DrVinay Aggarwal and Pushpanjali Medical Publications for anexcellent work related to high quality books that benefitedmedical fraternity immensely andalso for conducting a seriesof Medical workshops to fine tune patient management skillsof clinicians. He was all praise for Dr Parkash Gera andDr Ashok Grover, Chairman and Organizing Secretary

respectivelyoftheconferenceforworkingoutacomprehensivescientific programme to be conducted by more than 50 eliteexperts. According to Dr Ajay, organizing such a conferenceis a Herculean task and calls for great amount of wisdom,vision and courage.

Dr Ajay thanked Dr Atul Gupta, President, IMA-East DelhiBranch and Dr Arvind Narayan, Secretary of the branch for

their initiative of joining hands with Pushpanjali Health Carefor an excellent conference.

Dr Vinay speaking on the occasion thanked Dr Ajay for hisinspirationalpresenceandencouragement,whichaccordingtohim would help Pushpanjali to further strengthen the resolveto set an example / benchmark in health care industry for itspioneering “Cooperative Corporate” concept.

The conference was a roaring success as more than 200delegates from NCR Delhi and adjoining states attended thesame, while pharmaceutical and allied industry supportedwhole heartedly the cause of the conference.

Books released by Pushpanjali Medical Publications entitled“Medical Emergencies IIIrd edition”, “Pocket Book ofPoisoning” and “Baby’s Own Cook Book” did brisk businessand were a sell out from the stall put up by PushpanjaliMedical Publications under the supervision of Ms Tabassum.

Theconferencebasedonthefeedbackfromattendingdelegatesand the faculty, was an excellent job done and they were allpraise for Dr Ashok Grover, Organizing Secretary and histeam and Mr Atul Gandotra, Conference Coordinator and histeam, who played their respective roles in the best possiblemanner under the overall leadership of Dr Vinay Aggarwal,Chairman and Managing Director, Pushpanjali Health Care.

Chief Gust Dr. Ajay Kumar (C) flanked by Dr. Ashok Grover, Dr. Atul Gupta, Dr. Vinay Aggarwal, Dr. Parkash Gera, Dr. Vijay Agarwal and Dr. Arvind Narayan (L to R)

Dr. Ashok Grover (Org. Sec.) And Dr. Parkash Gera (Chairman) watchful on the proceedings

A panaromic view of the audience

A session in progress


Dr. Mukesh Ajmera (L) and Dr. Vinay Aggarwal assessing the scientific sessions while Mr. Atul Gandotra discusses logistics with Dr. Naveen Atal

Chief Gust Releasing Medical Emergencies 3rd edition together with the editors Dr. Rajiv Gupta Dr. Ashok Grover, Dr. Vinay Aggarwal and Dr. Parkash Gera (L to R)

Dr. O. P. Kalra, Dr. Sunil Parkash and Dr. N.P. Singh ( L to R) all absorbed while the presentation is on

A beaming Dr. Mamta Grover (L) on the release of her Baby’s Own Cook Book

Pushpanjali Publication team busy selling books

Editors Dr. N.P. Singh and Dr. Ashok Grover together with Dr. Vinay Aggarwal and Dr. Ajay Kumar releasing Pocket Book of Posioning

The delegates learning the finer naunces of CPR

A worm eye view of the trade exhibition at the venue


Guidelines for Submission of Manuscripts

You are invited to contribute your articles,case reports, clinical experiences and anyotherrelevantmaterialwhichisforthebenefitof clinical community at large. The articles/contributionshouldbesent to:

TheEditor in-ChiefDr.VinayAggarwal

&TheEditor

DrAshokGroverPushpanjaliMedicalPublicationsPvt.Ltd.

A-14,15,Pushpanjali,VikasMargExtn. Delhi–110092

E-Mail :[email protected]

[email protected]

Manuscripts can be submitted by e-mail,but it is mandatory that photographs (if any)shouldbesubmitted inglossypaperbypost.

Tomaintaintheuniformitythearticles,authorsshould followthe followingpattern:

All Manuscripts submitted to Medi-Focusshould not have been published in any formin any other publication, and become theproperty of the publishers. All manuscriptsmustbeaccompaniedbythefollowingwrittenstatement signed by all the authors. “Theundersigned author (s) certify (ies) that thearticle is original, is not under considerationby any other journal, and has not beenpreviouslypublished.Allcopyrightownershipof the manuscript entitled (title of article)is hereby transferred to the publishers ofMedi-focus.”

Articles will be edited for style and grammar.Technical jargon is to be kept to a minimum.Americanspellingsareused in the Journal.

Preparation of Manuscriptsformat. The manuscript must not exceed 10-12 pagestypedindoublespace(including 15-20 references). Number all pages in sequence, beginning with the title page. Submit a copyofallelementsarrangedas follows:

Title Page.Thisshouldcontainthetitleof themanuscript (5-6 words title) the names of allauthors,andtheiraffiliations,ashorttitle(notmore than 20 letters to be used as runninghead)andatthebottomofthepage,institutionwhere theworkhasbeencarriedout, and theaddress for all correspondence and reprints,includingfax, Phone and E-mail.

Structured Abstract. Should be a factualcondensationoftheentireworkwithobjective,

methods, results, conclusions and shouldbe in one para. The abstract should statethe purposes of the study or investigation,basic procedures (selection of study subjectsor laboratory animal; Observational andanalytical methods), main findings (givingspecific data and their statistical significance,if possible), and the principal conclusion. Itshould emphasize new and important aspectsof thestudyorobservations.

Clinical Briefs must not exceed 1000 wordswithone figureand5-8references.

Text. Authors must consider and follow theformat : Introduction, Material and Methods,Results, Discussion, and Conclusion (ifnecessary). The matter must be written ina manner which is easy to understand, andshould be restricted to the topic discussed.Donotusevertical linesorunderlining inthetext.

Acknowledgmentsshouldbeplacedasthelastelementof the textbeforereferences.

Abbreviate measurements (cm, ml).Abbreviations should be used sparingly andmustbeprecededby the full forminitially.

References. In citing other work, onlyreferences consulted in the original should beincluded.Ifitisagainstcitationbyothersthisshouldalsobestated.

Use the Sequential numbering system.Arrange the reference list in the sequence inwhich the references are first cited. In thetext, references cited should be superscriptedandshouldappearon topof the lineafter thepunctuation. Responsibility for the accuracyand completeness of references lies with theauthor.

References should not exceed 15-20 in number.

The Journal follows the Vancouver system of references. References should be numberedandlistedconsecutivelyintheorderinwhichthey are first cited in the text. Tables shouldbe identified in the text by superior Arabicnumerals.Thefulllistofreferencesattheendofthepapershouldinclude:namesandinitialsofallauthors (unlessmore than6,whenonlythe first 3 are given followed by et al); thetitleof thepaper; the journal title abbreviatedaccording to the style of Index Medicus; yearof publication; volume number; first and lastpagenumbers.Referencesofbooksshouldgivethe book title, place of publication, publisher

Vol. 5, Issue 3 & 4 April - Sept 2007�0

and year; those of multiple authorship should also includethe chapter title, first and last page numbers, and names andinitialsofeditors.

1. Mehta MN, Mehta JN. Serum lipids and ABO bloodgroups in cord blood of neonates. Indian J Pediatr1984;51 :30-43.

2. SmithGDL.ChronicEarDisease.Edinburgh;ChurchillLivingstone,1980 :78-81.

3. MalhotraKC.Medicogeneticproblemsof Indiantribes.In Verma IC, ed. Medical Genetics in India. Vol. 2.,Pondicherry;AuromaEnterprises,1978;51-55.

Papers accepted but not yet published should be included inthe references followed by “In press”. Those in preparation,personal communications and unpublished observationsshouldbereferred toassuch in the textonly.

For more detailed information about the Vancouversystem, authors should consult “Uniform requirements formanuscripts submitted to biomedical journals’ (Br MedJ.1982;284 :1766-70).

Legends.Adescriptivelegendmustaccompanyeachillustrationandmustdefineallabbreviationsusedtherein.

Illustrations and graphs. Submit glossy black and whitephotographs.Thecostreproductionofcolourphotographswillbe borne entirely by the author. Number all illustrations withArabicnumericals (1,2).

Tables. These must be self-explanatory. The data must beclearly organized and should supplement and not duplicatethe text. Explanatory matter should be given as footnotes.Statisticalanalysesusedmustbeappropriate.Eachtablemusthave a title and should be numbered with Arabic numericals(1,2).

Manuscript Submission Checklist

1. Threecopiesofmanuscript inhardcopy

2. Name and address of author responsible forcorrespondence.

3. StructuredAbstract (150-200words)&3-5keywords.

4. References,citedconsecutively in the text.

5. Threeglossyprints for illustrations.

6. Documentation of permission to reuse any previouslypublishedmaterial.

7. Covering letter, including statement of originality andsignifyingapprovalof finalcopybyallauthors.

8. Upon final acceptance of the manuscript, a CD diskin MS Word should be submitted. The disk should belabeled with the title of article, file name and versionused and must contain the final revised manuscriptmaterial.

medifocus april 2007

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