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Guest Lectures 21 Guest Lectures INTERNATIONAL PEDIATRIC UPDATE 2004 Proceedings & Abstract Book Anemia Beyond Iron Deficiency Dr. M R Lokeshwar Anemia is defined as a reduction of the red blood cell volume or hemoglobin concentration and hematocrit below the range of values occurring in healthy persons, or two standard deviation below the mean for the normal population, age and sex1 Anemia is a global problem of immense health significance affecting persons of all ages and economic groups. It is ranked as the commonest chronic malady mankind has ever suffered. Approximately 1500 million people i.e. 30% of the world population suffers from anemia most of them suffer from iron deficiency state.2,3 It is more common in developing countries like ours. 30-50% of pregnant ladies and 60 to 80% of school going children are reported in some studies to be iron deficient. The prevalence of iron deficiency anemia in a developing country like India has been found to be as high as 63% in 1-3 years.age group and 44 % in the age group 3 to 6 years of children as per study by I.C.M.R.in 1977.4 More recent reports of N.F.H.S.-2 shows that the prevalence has not much changed in 199899 and are still 74% among children 6-35 month age.5 (Fig. 1 shows the WHO criteria for diagnosis of anemia) Fig. 1 WHO Criterion for Diagnosis of Anemia6 Age / Sex Group Children 6 Mon - 6 yr Children 6-14 yr. Adult males Adult females (non-pregnant) Adult females (pregnant) Grading of Anemia Mild Anemia Moderate Anemia Severe Anemia Very Severe Anemia Hb (g/dl) Less than 11 Less than 12 Less than 13 Less than 12 Less than 11 10 gm%, But < than Normal For Age 7-10 gm% < 7 gm%. < 5 gm% 22 The anemia of childhood may be classified into 2 broad groups: 1 Those resulting primarily from decreased or ineffective production of red blood cells or hemoglobin; and 2 Those in which increased destruction or loss of red blood cells is the predominant mechanism. A morphologic classification : It is often used on the basis of indices. Anemia can be classified into three types. 1) Microcytic Hypo chromic anemia M.C.V. less than 75 cu.mm, M.C.H. is less than 29pg & M.C.H.C. less than 32% 2) Macrocytic anemia Where M.C.V. is greater than 98cmm 3) Normocytic Normochromic anemia Where M.C.V. is 75-98 cmm, M.C.H. is 29pg to 34pg and M.C.H.C. is 30-36% (The Fig. 2, an Algorithm on next page shows approach to microcytic hypochromic anemia.) Classification of anemia based on red blood cell mean volume (M.C.V.) & (R.D.W.) Anemia in childhood may also be classified by variations in cell size and shape, as reflected by alterations in the red blood cell distribution width (RDW). A knowledge of both the MCV and the RDW can be helpful in the initial classification of the anemia of childhood RDW is the coefficient of variation of red cell volume distribution RDW is the objective documentation of subjective anisocytosis Normal range: 11.5 to 14.5 % (Refer to Fig. 3 for RDW values in various diseases) As I.D.A. is very common and with few clinical & physical findings and mimic other types of anemias, many a times these children are investigated extensively & treated for I.D.A. without confirming the diagnosis. Few illustrative cases will help drive home this point. INTERNATIONAL PEDIATRIC UPDATE 2004 Fig. 2 Algorithm of approach to microcytic hypochromic anemia P.S. Examination / Red Cell Indices Hypo chromic, microcytic anemia (MCV <75 u3, MCH <29 Pg., MCHC <32%) S. Iron studies Normal or decreased Normal or increased Iron store / Ferritin EPP Decreased Increased IDA Anemia TIBC increased of chronic Rectic increased disorder Normal or decreased FEP Normal Abnormal Normal Hemoglobinopathies BM Examination & / Iron stain Thalassemia Ring sideroblast Sideroblastic Anemia TIBC Normal FEP increased TS decreased Fig. 3 RDW Values in various diseases RDW Normal RDW High Low MCV Thal trait Normal MCV Normal anemia High MCV Aplastic IDA Chronic liver disease, malignanies, myelofibrosis, myelotoxic drugs Megalo. An., Imm. Hem. An. Case 1 : Kamlesh, Age 8 yrs. Child was referred for anemia of 7 gm% O/E : Clinically NAD except pallor. No lymphadenopathy, No hepatosplenomegaly, No petechie / purpura Investigations showed: Hypochormic, microcytic anemia with MCV 60 u3, RBC 3.4 Mil. RDW 18%, T.S.: 8% Diagnosis: I.D.A. Child was treated with Syp. Tonoferron for 3 months Hb. increased from 7 to 9 gm% in 23 1 month but no further increase . Smear repeated showed basophilic stippling. Father working in the standard battery, fathers teeth showed blue lines Further investigations confirmed the diagnosis of Lead Poisoning in father & the son Case 2 : Gurdeep Singh 5 yrs. male child C/o Pallor since early childhood H/o Cough, cold 10 days No bleeds / Jaundice / Wt. Loss / Bl. Trans. Punjabi community. No H/o consanguinity Pallor+, No icterus. LN / Liver / Spleen NP, S/E-NAD Investigations: Hb. 9.0 gm%, WBC 9800/cumm, P 60 % L 40% MCV 60, MCH 25, RDW 12, RBC 6.5 mill S. Iron: 35, TIBC: 350, TS: 10%, S. Ferritin: 25 ng/ml HbF 0.6%, HbA2: 3.3% Child was initially treated with oral iron & folic acid with no response Proceedings & Abstract Book No single principle can answer All lifes complexities - Felix Frankfurter Experience may be defined as the ability To continue making the same mistakes With increasing confidence. - Dr. D. W. Webb Investigations: repeated after 2 months Hb. 10 gm%, WBC 9800/cumm, MCV 60, MCH 25, RDW 12, RBC 6.5, Retic 1% P 60 L 40 Hypo / Micro +, In view of High RBC count, low MCV, low Hb, Normal RDW, Nestroft: +ve Hb F: 1%, Hb EPP: NAD, Hb A2 : 3.6%. Sickling: Negative Diagnosis : Thalassemia Minor High RBC, low MCV, low Hb, normal RDW suggestive of thalassemia minor. Microcytic anemia non-responding to iron are due to - Ineffective iron preparation / inappropriate dose - Malabsorption, Persistent bleeding - Thalassemia minor - Anemia of chronic infection - Associated Folic acid B12 deficiency - Sideroblastic anemia Repeated investigations did not give any clue to the diagnosis No evidence of thalassemia minor, Coombs test ve, Bone marrows : Mild erythroid hyperplasia, no evidence of megaloblastosis. On routine round BP was taken : 180/110 mmHg. Further investigations Creatinine 4.0 mg%, BUN 79 mg/dl Urine R : Albumin ++, Microscopic - Pus cells 10-15/hpf. Diagnosis : Chronic Renal Failure Carry home message : Routine thorough clinical examination must evaluation like blood pressure must be taken CBC Burr cells may be indicative of underlying pathology urine exam. must be done Carry home message: Nestroft test useful as screening test in hypochromic, microcytic anemia to suspect thalassemia minor. But not diagnostic. High RBC, low MCV, low Hb, normal RDW suggestive of thalassemia minor. HbA2 may be borderline low in thal minor when associated with IDA. Repeat the test after treatment. Case 4 : Ganesh, Age 10 yrs H/O Persistent anemia not responding oral iron therapy since 6 months H/O loose motion off &on Since 4-5 years. Large bulky stools Distention of abdomen ++, Failure to thrive/ No hepato splenomegaly. Results of investigations Hb 7 gm%, MCV 60 cumm, R.D.W.18 RBC 3.4 m. T.S. 6% HbF 0.8%, HbA2 2.8% Further investigations confirmed the diagnosis of Gluten Induced Enteropathy with Malabsorption Syndrome, Anti-gliadin antibodies: +ve Child was given parenteral iron and correction of the diet, child responded well and growth improved. Case 3 : Master Mohd. Ashraf, Age 11 yrs. C/o marked pallor noticed by the family physician since 2 months C/o Mild puffiness of the eyes O/E : Conjunctiva and.nails : pale, No lymphadenopathy, No hepatosplenomegaly, No bony tenderness, No petechiae / purpura /Ecchymosis Investigations done : Hb 5 gm%, Retic count 2%, MCV 80 u3, MCH 27 Pg, MCHC 33 %, RDW 18%, Platelet count 4,50,000/cmm. PS Exam. : Micro +, Normo ++, Occasional Macro +, Burr cells +, Sr.Iron 35 ug/dl, TIBC 355 ug/dl. TS 10 % Child was treated with oral iron therapy, Hb increased upto 9 gm%, no further improvement. 24 Case 5 : Rohit, 8 yrs male C/o Pallor off & on : for 3 yrs No H/o feverH/o jaundice : 2 yrs. back O/E: Pallor +, No koilonychia / platynychia, No generalized lymphadenopathy, Liver : just palable, Spleen : 3 cm Results of investigations done Hb 6.5 gm%, Retic 7.0%, MCV 82, MCHC 37, MCH 27, RDW 16, WBC 9600/cmm, Platelets 1,86,000/cmm INTERNATIONAL PEDIATRIC UPDATE 2004 Liver profile : Within normal limits. Multiple investigations : No conclusion Child was referred for further management PS Examination Diagnostic. Diagnosis : Spherocytosis Mind is like a Parachute It works only when it is open What mind can think, Eyes can see! Case 6 : Baby Navita, Age 1 month Referred by pediatrician for persistent progressive anemia & enlarged liver & spleen. Antenatal period No H/o fever / rash during early antenatal period in mother No H/o lymphadenopathy in the mother H/o fever with chills during 8th month of pregnancy in mother O/E : Wt.3.5 kg, AF 3 x 3cm, Conjunctiva / Nail: Pale, No lymphadenopathy, Liver 3 cm, Spleen 2 cm. Results of investigations done: Hb.10.8 gm%, WBC 20,800/cmm, P60%, L40%, Normoblasts 8-10/100 WBC, MCV 58 u3, RDW 18%, Platelet count 1.3 lac/cmm. K.B. test in mother : -ve Coombs test: Direct & Indirect ve, G6PD: Normal activity Child was treated with Oral iron drops, multivitamin drops Child was brought again after 10 days with further drop in Hb, fever spiky ranging from 100 102 F, persistence of hepatosplenomegaly Differential diagnosis : - Anemia due to intrauterineinfection - Chronic feto-maternal Hg. - Congenital spherocytosis - Congenital / Neonatal Malaria PS Exam : Microcytic, hypochromic anemia P. Vivax present. Diagnosis malaria Child was treated with Chloroquine & packed cell transfusion was given Carry home message: What mind can think, eyes can see ! PS exam. is a key to diagnosis Case 7 : Raghavendra, Age: 3 months boy, Wt : 4 kg. H/o Feer and cold cough off & on 25 Child was referred for progressive pallor : noticed by family physician O/E: Pallor, listlessness, Failure to thrive Distension of abdomen No jaundice, Occasional cervical gland non-specific Liver = 3 cm, Spleen = 3 cm Results of investigations done Hb 5.0 gm% Retic 1.8 % MCV 68 cumm MCHC 30 % MCH 21 Pg. RDW 18 % WBC 3500/cmm Plat. 88,000 Child was treated with Iron and folic acid without much response Further investigations done to rule out abnormal hemoglobinopathy, Childs HbF 8%, HbA2 : 3.2%, Mother & Father : HbA2 : 2.3% & 3.1%, No evidence of thalassemia Peripheral smear examination did not show any spherocytes TORCH titre in mother child CMV IgM +ve +ve CMV IgG +ve +ve Rubella IgM -ve -ve Rubella IgG +ve -ve Toxo IgM -ve -ve Toxo IgG -ve -ve Diagnosis: CMV Infection in Mother & Child Carry home message: High index of suspicion is key to the diagnosis Proper history of the mother gives a clue to the diagnosis H/o fever with rash in the mother may be present. Anemia & hepatosplenomegaly in early infancy Keep in mind intrauterine infection (after ruling out other common causes) Case 8 : Baby Kajal, Age 2,1/2 yr. Child was admitted on surgical side for swelling over the hand. ? cellulitis X-ray hand showed osteomyelitis CBC showed : Hb 6 gm%, WBC 22,300/ cmm, P70%, L28%, M1%, E1%, Child was referred for correction of anemia, as was to be taken up for surgery Proceedings & Abstract Book P.S. examination showed sickle cells. No surgery required. References (1) M.R. Lokeshwar V.P. Choudhry - Introduction to anemia in children I.A.P. Text book of pediatrics. I.C.M.R.Technical report series no. 26. National Institute of nutrition. 1977. Hyderabad. (2) DeMayer E.H. Adiels Tegman M The prevalence of anemia in the world, World health statistics 1985, 38, 302-316. (5) N.F.H.S (2000) India 1998-1999. National Family Health Survey-2, Key findings Anemia among women and children. International Institute for Population Science Mumbai 2000-19. (3) Agarwal D.K., Upadhyay S.K., Tripathi A.M., et.al. Nutritional status, physical work capacity & mental function in school children, New Delhi Nutrition foundation of India Scientific report No.6. 1987. (4) I.C.M.R. Studies on preschool children. (6) Dallaman P.R. Iron deficiency and related nutritional anemia In Nathan D, G., Oski F.A Hematology of infancy and childhood. W.B. Saunders 1987, 274-314. Evaluation and Management of Intractable Epilepsy Dr. Vrajesh Udani, Consultant Pediatric Neurologist, P D Hinduja National Hospital & Medical Research Center, Mumbai In the majority of children epilepsy remains a mild disorder with 60 80% remitting spontaneously or with treatment 123 . Epidemiological data suggest that there is a 68% probability of achieving a 5 year remission 1. Seizure control, however, remains poor in about 15 20 %. Though Indian studies suggest a higher incidence (40 70%) of intractability4 , these are from tertiary care centers with an inherent bias towards more difficult cases. If a minimum of 20% were taken along with a minimum point prevalence of epilepsy of 5 / 1000 (in India figures vary from 4 -7/1000), the load of intractable epileptics would be about 1 million persons. The psychosocial, intellectual, financial and human cost of this is considerable for a developing nation. Medical Intractability : There is no consensus defining intractability. Some have used frequency of seizures as a criterion5. However, less frequent severe status episodes are as devastating as more frequent brief seizures. Others have used a time-bound (usually 2 years) lack of response to at least two frontline AEDs and a newer agent as monotherapy and even as rational polytherapy6. However, so called 26 catastrophic epilepsies of infancy and childhood can dramatically disrupt normal development in a few weeks to months, making a time-bound definition impractical. Other vague definitions call epilepsy intractable if it interrupts normal activities of life despite relevant therapy. Epileptic encephalopaties like LandauKleffner syndrome (LKS) and electrical status in slow wave sleep (ESES) defy the definition as seizures may be absent or very few; however, the epileptic process has a similar devastating effect on language and cognition as conventional intractable epilepsy syndromes. Associated neurological and developmental impairments must be considered as well. Weekly or monthly seizures in a high functioning adolescent obviously are more disruptive than daily brief seizures in a severely handicapped patient. The practical importance of these definitions is to decide appropriate alternative therapies, both medical and surgical. New anti-epileptic drugs (AEDs), the ketogenic diet and resective surgery are easily available in more developed nations. In the developing work the treatment gap is estimated to be high7 INTERNATIONAL PEDIATRIC UPDATE 2004 and specialized services are available in only a few centers. Risk Factors for Intractability: Age of Onset of seizures This is probably the most consistent risk factor in almost all studies 2,3,5,8,9,10. It is significant throughout the age spectrum in childhood8. Even in the MR population age of onset is significantly earlier in the intractable group as compared to the controlled group5. Remote Symptomatic Seizures: This is again consistent throughout studies 2,3,8,9,10 . Static neurological impairments and mental retardation make intractability more likely. In mentally retarded children with epilepsy intractability is seen in about half5, a figure probably threefold higher than those with normal intelligence2. This probably emphasizes the importance of the underlying neurological substrate in deciding the severity of the epilepsy. 10% of children become retarded due to intractable epilepsy5,11. Types of Seizure and Syndromes: Tonic 3,5, myoclonic2,3,5,9 seizures are the ones difficult to control. Atypical absence2,5, complex partial and even generalized tonicclonic (GTC)9 have been identified in some studies only. Typical absence seizures on the other hand are negatively correlated with intractability3. Infantile spasms (IS)2,8 and Lennox-Gastaut syndrome (LGS)2 are the most common syndromes identified in this group. Table 1 lists etiologies and syndromes associated with poor control. Other Factors: Studies have found male sex 9, status epilepticus 8 as important predictors. However, these have not been consistent. Analysis of 123 childhood cases9 revealed intractable epilepsy more in males with an age of onset of seizures below 2 years, with static or progressive neurological disease in the form of mental retardation / regression, and / or abnormal neurological findings, myoclonic, mixed seizure types of known epileptic syndromes. Prognosis: A 5-20 year follow up study of 145 children with medically resistant seizures revealed a seizure remission rate of 4% per year in normal / borderline intelligent children and 27 only 1.5% remission rate in retarded children10, implying that worst epilepsies may remit and must be considered when treatment decisions are taken. Several observers have documented lower mean IQ, poor academic performance, behavioral abnormalities and later, higher rates of unemployment and other psychosocial impairments in chronic active epilepsy11,12. In a prospective study of medically intractable complex partial seizures starting in childhood followed up for several years, only one-third achieved seizure free and full independent living13. What is responsible for this adverse outcome is still not clear. The consensus is that the abnormal neurological substrate, the seizures themselves, the EEG epileptic activity, the AEDs and the psychological effects of a chronic illness all play a role although to different degrees in different Understanding the individuals 11 . mechanisms of seizures induced changes in the developing CNS has been helped by the study of surgically obtained brain tissue. It is now accepted that in some, prolonged febrile status epilepticus triggers off hippocampal neural cell loss12 possibly through excitatory neurotransmitter release. The immature hippocampus appears particularly susceptible and may explain the learning / memory disorders seen in such children. A child with repeated status epilepticus demonstrated bilateral hippocampal atrophy on serial MRI with progressive intellectual deterioration. Many studies failed to demonstrate intellectual decline in intractable epileptics12. Another mechanism for intellectual decline is disruption of normal neural networks by severe paroxysmal EEG abnormalities classically seen in IS and in LGS12. This often improves with appropriate therapy. Factors In Pseudo Intractability: Errors in Diagnosis: These are seen in 20 30 % of patients referred to specialty clinics in the developed world3. However, in the only Indian study from Kerala4, 10 non-epileptic cases were detected from more than 1000 referrals on epilepsy. Common non epileptic disorders include pseudoseizures in the older adolescent and young adult and atypical migraine episodes, breath holding spells and sleep disorders in younger children. Proceedings & Abstract Book Sometimes the underlying etiology is overlooked e.g. neurometabolic disorders, biotin and pyridoxine dependent disorders and the occasional poliodystrophy like Alpers and Menkes syndromes. We have occasionally identified recurrent hypoglycemia and hypocalcemia / hypomagnesemia causing chronic epilepsy, emphasizing the need of always doing these basic tests. In the older child one must consider SSPE and rarely, childhood onset progressive myoclonic epilepsy syndromes like neuronal ceroid lipofuscinosis etc. Cortical dysplasias (CD) and other neuronal migration abnormalities are often missed on routine CT scans. Syndromic and seizure type misdiagnosis are more the rule than the exception in the developing world because of lack of awareness and technology. Infantile spasms are often labeled as GTC seizures and treated inappropriately with drugs like Phenobarbital (PB). Staring spells cause confusion between complex partial and absence seizures leading to inappropriate treatment of the later with drugs like carbamazepine (CBZ). Many juvenile myoclonic epilepsies (JME) have associated GTC seizures leading to treatment with CBZ and PHT rather than valproate (VPA). It must be realized that up to 96% of all childhood epilepsies can be classified into syndromes2 and those treating epilepsies must routinely do this diagnostic exercise. The careful history form the witness describing the episode details can avoid most errors. EEG is useful to confirm the clinical suspicion but is marred with problems like poor tracings and wrong interpretations. As far as possible MRI should be performed rather than CT in intractable epilepsies as subtle abnormalities are picked up only by this technique14 . Errors in Therapy: The plethora of drugs and irrational drug use are a recipe of errors of both omission and commission. The level of treatment competence is compounded by biased information from drug companies. Many epilepsies remain intractable because of simple mistakes which are easy to rectify4, 9. Inappropriate choice of drug: Wrong diagnosis of syndromes and seizures type often leads to errors. Often CBZ and 28 PB are used in infantile spasms and absence seizures leading to no response. Recent observations on AED induced seizures indicate the most common offenders being CBZ, PHT and VGB15. Often myoclonic, absence and drop attacks are precipitated. Inappropriate doses and dosing intervals: The most common error is to rely on mg / kg or serum drug levels to decide the maximum dose. In case of good clinical tolerance the dosage can be increased to higher than average dosage and level. On the other hand, serum levels help in identifying patients with ineffective absorption and rapid metabolism6. In those patients referred for epilepsy surgery, therapy omissions and inadequate dosage are noted in as many as 1/3 rd of patients6. Dosage intervals are different at different ages especially when polytherapy is used. For instance phenytoin which is often given at a dose of 5-6 mg / kg in a single dose in adolescence and adulthood needs higher and multiple doses in infancy and early childhood. VPA and CBZ likewise need thrice daily dosing for optimum effect unless one is using the controlled release formulations. Inappropriate polytherapy: Since the 1980s advantages of monotherapy have been disseminated widely in the literature. The biggest disadvantage of polytherapy is troublesome interactions necessitating frequent blood levels a facility often unavailable or expensive. Use of low dose polytherapy appears to be the rule in refractory epilepsy in India. In one study4, 57% were on low dose polytherapy at entry and at the end 76% were successfully switched to monotherapy resulting in an increase in the seizures free rate from 29% to 44%. The annual savings were estimated at approximately Rs. 700/- per patient just by this simple and effective adjustment. In India combination pills are still sold (e.g. PBI and PHT), a practice which should be strongly discouraged. Polytherapy is some times necessary in severe epilepsies; however drugs with minimum interactions and different mechanism of action should be used so called rational polytherapy. In the Mumbai study9, about 40% of patients who improved were on rational polytherapy regimens. In practice often inappropriate INTERNATIONAL PEDIATRIC UPDATE 2004 combinations like CBZ & PHT (both Na channel blockers) or PB & CLP (both GABA ergic) are used leading to virtually no increase in efficacy and a dramatic increase in adverse effects. Medical Treatment: This is described in a series of steps usually employed by the author. It is meant to be a general guideline and needs to be individualized. Complete Diagnosis: The initial task is to identify the clinical seizure type / types and if possible the epileptic syndrome and etiololgy. Clinical details are most important along with a sleep deprived EEG. EEG abnormalities are seen in more than 80% of children with intractability and a normal EEG should prompt a rethink of the diagnois 5,9 . Sometimes a video-EEG needs to be done to simultaneously capture clinical seizures and the ictal EEG. This is possible only when there are frequent, usually daily seizures and obviously can be performed in only a few referral centres. Ideally, a MRI should be done in all cases of intractable epilepsy. Recent studies 3,14 have shown that in refractory childhood epilepsy neurological substrates include developmental tumors like dysembryopathic neuroectodermal tumor (DNET) and ganglioglioma, focal and diffuse migration abnormalities like cortical dysplasia16,17 and lissencephaly and finally hippocampal sclerosis12,14 which may be the cause and sometimes the effect of frequent seizures. These lesions are often invisible on CT and usually need special MRI techniques like thin cuts, FLAIR imaging18 etc for best results. Many of these are amenable to surgical treatment. Functional neuroimaging like SPECT18 or PET17may demonstrate abnormalities in MRI negative cases as has been shown by Chugani & colleagues in infantile spasms 17. The diagnosis of the epileptic syndrome facilitates choice of drugs (Table 2). Long term realistic goals are also set at this time. For instance seizure freedom is not very essential in a severely handicapped child where the seizures are but one small part of the total problem. Drug History Review: This is critical for treatment planning. Often this is not possible due to non-availability of complete records. Uneducated parents are 29 often not even aware of the names of the different medications used. However, one must obtain information form the prescription and the parents to help select target drugs3 which would be tried one by one in a systematic manner with the aim of deciding their efficacy. As patients already come with 3-4 drugs on board, simultaneous with drawl of apparently ineffective drugs is carried out with slow upward titration of each target drug. Withdrawal of sedative drugs like CBZ or VGB seems to increase seizure control in many patients. Only two drugs should be used at any one time so that adverse effects do not outweigh the benefits. Parents must be counseled about the small risk of increasing seizures during this changeover and the physician must resist making hasty decisions during short term seizures exacerbations, concentrating rather on the broader picture and treatment plan. Each target drug should be stepped up to maximally tolerated doses, preferably confirmed by drug levels, before switching to the next target drug. A good response here points to a monotherapy regimen. The least favorable strategy using first line drugs is a change of drugs 3,9 while the most successful is higher than average dose monotherapy or rational polytherapy 9, though this is not consistent in all studies6. New AEDs: Before using newer drugs one must confirm both availability and affordability. Pharmacologically, these drugs have fewer drug interactions and side effects and more relatively easy to use. Though there are more than ten molecules available in the more developed nations, this review will concentrate on the five drugs available freely in the Indian metropolises i.e. clobazam (CLB), lamotrigine (LTG), gabapentin (GBP), vigabatrin (VGB) and topiramate (TPM). The last two are available only through the gray market at an exorbitant cost. Intractable partial epilepsies: All 5 drugs improve seizures though CLB, VGB and TPM are the most effective19, 20,21,22. Seizure freedom, however, is rarely obtained. CLB achieves almost full control in as many as 40%20 and our experience with this cheap easily available agent is similar. VGB has been reported21 to help as many as 50% of childhood refractory partial seizures achieving full control in about one third. Topiramate appears to be powerful in Proceedings & Abstract Book partial epilepsies though pediatric experience is at present limited. Intractable generalized epilepsies: LTG is the clear winner here with as many as 60% of children with severe epilepsy showing some response 23. There seems to be synergism with VPA and up to 35% become seizure free when both are used. All types of refractory generalized seizures respond including tonic, myoclonic-atonic, refractory absence and GTCs. CLB is also fairly effective though tonic seizures probably respond less favourably20. TPM seems to be effective though some evidence suggests better control in partial seizures vis-à-vis generalized seizures23. VGB and GBP are best avoided because of poor efficacy and a tendency to exacerbate myoclonic seizures15, 21. West syndrome: VGB has almost replaced steroids as first line treatment in infantile spasms in Europe22, 24. The results in various studies suggest an equal if not better response with fewer side effects. The response is rapid and is best in infants with tuberous sclerosis (TS) 25. In our experience of 12 cases, every childs seizure had completely resolved. TPM has been used in refractory infantile spasms at high doses and can be of help in half the cases26. Lennox Gastaut syndrome: LTG & VPA in combination have shown fairly good results in LGS with a response rate of about 50% and with some becoming seizure free27. CLB is also effective though tonic seizures may not respond well. TPM has shown promise28. Limitations: Most new AEDs are well tolerated. Neurobehavioral changes are some-times noted with CLB, VGB, GBP and TPM 19. Cognitive changes may be a real problem with TPM, especially if this is rapidly increased. Rash is seen in upto 10% of children with LTG, and more when given with VPA19, 21. In a developing nation many of these newer drugs remain elusive because of the high cost (barring CLB). Alternative Therapies: Ketogenic diet: In the 1920s it was shown that maintenance 30 of ketosis by a high fat, low carbohydrate diet has an anti-epileptic effect. In a recent intent to treat study 29 on 150 children followed for one year, 27% had more than a 90% decrease in seizure frequency. However, 45% stopped the diet either due to inefficacy or poor tolerance. Use of this diet in 22 children yielded > 90% seizure reductions in 7 children. Initial fears of how to use this diet in vegetarian children were unfounded. The main group of children in whom the diet is really helpful are young and / or handicapped children in whom compliance is assured. An added bonus is that behavior is vastly and almost universally improved. Parents often opt to continue the diet for this reason alone. Though it is safe in the majority, serious nutritional, metabolic and other effects are seen in about 10%30. Surgery for Epilepsy: This is possible due to advances such as simultaneous video-EEG and imaging techniques like the MRI, SPECT and PET, which have allowed a clear identification of the epileptogenic zone (EZ). If this is unifocal, it is often amenable to surgical treatment. In adult life the most common surgically remediable syndrome is mesial temporal lobe epilepsy (MTLE) usually caused by hippocampal sclerosis (HS). Anterior temporal lobectomy is the commonest surgical procedure and has already been established at two centers in South India with a surgical experience of over 100 cases. Surgery for childhood epilepsy is more complicated. It is often difficult to decide how long to wait with medical management as childhood epilepsies can be unpredictable at times with a small but definite remission rate 10 . More often, however, catastrophic epilepsies are allowed to continue with all their devastating effects because of the hesitancy of operating in very young children. Childhood epilepsies involve a complex interaction between the epileptic and rapid developmental processes making localization of the EZ difficult which is often extratemporal or multilobar 31 with rapid seizure propagation and therefore often difficult lateralization. On evaluation, the EZ may appear more diffuse than is classically seen in infantile spasms where focal lesions often give rise to a generalized epileptic syndrome and focal resections often INTERNATIONAL PEDIATRIC UPDATE 2004 ameliorate the epilepsy17. Developmental lesions are not uncommonly missed by MRI and when seen, the extent is often underestimated leading to sub-optimal resection and poor results. What helps in childhood epilepsy surgery is the developmental neuronal plasticity allowing large amounts of apparently functional critical cortex e.g. language to be resected with out permanent deficits31. Over the last few years epilepsy surgery in childhood and even infancy has established itself in specialized pediatric epilepsy centers and several surgically remediable syndromes (Table 3) have been identified. Three procedures are commonly done. Focal cortical resections, hemispherectomy and corpus callosotomy, a palliative procedure mainly done for recalcitrant drop attacks31. Seizure freedom is achieved in 60 70% overall with 0 20 % having only rare seizures32. Temporal lobe resections do better than extratemporal with a seizure free rate of 75 80%32. Not surprisingly adolescents do better than infants. We have a small experience of 17 children and adolescents operated in the last two years. Over a follow up period from 4m-18m, 12 are seizure free, 2 have markedly improved and 3 have done poorly. Though successful surgery does not necessarily improve intelligenc12 or employment33, there seems to be an improvement in behavior and quality of life34. References: 1. Cockerell OC et. Al. Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 1997; 38(1): 31-46. 2. Eriksson KJ, Koivikko MJ. Prevalence. Classification and severity of epilepsy and epileptic syndromes in children. Epilepsia 1997; 38(12); 1275-1282. 3. Aicardi J, Shorvon S. Intractable epilepsy In: Engel J, Pedley T (Eds). Epilepsy: A comprehensive textbook 1st edn. 1998; 1325 1331 4. Radhakrishnan K et al. Profile of antiepileptic pharmacotherapy in a tertiary referral centre in South India: a pharmacoepidemiologic and pharmacoeconomic study. Epilepsia, 1999; 40(2): 179-185. 5. Steffenburg Ulf. Intractable epilepsy in a population-based series of mentally retarded children. Epilepsia 1998; 39(7): 767-775. 6. Gilman JT et al. Medical intractability in children evaluated for epilepsy surgery. Neurology 1994; 44: 1341-1343 7. Bharucha NE, Shorvon S. Epidemiology in developing countries. In: Engel J, Pedley T (Eds) Epilepsy: A comprehensive Textbook 1 st edn. 1998; 105-117. 8. Berg AT et al. Predictors of intractable epilepsy in childhood: a case-control study. Epilepsia, 1996; 87(1): 24-30. 9. Udani VP et al. Difficult to control epilepsy in childhood A long term study of 123 cases. 1993; 30: 1199-1206. 10. Huttenlocher PR et al. A follow-up study of intractable seizures in childhood. Ann Neurol 1990; 28: 699-705 11. Bourgeois FDB. Antiepileptic drugs, learning and behaviors in childhood epilepsy, Epilepsia 1998; 39(9): 913-921. 12. Duchowny M et al. Neurobiologic considerations in early surgery for epilepsy. J. Child Neurol 1994; 9(Suppl): 42-48. 13. Lindsay J et al. Long term outcome in children 31 with temporal lobe seizures I: Social outcome and childhood factors. Dev Med Child Neural 1979; 21: 285-298. 14. Zupanc ML. Neuroimaging in the evaluation of children and adolescents with intractable epilepsy: I. Magnetic resonance imaging and the substrates of epilepsy. Pediatr Neurol 1997; 17: 19-26. 15. Guerrini R et al. Antiepileptic drug-induced worsening of seizures in children. Epilepsia 1998; 39: 352-10. 16. Palmini A et al. Focal neuronal migration disorders and intractable partial epilepsy: a study of 30 patients. Ann Neural 1991;30:741-749 17. Chugani H et. Al. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann Neurol 1990; 27: 406-413. 18. Zupanc ML. Neuroimaging in the evaluation of children and adolescents with intractable epilepsy: II. Neuroimaging and pediatric epilepsy. Pediatr Neurol 1997;17:111-121. 19. Cramer JA et al. New antiepileptic drugs; comparison of key clinical trials. Epilepisa 1999; 40(5): 590-600. 20. Sheth RD. Clobazam for intractable pediatric epilepsy. J. Child Neurol 1995; (10): 205-208. 21. Belanger S. et al. Role of vigabatrin and Iamotringine in treatment of childhood epilepsy syndromes. Epilepsia 1998; 39(8): 878-883. 22. Moreland EC et al. Topiramate for intractable childhood epilepsy. Seizure 1999; 8(1): 38-40. 23. Eriksson AS et al. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: A randomized, double blind, crossover study. Epilepsia 1998; 39(5): 495501. 24. Vivegano F, Cilio MR. Vigabatrin versus ACTH as first line treatment for infantile spasms: A randomized prospective study. Epilepsia 1997; 38(12): 1270-1274. 25. Hancock E, Osborne JP. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis; literature review. J Child Neurol 199; Proceedings & Abstract Book 14(2):71-74. 26. Glauser TA et al. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia 1998;39(12): 1324-1328. 27. Donaldson JA et al. Lamotrigine adjunctive therapy in childhood epileptic encephalopathy (the Lennox Gastaut Syndrome) 1997; 38(1): 6873. 28. Glauser TA. Topiramate use in pediatric patients. Can J Neurol SC 1998;25(3): 58-12. 29. Freeman JM et al. The efficacy of the ketogenic diet-1998 A prospective evaluation of intervention in 150 children. Pediatrics 1998; 102(6): 13581363. 30. Ballaban Gil K et al. Compliations of the ketogenic diet. Epilepsia 1998; 39(7): 744-748. 31. Wyllie E. Surgical treatment of epilepsy in children. Pediatr Neurol 1998; 19(3):179-188. 32. Wyllie E. et al. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 1998; (44): 740 748. 33. Reeves AL ET al. Factors associated with work outcome after anterior temporal lobectomy for intractable epilepsy. Epilepsia 1997; 38(6): 689695. 34. Gilliam F et al Epilepsy surgery outcome: comprehensive assessment in children. Neurology 1997: 48: 1368-1374. Table 1: Clinical factors associated with Intractability Factors Examples Epileptic syndromes West syndrome, LGS, severe myoclonic epilepsy, progressive myoclonic epilepsy, Kojeknikows syndrome. Etiologies Tuberous sclerosis, Sturge-Weber syndrome, tumors cortical developmental malformations, brain damage following ischemia, hypoglycemia, trauma, Rasmussens encephalitis. Seizure types Tonic seizures, myoclonic-atonic seizures, atypical absence seizures, mixed seizures. Associated clinical features Mental retardation, neurologic abnormalities, early age of seizure onset, status epilepticus. Modified from Aicardi J, Shorvon SD, Intractable Epilepsy chapter in Epilepsy A Comprehensive Text book, Vol. 2; 1325-1331. Table 2: Choice of Antiepileptic Drugs in different syndromes and seizure types West syndrome ACTH, prednisone, VGB*, NZP, CLP, VPA, TPM Lennox Gastaut syndrome VPA, CLB, LTG, TPM, FBM, CBZ**, PHT** Severe myoclonic epilepsy VPA, CLB, PB, VGB, stiripentol Generalized seizures VPA***, CLB, LTG, TPM ESM+, CLP, NGP, acetazolamide Partial seizures CBZ, PHT, VPA, PB, CLB, VGB, TPM, LTG, GBP, acetazolamide * First choice in TS ** May increase myoclonic, atonic & absence seizures ***High doses may be needed VPA = Valproate, CBZ = Carbamazepine, PHT = Phenytoin, PB = Phenobarbital, CLP = Clonazepam, NZP = Nitrazepam, ESM = Ethosuxamide, CLB = Clobazam, LTG = Lamotrigine, VGB = Vigabatrin, TPM = Topiramate, GBP = Gabapentin. 32 INTERNATIONAL PEDIATRIC UPDATE 2004 Table 3 : Surgically Remediable syndromes (Indian context) Epileptic syndrome / Etiology Procedure Mesial temporal lobe epilepsy (Hippocampal sclerosis) Anterior temporal lobectomy Lesions tumors, hamartoma, vascular malformations, acquired*, cortical dysplasia*# Lesionectomy Hemispheric syndromes; Strokes, Sturge-Weber syndrome, Hemimegalencephaly, Rasmussens syndrome Hemispherectomy Drop attacks Corpus callosotomy * Will need electrocorticography guided resection *# Only MRI positive cases Use of Cough Mixtures in Children Dr. Suhas V. Prabhu, Visiting Consultant Pediatrician, P D Hinduja National Hospital & Medical Research Center, Mumbai Cough is one of the commonest symptoms with which a child is presented to the pediatrician who then reflexly prescribes a cough mixture. However one must not lose sight of the fact that the cough reflex basically serves a protective and useful purpose. Also the cough may be of varying etiology and of different types. Therefore any cough merits a thorough analysis before deciding on the need and type of therapy required. The Cough Reflex: Cough is a reflex generated from 3 different groups of receptors.1 The afferents of all the three are carried by the IXth & Xth cranial nerves. The locations of these 3 groups of receptors are: a) Those lining the respiratory mucosa right from the pharynx down to the terminal bronchioles b) Those lining the pleura c) Interstitial (J) receptors inside the lung parenchyma. In addition, cough may also result from direct stimulation of the cough centre in the 33 medulla oblongata by various drugs and even by inputs form the higher centres (cortex). This type of cough is called the psychogenic cough or more preferably habit cough. Types of Cough: From the point of view of management however, cough can be divided into two types: Dry cough and Wet (or productive) cough: Dry cough: Cough which is not associated with the production and expelling of sputum is described as non-productive or dry cough. Stimulation of the pleural or J receptors always evokes this type of cough. Cough which is central in origin, i.e. because of direct stimulation of the cough centre is also of this type. Sometimes dry cough can also be produced by stimulation of those receptors lining the respiratory mucosa (as for example in an impacted bronchial foreign body or bronchial asthma.) Such cough may only be distressing to the child and does not really serve any physiological purpose. These types of cough are therefore Proceedings & Abstract Book termed as useless and of no benefit to the patient. They therefore may need to be suppressed by cough suppressant drugs or anti-tussives. Productive Cough : Cough may be productive i.e. associated with the expelling of sputum. Sputum consists of a mixture of mucus, inflammatory exudates, debris, etc. from the lower respiratory tract (i.e. the tracheobronchial tree). The purpose of the cough is to aid tracheo-bronchial toilet and clear the airway. Clinical situations with this type of cough are chronic bronchitis, bronchiectasis, resolving pneumonia, etc. Sputum may also be produced due to cardiac or haemodynamic causes such as left ventricular failure or pulmonary oedema. If the cough is successful in expelling the sputum, it helps to clear the respiratory tract and improve gaseous exchange and therefore is a useful cough. Many young children will not expectorate i.e. bring out the sputum by mouth; instead they swallow it. Nevertheless, the purpose of expelling it from and thereby clearing the respiratory tract is still achieved. Using a cough suppressant in such patients with useful cough causes sputum retention which can have harmful effects. However, sometimes the sputum may be so thick or tenacious that the cough is unsuccessful in expelling the sputum. The cough is then no longer useful and soon becomes exhausting for the patient. In such cases, it can be made useful by medicines that liquefy the sputum and enable it to be expelled. Such medications are termed as expectorants or pro-tussives. Sometimes however, even in a wet cough, it is not possible to facilitate expectoration, because the sputum is too tenacious. Then this cough, although wet, needs to be suppressed. A good example of this is Pertussis. Therefore, generally speaking, wet or productive cough performs a useful physiological function and may need to be aided to make it more effective rather than using cough suppressant drugs. However, in certain clinical situations, such a cough, although beneficial in clearing the respiratory tract may have other ill-effects and therefore need to be suppressed with anti-tussives. Examples are increased intracranial tension, after eye surgery, in a child with cough syncope or to allow an exhausted child a short rest. They may also 34 be considered in a run-down terminally ill patient. Cough Medications: One of the reasons why there is so much confusion and uncertainty about cough medications is that clinical assessment of their efficacy is difficult. No experimental cough produced by inhalation of irritants (commonly capsaicin) can properly represent the cough of disease. Also judging the efficacy in clinical trials is prone to error. It has been well shown that subjective assessment by the patient is not a reliable method of judging the frequency or severity of cough. Interestingly also, the cough reflex is under substantial voluntary control and there can be a lot of psychological factors affecting cough. This adds to the difficulty of objective assessment. Thus there are enough studies documenting the effectiveness of placebos in a wide variety of causes of cough from pharyngitis to chronic bronchitis. This does not mean that all cough medicines act by a placebo effect; there are also definite controlled studies showing the beneficial effect of drugs esp. opiates in reducing cough.2 As discussed above, cough medications are basically of two types: I} Cough suppressants (which suppress the cough reflex) II} Expectorants (which ease expectoration of sputum). I} Cough suppressants (Anti-tussives): It is quite obvious from the earlier discussion that these are useful primarily in dry cough which is distressing to the patient and are only rarely to be used in wet or productive cough. These drugs may act by: A] Reducing the sensitivity of the cough receptors or B] Suppressing the cough centre in the medulla oblongata directly or via the cerebral cortex and the sub-cortical paths. A] Drugs reducing the sensitivity of the cough receptors: i) Anaesthetic agents : One such example is local anaesthetic agents such as lignocaine which have to be applied directly onto the respiratory epithelium. They are useful, for example, as a spray prior to procedures such as a bronchoscopy but are unsuitable for use in clinical practice for relieving dry cough. Benzonatate is another INTERNATIONAL PEDIATRIC UPDATE 2004 local anaesthetic, related to amethocaine that may reduce cough by depressing pulmonary stretch receptors and so moderating the response to the lung inflation that is the first stage of the act of cough. The adult dose is 100 mg t.d.s. However, the effect of this drug comes on after 5 to 7 days of administration so that occasional single doses are useless. This has effectively made this drug unattractive and it has not been fully evaluated. Ambroxol hydrochloride, which is primarily believed to be an expectorant, has in some studies shown to have a local anaesthetic effect on the pharyngeal mucosa when administered in 20 mg doses in lozenge form (in adults).3 ii) Demulcents: Demulcents are drugs that glutinously coat the pharynx and reduce cough. It is thought that the coating of the mucosa protects the receptors from the effects of irritants and therefore reduces the cough. Demulcents are usually administered in form of lozenges to the chewed or sucked on. It is well known that simple swallowing (of liquids or solids) inhibits cough by an unknown mechanism.4 This may be the principle on which demulcents work. They are however useful only when the cough arises from above the larynx i.e. in upper airway disease such as tonsillitis or post-nasal drip. Demulcents have long been a part of homeremedies for cough. The classic example of a demulcent is liquorice which has been apart of folk medicine for cough since many centuries. It continues is an ingredient of many home remedies as well as over-thecounter cough preparations. Another ingredient of the same type is honey which again is often used as a home remedy or an ingredient of many cough mixtures (Honeytus). Others of doubtful benefit are various syrups, glycerol, etc. iii) Humidification: When cough arises from below the larynx, steam inhalations and a warm moist environment give relief of cough. This is based on the experimental fact that cold dry air is a known stimulant of the cough receptors lining the pharynx, larynx and trachea. (This in fact is the mechanism by which patients with adenoidal enlargement who are mouth breathers get cough.) It is traditional to add tincture benzoin to the inhalation. It is postulated that the benzoin may promote secretion of dilute mucus and so help to give a protective 35 coating to the inflamed respiratory mucosa. In fact, it may only to make the steam smell therapeutic and add to the psychological effect. iv) Bronchodilators: In cough due to bronchial asthma, the cough is caused by the bronchoconstriction itself and in such cases cough mixtures will not relieve the cough. Simple use of bronchodilators, such as beta-agonistic or anticholinergic drugs (usually by inhalation) or theophyllines will itself relieve the cough. B] Antitussives acting on the CNS: These act as mentioned earlier on the cough centre or via higher centres. They can be divided into the opioid group of drugs and the non-opiates. The Opiates: The basic opiates like morphine, heroin and methadone are not used because of their respiratory depression and addictive properties. a) The earliest prototype opiate drug for cough is of course codeine (an ingredient of Corex, Tossex, Phensedyl cough linctus, Mits linctus codeinae, etc.).5 Codeine is used in the dose of 1 mg/kg per dose and probably acts on the medullary cough centre. Drawbacks of this drug are: 1) There is a potential for drug addiction and abuse esp. in older children. 2) They dry the mucosa and thicken the sputum; so are unsuitable in wet cough. 3) Can cause constipation and other G-I side effects. 4) Higher doses (esp. in small infants) can cause respiratory depression. In order to counteract this respiratory depression of opioids, they have been on occasion combined with a respiratory stimulant; e.g. combination of leptazol & dihydrocodeione (Cardiozol-Dicodid drops) but these have to still be used with caution. These side-effects have led to the restricted usage of codeine in pediatric practice. It is usually reserved for children with severe cough who have failed to respond to other anti-tussives listed below. b) Dextromethorphan is the standard antitussive agent for use in children (Alex, Deletus, Tuspress, Ascoril-D, Chericof, Benylin, Tuspel-D, etc.). It is the only antitussive recommended by the World Health Organization for the routine treatment of cough in children. It is the d-isomer of Proceedings & Abstract Book codeine analog levorphanol.6 It has antitussive effect almost on par with codeine but does not have the drawbacks of codeine listed above. (In very high doses in infants however, they may be significant respiratory depression). It is recommended to start with 0.5 mg/kg per dose but doses 3 times higher be safely given to provide relief. It however has a short half-life of 5 hours necessitating dosing 3 to 4 times a day. This also makes it unsuitable for providing the prolonged action required for night-time relief of cough. However, there is a sustained release preparation available (Lastuss-LA), that reduces the dosing to once or twice a day, which is therefore much more useful. c) Pholcodeine. (Tixylix) This drug has been promoted over dextromethorphan as being more potent and having a longer half-life. These two properties together help this drug provide better nocturnal relief and it needs to be administered just once or twice a day. d) Noscapine. (Coscopin) Has action similar to dextromethorphan but is a potent releaser of histamine and this can have undesirable side-effects and make it unsuitable for use particularly in asthmatic children. The non-opiates: A great many synthetic centrally acting non-opiate anti-tussives have been introduced. 7 They include carbapentane, piperiodone (Sedulon), pipazethate (Selvigon), chlorphedianol (Detigon) and levopropoxyphene. Their advantage is the claim that they are not addictive. They are not as effective as the opioid derivates listed above and have therefore not managed to replace them. II} Expectorants: Expectorants are drugs that help to liquefy and reduce the tenacity of respiratory secretions, thereby easing expectoration. The rationale behind the use of expectorants (which have also been termed as protussives)1 is that they reduce the amount of coughing needed by increasing its efficiency. Reliable experimental data on expectorants particularly in children is scarce.8 Studies on some commonly used expectorants like ammonium chloride are non-existent. Also, different studies yield contradictory data and many animal studies are irrelevant. The methods by which these drugs ease expectoration fall into four main groups:7 36 A] Those acting reflexly via the stomach: These include ammonium chloride, citrates, iodides, ipecac, etc. Although they are common adjuvants in many cough mixtures, hard data from controlled trials on their efficacy is lacking. B] Direct stimulation of secretion by bronchial mucosal glands: These include guaiacols (such as guaiphenesin), volatile oils (such as menthol, eucalyptus oil), creosote and perhaps iodide. The most popular of this group is guaiphenesin which is the ingredient of many cough syrups. Some studies have shown significant improvement in ease of sputum expectoration, decrease in sputum viscosity and earlier clearance of secretions when compared to placebo.9 Adult doses typically are 200 mg thrice a day; there is not enough data on children. In spite of its widespread use even in the U.S., it does not have FDA approval. Volatile oils such as menthol, camphor, terpineiol, and chlorothymol and eucalyptus oil are extremely popular as an ingredient of home remedies or ayurvedic cough syrups. They are often found as an adjuvant in allopathic preparations as well. Because of their volatile nature they can also be taken as an inhalation with steam or from evaporation from balms and rubs applied on the chest, nose or personal belongings. C] Reducing viscosity of secretions: i) Humidifying inhalations of water (steam). This is another traditional home remedy for cough with a sound physiological basis. Besides its anti-tussive effect (described earlier), steam helps to liquefy sputum and aids expectoration. It can be administered using a simple steamer but using a nebulizer increases the effectivity by reducing the particle size, allowing it to penetrate deeper down into the tracheobronchial tree. ii) Altering the secretion chemically e.g. Nacetylcysteine. This molecule has a free sulphydryl group which opens the disulphide bonds in the mucus; this markedly reduces its viscosity, enabling easy expectoration. It is effective in both, normal individuals as well as patients with abnormally viscid mucus secretions (cystic fibrosis). It has to be administered by inhalation or instillation and there is data that its presence in the respiratory tract can INTERNATIONAL PEDIATRIC UPDATE 2004 interfere with the action of some antibiotics. This has led to restrictions in its use for short periods in selected cases of patients on ventilators, in the care of tracheostomies and home care of chronic bronchitis and noninfected cystic fibrosis. Other more commonly used mucolytics, claimed to have properties of promoting the secretion of liquefied secretions, are bromhexine and its metabolite ambroxol. A traditional home remedy, the extract of the leaves of the Asian plant (Adhatoda vasica) used for decades as vasaka contains precursors of these two molecules. 10 Another home remedy the leaves of the tulsi plant (Ocimum sanctum) also contains similar compounds. There are several studies showing some improvement in adult patients with chronic bronchitis in doses of 60-120 mg/day. 11,12 There are however no adequate trials in children documenting unequivocal benefit. To this day both these drugs do not have US FDA approval for use either in children or adults. iii) Enzymes e.g. trypsin which directly attacks and breaks down the mucus (but not the pus). Their action is not as effective as that of acetylcysteine. Like the latter, they also have to be administered directly into the respiratory tract. Oral Chymotrypsin although widely used, has not been shown to be beneficial. iv) Iodides. Iodides alter proteins so that they are more readily hydrolysed by enzymes derived from leucocytes in the sputum. Small doses of iodides are useless. It must be given to the limits of its tolerance; this makes its use unpopular. D] Drugs which directly stimulate the vagus centre such as centrally acting emetics and cholinergic drugs that stimulate the parasympathetic nerve endings on the bronchial glands are generally not used because of their undesirable side effects. Cough Mixtures: Most cough medications in the market are mixtures. Single ingredient medications for cough are rarely available. Many a times the combination of drugs in the mixture is irrational, e.g. a bronchodilator with a cough suppressant or an anti-tussive with an expectorant. It is therefore important to choose the cough mixture carefully before prescribing. A combination of a demulcent 37 with an antitussive may be desirable (in pharyngitis) and a mucolytic with a bronchodilator may find rational use in a patient with chronic bronchitis. Many cough mixtures have other ingredients such as nasal decongestants, anti-pyretics, anti-histaminics etc. These other ingredients may have a role to play in the associated symptoms that the patient with cough may also have. a) Nasal decongestants such as psuedoephedrine, phenylephrine or phenylpropranolamine (PPA) are added for relieving associated nose block. Caution has been advised in using the latter (PPA) because of data suggesting increased chances of stroke in teenage children who have received PPA. b) Although anti-histaminics (such as diphenhydramine or chlorpheniramine maleate or cetrizine) have been touted to have anti-tussive effects, these have not been proved in controlled trials.13 However their use in cough syrups may be justified for taking care of the associated symptoms such as sneezing or nasal watering. Besides, some anti-histaminics, particularly the traditional ones like chlorpheniramine maleate have a drying effect on the respiratory mucosa which has a deleterious effect. c) Antipyretics like acetaminophen (paracetamol) are often added to the cough mixture. The justification for this is to take care of the associated symptoms of headache, body ache or fever. Quite often, the combination of such ingredients is not in the correct proportion to ensure correct dosing of all the ingredients. A careful examination of the composition must be done before opting to use such combination cough mixtures. Choice of therapy in cough: The choice of therapy depends on several factors, but primarily depends on the type and severity of the cough. Based on the above discussion, the following guidelines can be formulated: 1) Cough is a protective reflex. It is not required (and in fact may be dangerous) to treat it as an undesirable symptom that must be completely eliminated at any cost. Cough that is mild, productive and not distressing to the patient may best be left alone. Proceedings & Abstract Book 2) If the cough is due to the bronchospasm of asthma, no cough syrup is required, simple bronchodilators will effectively relieve the cough. 3) In dry cough which is useless, simple measures like frequent fluid intake, humidification and use of demulcent lozenges, are very beneficial and may suffice in many cases. If the cough is very distressing or disturbing to the patient, Dextromethorphan is probably the drug of choice in such cases. Pholcodeine or Codeine may be required for more severe cases such as in Pertussis but must be used judiciously. 4) In case of wet cough, increased fluid intake and steam inhalation should be encouraged. If available, nebulization with simple saline solution may help. Local application or inhalations of volatile oils is probably useful. In severe cases, expectorants like ammonium chloride, citrates, menthol, bromhexine or ambroxol although unproven in clinical settings in children may be used. 5) Other ingredients in the cough mixture must be judiciously examined and such syrups may be used for the beneficial effects of such ingredients on the associated symptoms such as running nose, sneezing, throat pain, fever, etc. Care must be taken to see that these ingredients are in the correct proportion and do not have an adverse effect on the cough. In summary, drug therapy of cough is not always necessary and home remedies may suffice for mild cases. With proper evaluation and thought, rational drug therapy of cough is possible with full pharmacological knowledge of all the ingredients of the cough mixture and the associated symptoms in the patient. Also it must be remembered that cough is not a disease but a symptom and the underlying cause of the cough should also be simultaneously evaluated and treated. References: 1. Irwin RS, Widdicombe J. Cough in Text Book of Respiratory Medicine W.B. Saunders Co. 2nd Ed. 1994 Ed. Murray JF & Nadel JA. Vol 1, pp 52941. 2. 3. 4. 8. Parvez L. Vaidya M. et. al. Evaluation of antitussive agents in man. Curr. Med Res and Opinion 3(2) 1975 pp. 63-67. Schroeder K , Fahey T. Over-the-counter medications for acute cough in children and adults. Cochrane Database of Systematic Reviews CD001831, 2001. Last updated Sept 2003. 9. Fischer J, Pschorn U et. al. Efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. Randomised, double-blind, placebo controlled trials regarding the local anaesthetic properties. Arzneimittel-Forschung 52(4) 2002 pp. 256-63. Rubin BK . An in vitro comparison of the mucoactive properties of guaphenesin, iodinated glycerol, surfactant and albuterol. Chest 116(1): Jul 1999 pp 195-200. 10. Sehgal SK, Mohan M. Bromhexine. Ind Pediatr 27 (5) 1990 pp. 479-83. Haslett C. Lung Defences and Immunology in Crofton and Douglas Respiratory Diseases. 5th Ed. Ed. Seaton A, Seaton D, Leitch AG. Blackwell Science 2000. Vol. 1 pp 83-84. 5. Monthly Index of Medical Specialities Ed. Gulati CM. 24(3) Mar 2004 pp 237-45. 6. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 9th Ed. Ed. Hardmann JG, Limbird LE. Mc-Graw-Hill 1996. pp 551-2. 7. Laurence DR. Clinical Pharmacology 3 rd Ed. ELBS, J.W. Churchill Ltd. 1969. pp 322-6. 38 11. Germouty J, Jirou-Najou et. al. Clinical efficacy of ambroxol in the treatment of bronchial stasis. Clinical trial in 120 patients at two different doses. Resp. 51 1987 Suppl 1. pp 37-41 12. Ericsson CH, Juhasz J. et. al. Influence of Ambroxol on tracheobronchial clearance in simple chronic bronchitis. Eur J Resp Dis. 70 (3):Mar 1987 pp. 163-70. 13. Paul IM, Yoder KE et. al. Effect of Dextromethorphan, Diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics, Jul 2004; 114: pp 85 - 90. INTERNATIONAL PEDIATRIC UPDATE 2004 Non-Invasive Ventilation in Pediatric Age Dr. Giuseppe A. Marraro, Department of Anesthesia & Intensive Care - Pediatric Intensive Care Unit, Fatebenefratelli & Ophthalmiatric Hospital - Corso di Porta Nuova, 23 –Milano, Italy The feasibility to apply a ventilatory mode capable of avoiding airway invasion has been evaluated and tested for long time. Two modes have had large consensus, which uses different methodologies to attain respiration, i.e. 1. Negative Pressure Ventilation by means of either iron lung or chest cuirass, and 2. Positive Pressure Ventilation in spontaneous breathing, with CPAP, or Non-invasive Positive Pressure Ventilation with mask. A new ventilatory mode has been recently introduced in clinical practice, which uses a biphasic negative and positive external pressure to obtain gas exchange. Negative ventilation has been used in the treatment of neuromuscular and chronic obstructive pulmonary disease, to reduce respiratory fatigue and put respiratory muscles to rest. Relevant beneficial effects were not observed in home assistance of these patients.1,2 The use of non-invasive ventilation has been implemented with the arrival of CPAP and the use of masks instead of tracheal tube to apply positive pressure ventilation (NPPV). The advantages deriving from CPAP in the treatment of Acute Respiratory Failure (ARF) are: increase of PaO 2 and Functional Residual Capacity (FRC), open lung approach and reduction of cardiac transmural pressure. CPAP can also reduce work of breathing and inspiratory threshold load if CPAP is less than 85% of static intrinsic PEEP (PEEPi, stat). NPPV is obtained increasing alveolar and intramural pressure of the lung. Beneficial effects of its application are: increase of alveolar ventilation, improvement of gas exchange, reduction of hypoxemia and acidosis, reduction of muscle fatigue and elastic lung work when external PEEP is used to counterbalance PEEPi due to dynamic hyperinflation. 39 General criteria for NPPV application in pediatric age are: Moderate or severe dispnea; Tachypnea (respiratory frequency double than expected for the specific child); Use of accessory muscles and paradoxical abdominal respiration; Severe deterioration of gas exchange with PaCO2 >45 and/or pH <7.35 or PaO2/FiO2 <300. Eligibility criteria are : awake and collaborative child, hemodynamical stability, not abundant secretions, presence of airway protective reflexes, absence of facial trauma or anatomical malformation, and not gastrointestinal bleeding. Exclusion criteria are : unconsciousness, not collaborating or agitated patient, respiratory arrest, hemodynamic instability (hypotension, arrhythmia, etc.), insufficient protection of airways (lack of cough, abundant secretions), airway obstruction, vomiting, trauma, burns and face malformation, pneumothorax not drained. There is a high evidence-based efficacy in the treatment of chronic lung disease3-5, in cardiogenic pulmonary edema 6 , in immunocompromised patients,7,8 in difficult weaning from ventilator9 and in restrictive lung pathology.10,11 There is a moderate evidence-based efficacy in cystic fibrosis, asthma, postoperative respiratory failure12-14 and in do not intubate patients.15-16 Extubation failure, ARDS and pneumonia have shown evidence-based efficacy. There are indispensable factors resulting in NPPV efficacy: 1. Patient selection; 2. Early treatment; 3. Comfortable ventilator-patient interface; 4. Psychological patient support; Proceedings & Abstract Book 5. Continuous monitoring; 6. Skilled and motivated team. Respiratory-patient interface can be either the facial mask, or the nasal mask, or, more recently, the helmet. There is not agreement on the ideal interface to be applied during NPPV. The characteristics of the mask should be lightness, transparency, adherence, perfect sealing and adaptability to anatomical conformation. Nasal mask has reduced dead space, provokes less claustrophobia, reduces vomiting stimulation, and allows secretion elimination, easy feeding without removal of interface and better speech. For these reasons it is better tolerated by the patient. Efficacy is limited if nasal resistance is more than 5 cmH2O/l/s. Facial mask is preferable in severe respiratory failure because improves minute ventilation and bypasses nasal resistances. Using <25 cmH2O of pressure, aerophagia is rare and nasogastric tube is not necessary. Recently, the helmet has been tested in clinical practice and appears to have advantages compared to masks for the absence of facial decubital necrosis (occurring in more than 7% of cases using masks!) but can create arm-pit decubitus due to the securing system. In preliminary reports, it appears to be more comfortable because of the possibility for patients to see, speak and read. Its application is possible independent of facial anatomy.17-18 Non-invasive ventilators use different systems: â Single tube system; â Two levels of pressure (BiPAP); â Active expiration through an expiratory valve (increase of work of breathing); â Passive expiration, a part of EPAP flow; â Need of CO2 re-breathing using a special valve non-re-breather or applying EPAP of 8 cmH 2 O in presence of high respiratory rates. â Flow trigger. Some ventilators, like Respironics BiPAP and Puritan Bennett PB-335, compensate automatically the air leakage due to interface and open mouth; Characteristics of NPPV ventilators are: 1. Basic Ability to reach 30 cmH2O pressure (control 40 pressure) Ability to provide 60 l/min of inspiratory flow Assisted/controlled ventilation mode Bilevel PSV modality Ability to reach a respiratory rate of 40 breaths /min Flow trigger. 2. Optional Rapid increase in pressurization time Possibility to modify pressurization curve Possibility to modify inspiratory and expiratory trigger Possibility to modify I:E ratio in ACV Easy alarms suspension. Criteria for NPPV withdrawal are: â Inability to tolerate the interface (discomfort, pain) â Dyspnea or no gas exchange improvement â Need for tracheal intubation to perform bronchosuctioning and to protect airways â No improvement in mental status after 30 min of NPPV application in case of coma due to CO2 retention or in presence of psychomotorial agitation connected with hypoxemia. Non-invasive ventilation using external bi-phasic negative-positive ventilator. A new mode of non-invasive ventilation, similar to spontaneous breathing, is under clinical research for the treatment of several acute and chronic lung diseases in children and adults. To attain inspiration and expiration, this ventilatory model uses an external cuirass positioned on the chest and abdomen. Positive and negative pressures are applied alternatively inside this cuirass and are regulated electronically by a software program. The inspiratory phase is obtained by generating a negative intrathoracic pressure, like in physiological condition, and similarly to the iron lung, but with limited total involvement. During the negative phase, the air flows into the lung if patency and stability of upper airway is present. The expiratory phase is passive but is favored by external chest19 and diaphragm compression.20 This ventilatory mode does not need an interface to link patient airways to ventilator and does not apply positive pressure to the INTERNATIONAL PEDIATRIC UPDATE 2004 lung, resulting in better clearance of secretions. Moreover, it reduces those specific hemodynamic variations deriving from conventional positive pressure ventilation.21-23 This new concept of ventilation is implemented by the RTX Respirator (Medivent Ltd), which is able to perform Controlled Ventilation, Synchronized Ventilation, HFO, and Triggered ventilation [e.g. from ECG24] and Continuous Negative Ventilation in spontaneous breathing. This latter ventilatory mode is similar to CPAP, in increasing functional residual capacity and maintaining bronchioles and alveoli continuously open. Not applying positive pressure inside the lung, hemodynamic stability is bigger. The ventilator is able to change I:E ratio, to facilitate secretion clearance using a special system to assist the cough. Movement of secretions is obtained using HFO, while expulsion of secretions is achieved using assisted cough with a high inverted ratio (5:1). There are several experiences in the use of this new respiratory mode in different acute and chronic lung pathologies in pediatric age25,26: The ventilator is able to reduce the need of intubation and conventional mechanical ventilation. References 1. Celli B, Lee H, Crimer G, et al. Controlled trial of external negative pressure ventilation in patients with severe chronic airflow obstruction. Am Rev Resp Dis 1989; 140:1251-1256 pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting. Int Care Med 1996; 22: 13451350 2. Zibrak JD, Hill NS, Federman EC, et al. Evaluation of intermittent long-term negative-pressure ventilation in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 138:1515-1518 13. Matte P, Jacquet L, Van Dyck M, Goenen M. Effects of conventional physiotherapy, continuous positive airway pressure and no-invasive ventilatory support with bilevel positive airway pressure after coronary artery bypass grafting. Acta Anaesth Scand 2000; 44:75-81 3. Meecham Jones DJ, Paul EA , Jones PW, Wedzicha JA. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. AJRCCM 1995; 152:538-544 4. Clini E, Sturani C, Rossi A, et al. The Italian multicetre study on nonnvasive ventilation in chronic obstructine pulmonary disease patients. Eur Respir J 2002; 20:529-538 5. Keenan SP, Kernerman PD, Cook DJ, et al. Effect of noninvasive positive pressure ventilation on mortality in patients admitted with acute respiratory failure: a meta-analysis. Crit Care Med 1997; 25:16851692 6. Mehta S, Jay GD, Woolard RH, et al. Randomized prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema. Crit Care Med 1997; 25:620-628 7. Antonelli M, Conti G, Bufi M, et al. Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial. JAMA 2000; 12:235-241 8. Hilbert G, Gruson D, Vargas F, et al. Non invasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever and acute respiratory failure. N Engl J Med 2001; 344:481-487 9. Ferrer M, Esquinas A, Leon M, Gonzalez G, Alarcon A, Torres A. Non-invasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med 2003;168:14381444 10. National Association for Medical Direction of Respiratory Care, Consensus Conference. Chest 1999 11. Bach JR, Ishikawa Y, Kim H. Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 1997; 112:1024-1028 12. Gust R, Gottschalk A, Schmidt H, et al. Effects of continuous (CPAP) and bi-level positive airway 41 14. AuriantI, Jallot A, Herve P, et al. Noninvasive ventilation reduces mortality in acute respiratory failure following lung resction. Am J Respir Crit Care Med 2001; 164:1231-1235 15. Freichels T. Noninvasive positive pressure ventilation for patients with terminal respiratory failure:The ethical and economical costs of dealing with the inevitable are too great. Am J Crit Care 1994; 3:162 16. Meduri GU, Fox RC, Abou-Shala N, et al. Noninvasive mechanical ventilation via face mask in patients with acute respiratory failure who refused endotracheal intubation. Crit Care Med 1994; 22:15841590 17. Klein M, Weksler N, Bartal C, Gurman GM. Helmet noninvasive ventilation for weaning from mechanical ventilation. Respir Care 2004; 49:1035-1037 18. Piastra M, Antonelli M, Chiaretti A, et al. Treatment of acute respiratory failure by helmet-delivered noninvasive pressure support ventilation in children with acute leukemia: a pilot study. Intensive Care Med 2004; 30:472-476 19. Zidulka A, Gross D, Minami H, et al.Ventilation by high-frequency chest wall compression in dogs with normal lungs. Am Rev Respir Dis. 1983;127:709-713 20. Kacmarek RM, Home Mechanical Ventilation Equipment in Respiratory Care Equipment 2nd Edition, Branson et al. eds. (New York: Lippincott, 1999) 21. Al-Saady NM, Fernando SS, Petros AJ, et al. External high frequency oscillation in normal subjects and in patients with acute respiratory failure. Anaesthesia 1995; 50:1031-1035 22. Shekerdemian LS, Bush A, Shore DF, et al. Proceedings & Abstract Book Cardiopulmonary interactions after Fontan operations: augmentation of cardiac output using negative pressure ventilation. Circulation 1997; 96:3934-3942 23. Shekerdemian LS, Schulze-Neick I, Redington AN, et al. Negative pressure ventilation as haemodynamic rescue following surgery for congenital heart disease. Intensive Care Med 2000; 26:93-96 24. Plein S, Bulugahapitiya S, Jones TR, et al. Cardiac RM imaging with external respirator: synchronizing cardiac and respiratory motion. Radiology 2003;227:887-882. 25. Marraro GA, Luchetti M, Cereda G, Galassini EM, Mazza G. Non-invasive ventilation of acute respiratory failure in infants with spinal muscular atrophy (SMA) type 1. PCCM J 2003, abstracts book 26. Marraro GA. La ventilazione non invasiva in età pediatrica. Proc. Of Congress Il neonato con sofferenza respiratoria. Brescia 2003, 10-14. Food Hypersensitivity and Allergic Disease Prof. R. K. Chandra, Université Internationale des Sciences de la Santé, Switzerland. Introduction : Allergic disease continues to increase in prevalence worldwide. There is preliminary data from India to suggest that both eczema and asthma, especially the latter, are on the ascendant. It is important for physicians to understand the clinical features, pathophysiology, diagnosis, management and prevention of allergies. I wish to emphasize the concept of allergic march. By this is meant the sequence of events that leads to clinical allergic disease. The first step is the development of sensitization to foods, which is followed by gastrointestinal symptoms, skin rashes, wheezing, asthma and rhinitis. This concept means that if we can prevent food allergy in the first few months of life, we can expect to prevent the later manifestations Clinical features: Virtually all organs of the body can be affected. As noted above, the earliest manifestation is usually gastrointestinal features such as colic, vomiting, diarrhoea, and blood in stools and malabsorption. This is followed in the second half of the first year with skin rashes including frank atopic eczema. Wheezing may follow and then 42 frank asthma. Hay fever usually does not occur until after 8 years of age. Diagnosis: In addition to a detailed history, skin tests can be done. It is best to do scratch or prick tests rather intradermal tests. In India, there are very few qualified allergists. The other methods include testing blood for IgE antibodies, cytotoxic IgG antibodies, immune complexes and cell-mediated reactions. Food challenge is the gold standard. Management: Avoidance of involved foods is the best way to reduce symptoms. However, the correct diagnosis must be established first. Otherwise, iatrogenic malnutrition may result- Self-administered adrenaline is to be kept for the medical emergency of anaphylaxis. The management of eczema, asthma and hay fever is on standard lines. Precautions to Prevent Allergic Disease: It is established that genetic factors, especially history of allergy among parents, is important. However, we cannot control this because we do not choose our parents. In addition, certain environmental factors such INTERNATIONAL PEDIATRIC UPDATE 2004 as diet, nutrition, pollution, cigarette smoke, pets such as cats, dust and pollen, play a crucial role in development of allergy among children. The following precautions during pregnancy, lactation and early childhood help in reducing the risk of allergy in babies. The earlier one can start these measures, the better. 1. During pregnancy, avoiding exposure to cigarette smoke, cats, birds, dust, and to large quantities of certain foods that cause problems in babies (dairy products milk, cheese, nuts especially peanut and tree nuts, egg), would help. 2. The same dietary and other precautions should be continued during the first 6 months of life. It is helpful to breast feed the baby exclusively, for as long as possible, but about 4 months is ideal. 3. From 6 months onwards, introduce new foods one at a time every week, starting with vegetables, fruits, cereals (rice is the best) and grains. Meat can be given from 9 months, egg from 12 months, fish from 18 months. Both the mother and the baby should be given an ideal preparation of vitamins and minerals. From all the research available, IMMUNOBOOST-Y (for young adults) and IMMUNOBOOST-C (for children), both available in the metro areas of Delhi and Kolkata (or by email:[email protected]) are the best to optimize the immune system and to prevent allergies from developing. Those with clinical features of allergic disease, the regular administration of these multivitamin preparations will reduce the need for anti-asthma mediations and visits to doctors and hospitals. Basics of Neonatal Mechanical Ventilation Surg Cdr Girish Gupta, Neonatologist, INHS Dhanvantari, Port Blair, Andamans, India - 744 103 Learning Objectives: After reading this article the reader should be able to: 1. Decide need for ventilation 2. Set up ventilator 3. Monitor neonate on ventilator 4. Identify complications 5. Wean and extubate from ventilator Mechanical Ventilation (MV) is an intervention which facilitates management of respiratory dysfunction in neonates with resultant improved survival and outcome. The goals of ventilation are as follows: 1. Appropriate oxygenation 2. Appropriate ventilation 3. Prevent organ injuries 4. To ensure intact survival 43 DECISION MAKING FOR INITIATING MV Before commencing MV several factors need consideration in addition to clinical condition. These include likely outcome, financial effects and ethical issues. The decision has to be made after detailed discussion with parents. If more babies need MV than the number of ventilators available, then the baby with better likely outcome should be given higher priority for ventilation. REQUIREMENTS FOR MV Trained Resource : One should have adequately trained personnel viz. doctors, nurses, respiratory therapist, physiotherapist, radiographers etc., well versed in their respective roles in neonatal MV. Proceedings & Abstract Book Investigative modalities : One should have functioning and adequate monitoring and investigative facilities of Pulse-oximetry, multisystem monitors, ABG machine, Portable X Ray machine, Trans-cutaneous capnometry, BP measurement, FiO2, USG machine. NICU setup: Before starting MV, NICU should have well established level II neonatal care with special attention to infection prevention. There must be central oxygen supply if not then a manifold room to be created before starting MV in the unit. It is also desirable to have central compressed air supply. INDICATIONS FOR MECHANICAL VENTILATION [1] i. Clinical criteria 1. Respiratory disorders conditions with impending respiratory failure manifesting as a. Retractions moderate to severe b. Tachypnoea c. Central cyanosis with FiO2 > 40% Clinical scoring systems may be used to initiate MV. 2. CNS disorders 3. CVS disorders including shock states 4. GIT: NNEC, Postoperative neonates 5. Babies < 28 weeks, may be ventilated or given CPAP electively. ii. Blood gas criteria 1. PaCO2 > 50 mm Hg 2. PaO2 < 40 50 mm Hg, on O2 by hood or CPAP at FiO2 > 60 % 3. pH <7.2 with respiratory distress. VENTILATOR Make the choice of a ventilator, preferably, having pressure-limited, time-cycled and continuous flow with SIMV. Buy it from an authentic dealer with good after sales service. One can enquire from the local units who are using a ventilator and verify about the ventilator performance and after sales maintenance service provided by the supplier. Always keep the dealers and maintenance engineers contact numbers in the unit for tackling emergency equipment failures. Ventilator should have an UPS as power back up. The electrical connections should have a good power supply and proper earthing, to prevent electrical 44 equipment accidents. Ventilator should be placed in such a way that there is enough space for nursing procedures, air circulation and resuscitation. It should not be placed too close to the walls, as it will get overheated. PARTS OF A VENTILATOR They are following: 1. Compressor 2. Oxygen source 3. Ventilator 4. Breathing circuit 5. Humidifier 6. Test lung GETTING THE INFANT READY FOR THE VENTILATOR Place the infant on the firm surface. Position the infant in such a way that the chin, sternum and umbilicus are all lined up in a single plane. Equipments needed for intubation should always be kept ready. Size of Endo-tracheal tube depends on weight of the neonate and has been shown below Wt (grams) Sizes (ID mm) <1000 2.5 1000 - 2000 3 2000-4000 3.5 >4000 4 Correct depth of tube to be inserted : An endotracheal tube has a black portion at the tip, called as vocal cord guide. The tube should, therefore, be inserted to the point where the complete vocal cord guide has just passed the glottis. The tube also has numerical markings in cms. The reading visible on the tube at the lip should be equal to weight of the baby in kg + 6. e.g. for a baby weighing 3 Kg, the reading at the lip should be 3+6 = 9. Confirming the correct position of the tube Fixing the tube: Fixing the tube, traditionally, is done by cutting the adhesive (Elastoplast) into shapes of Y or H. The main point to be ensured in tube fixation is that it must prevent tube displacement and minimize skin trauma secondary to adhesive application. Adhesives at times, are not only INTERNATIONAL PEDIATRIC UPDATE 2004 associated with ineffective fixation of tube but also result in micro abrasions, and secondary infection. Girisam ETAT (Endotracheal Tube and Auxiliary Tube) fixator is a device, which supports the babys head, allows effective tube fixation with zero tube mobility and does not traumatize skin. It also has additional openings for passage of orogastric tube and oropharyngeal care. It may be used if available. Position in which the babies are to be ventilated: The important thing to practice is that whichever may be the position, the shoulders must be gently elevated, so as to push the diaphragm down and facilitate MV. SETTING THE CONTROL PANEL The following parameters are required to be set on Ventilator which is conventionally pressure limited, timed cycled continuous flow in neonates, after deciding the mode of Ventilation. Fraction of inspired oxygen (FiO2): I t determines the percentage of oxygen being delivered to the lungs in each breath. Changes in FiO2 alter alveolar oxygen pressure and thus, oxygenation. Peak inspiratory pressure (PIP): Changes in PIP affect both PaO 2 (by altering MAP) and PaCO2 (by its effects on tidal volume and thus, alveolar ventilation). Therefore, an increase in PIP improves oxygenation and decreases PaCO2. Use of a high PIP may increase the risk of barotrauma with resultant air leaks and BPD; thus, exercise caution when using high levels of PIP. The level of PIP required in an infant depends largely on the compliance of the respiratory system. Starting PIP can be approximately set at the pressures required during bag mask ventilation. A useful clinical indicator of adequate PIP is gentle chest rise with every breath, which should not be much more than the chest expansion with spontaneous breathing. While absent breath sounds may indicate inadequate PIP (or a blocked and/or displaced ETT or even ventilator malfunction), the presence of breath sounds is not very helpful in determining optimal PIP. Always use the minimum effective PIP. Positive End expiratory pressure (PEEP): It is the pressure in the lung at the end of 45 expiration. Adequate PEEP helps to prevent alveolar collapse, maintains lung volume at end-expiration, and improves V/Q matching. Increases in PEEP usually increase oxygenation associated with increases in MAP. However, in infants with RDS, a high PEEP (>6 cm H 20) may not improve oxygenation further and, in fact, may decrease venous return, cardiac output, and oxygen transport along with decrease in pulmonary perfusion by increasing pulmonary vascular resistance. By reducing ä pressure (PIP minus PEEP), an elevation of PEEP may decrease tidal volume and increase PaCO2.While both PIP and PEEP increase MAP and may improve oxygenation, they usually have opposite effects on PaCO2. Generally, older infants with chronic lung disease tolerate higher levels of PEEP without carbon dioxide retention and with improvements in oxygenation. PEEP also has a variable effect on lung compliance and may impact the PIP required. With RDS, an improvement in compliance occurs with low levels of PEEP, followed by a worsening of compliance at higher levels of PEEP (>6 cm H20). A minimum PEEP of 2-3 cm H 2 0 is recommended, since endotrachael intubation eliminates the active maintenance of FRC accomplished by vocal cord adduction and closure of the glottis. This mechanism of vocal cord adduction is responsible for production of grunt and hence, is the natural mechanism of elevating PEEP in a neonate with respiratory malfunctioning. Ventilatory Rate (VR)[2] Changes in frequency alter alveolar minute ventilation and, thus, PaCO2. Increases in rate and, therefore, in alveolar minute ventilation decrease PaCO 2 proportionally, and decreases in rate increase PaCO 2 . Frequency changes alone (with a constant I/E ratio) usually do not alter MAP nor substantially alter PaO 2. Any changes in inspiratory time that accompany frequency adjustments may change the airway pressure waveform and thus alter MAP and oxygenation. MV= TV X VR TV∝ (PIP PEEP) v MV=Minute Ventilation v TV=Tidal Volume v VR=Ventilatory Rate Respiratory rate of 40-60/min. is usually Proceedings & Abstract Book adequate. Higher respiratory rates may be required in case of PPHN. Flow rate : Flow rates of 5-8 l/min are sufficient. Flow rate should be around eight to ten times of minute ventilation. It is also machine specific, some machines may need higher flow rates. To maintain an adequate tidal volume, high flows are needed when inspiratory time is shortened. Inspiratory and expiratory times (Ti, Te): Ti of 0.3 to 0.4 is generally sufficient for most disorders. Do not change Ti unless there is persistent hypoxemia unresponsive to changes in PEEP, PIP and FiO2. The major effect of an increase in the I/E ratio is to increase MAP and thus improve oxygenation. However, when corrected for MAP, changes in the I/E ratio are not as effective in increasing oxygenation as are changes in PIP or PEEP. A reversed (inverse) I/E ratio (inspiratory time longer than expiratory time) has been demonstrated to be effective in increasing PaO 2; however, adverse effects may occur. Changes in the I/E ratio usually do not alter tidal volume, unless inspiratory and expiratory times become relatively too short. Thus, carbon dioxide elimination usually is not altered by changes in I/E ratio unless Te is so small that it results in auto PEEP with resultant CO2 retention. Mean Airway Pressure (MAP): MAP can be calculated by dividing the area under the airway pressure curve by the duration of the cycle as follows: TI MAP = K (PIP PEEP) ---------------- + PEEP TI + T E This formula includes the constant determined by the flow rate and the rate of rise of the airway pressure curve (K). This equation indicates that MAP increases with increasing PIP, PEEP, TI and flow (increases K by creating a more square waveform). PATHOPHYSIOLOGY-BASED VENTILATORY STRATEGIES Respiratory distress syndrome (RDS) RDS is characterized by Low compliance Low FRC An optimal conventional ventilation 46 strategy may include: Early ventilation Lowest PIP and tidal volume PEEP (3-5 cm H20) Permissive hypercapnia (PaCO2 45-60 mm Hg) to prevent barotraumas and subsequent CLD (2) Judicious use of narcotic analgesia Meconium aspiration syndrome (MAS) MAS is characterized by Air trapping High risk of Persistent pulmonary hypertension (PPHN) Strategy for ventilation would involve Commence ventilation after careful evaluation. Minimal handling Attaching one pulse-oxymeter to right upper limb and one pulse-oxymeter to lower limb for early detection of PPHN. Tele-monitoring Preventing any condition that may disturb the baby. Analgesia / Paralysis. Persistent pulmonary hypertension (PPHN): Persistent pulmonary hypertension of the newborn may be primary or associated with aspiration syndrome, prolonged intrauterine hypoxia, congenital diaphragmatic hernia, or other causes. Ventilatory treatment of infants often is controversial and varies markedly among centers. In general, following should be the strategy for ventilatory parameters: Adjust FiO2 to maintain PaO2 at 80-100 mm Hg to minimize hypoxia-mediated pulmonary vasoconstriction; Adjust ventilatory rates and pressures to maintain an arterial pH of 7.45 (sometimes combined with bicarbonate infusion). Prevent low PaCO2 (<25 mm Hg), which can cause cerebral vasoconstriction and subsequent neurologic injury. Use Narcotic analgesia / paralysis judiciously Minimal handling Dimming the lights Talking in low tone or whispers Attaching one pulse-oxymeter to right INTERNATIONAL PEDIATRIC UPDATE 2004 upper limb and one pulse-oxymeter to lower limb for early detection of PPHN. Tele monitoring Preventing any condition which may disturb the baby. Chronic lung disease (CLD): CLD usually has heterogeneous time constants among lung areas. Resistance may be increased markedly, and frequent exacerbations may occur. The ventilatory parameters suggested are: PEEP (4-6 cm H20) Longer inspiratory and expiratory times Low rates are preferred Hypercarbia (PaCO2= 45-55 mmHg) with compensated respiratory acidosis often is tolerated to avoid lung injury secondary to aggressive mechanical ventilation. PaO 2 >50 mmHg prevents cor pulmonale.[3] Avoid PaO 2 >80 mmHg to prevent O 2 mediated lung injury. MANAGEMENT AFTER INITIATING VENTILATION The following need to be monitored diligently during ventilation. The best monitors are the dedicated bedside nurse and resident doctor. 1. Look at the baby. Is the chest expansion adequate? Is there adequate air entry? Is the baby struggling on the ventilator? Is the baby having significant retractions? Is the baby having spontaneous respiratory efforts? What is the SpO2? Aim to keep SpO2 between 87-93%. What are the heart rate, capillary refilling time, blood pressure and colour of the baby? What is the neurological state of the baby? Ensure shoulder elevation. Do not be in haste to change settings till the baby stabilizes. It may take some time for the infant to synchronize breaths with that of the ventilator and for retractions to disappear, but if retractions persist then the settings need to be adjusted. 2. Look at the blood gases: The goal is to try and maintain the blood gases as close to normal as possible, while keeping the 47 barotrauma and oxytrauma to a minimum. Surrogate non-invasive: Blood gas approximation is done with pulseoximetry and transcutaneous capnometry. The end-tidal capnography is not useful in neonates because of smaller tidal volume and higher respiratory rates but may be useful in interpreting the trend of CO2. 3. Look at the ventilator Is it cycling? Is the ventilator delivering the set parameters? What tidal volume (VT) is the baby getting? Is there a significant leak? 4. Look at the humidifier Is it on? Does it have adequate water? Is there any loose or open connection? 5. Look at the circuit / water traps : Ensure that the water traps are emptied frequently of the condensed water else it might make ventilation more erratic 6.Look at the nursing flow chart How stable has the baby been? How is the baby handling? Are there lots of secretions? 7. Look at the X-ray X-ray chest should be done to see Position of the tube State and expansion of lung Progression / course of disease / effect of treatment. One should see to it that the X ray technician understands the concept of asepsis and observes asepsis strictly. It is important that the patient is restrained properly so as to get a good centralized exposure. 8. Heamtological monitoring 9. Bacteriological monitoring 10. Miscellaneous monitoring CHANGING THE VENTILATION SETTINGS Dont forget to tell the bedside nurse what changes you have made, and dont forget to document your changes as shown in the following table. Proceedings & Abstract Book Table:1. Proposed solutions to blood gas abnormalities Problem Possible solutions Comment Low Oxygenation Increase the FiO2 The easiest solution.Remember that babies whose oxygen requirements are changing significantly need to be clinically reassessed and consider a radiograph if the FiO2 increases by more than 10%. Increase MAP Increase the PIP Increase the PEEP.Increase the inspiratory time (but this may just hold the lungs fully inflated at a high pressure). Ensure that the inspiratory time is shorter than the expiratory time. Decrease the FiO2 Unless the baby is already in room air Decrease the MAP If the PEEP is higher than 5, then we can drop this down (if the reason for the high PEEP - e.g. pulmonary haemorrhage - has resolved) Decrease the PIP (but this may adversely affect ventilation Decrease the Ti. Decrease the tidal volume. Do this first if the baby has good chest movement and/or high tidal volumes Decrease the difference between the PIP and PEEP (usually by decreasing the PIP) Note: that there are no rules on how much to drop the PIP by - you need to look at the chest movement and look at the delivered tidal volume on the ventilator. In general, drop the PIP by decrements of 2 cms and monitor VT Decrease the frequency Drop the rate. If the gas is alkalotic, drop by a fraction that you want the pH to drop Note that for modes where every breath is assisted (e.g. PSV, SIPPV), it is futile to reduce the rate if the baby is breathing above the back up rate. So wean the pressure (or VT) instead. Ensure Tube patency and correct position. Increase the PIP till you get some chest movement but look at the tidal volume too Increase the tidal volume In general, you should not increase the PIP too high as you may find that the tidal volume increases significantly. But you need to give enough pressure to get chest movement. Remember that if you are having to put the PIP up a lot to get the same tidal volume in that you were giving previously, compliance is going down. Ask yourself Why? Look at the baby, listen to the air entry, and think about a radiograph, particularly if the FiO2 is going up. Increase the frequency Increase the rate. If acidotic, increase by a fraction that you want the pH to increase. High Oxygenation Over ventilation (Low PaCO2) Under ventilation (Low pH with a High PaCO2) 48 INTERNATIONAL PEDIATRIC UPDATE 2004 NURSING CARE 1. Change position every 4hrs 2. Record 1-2 hourly on ventilation chart. 3. Refill water in humidifier 8-12 hrly and SOS. 4. Remove condensed water from circuit and water traps 3-4 hrly and SOS 5. ETT care and suctioning with full aseptic precautions as shown in appendix B. 6. CPT, Percussion, Vibration, Postural drainage SOS as shown in appendix C. 7. Keep additional stand-by source of O2 8. Fluids adjustment for ventilated babies: Give 2/3rd of required maintenance fluids initially Keep on dynamically adjusting the fluids based on continuous assessment of weight, CFT and urine output, electrolytes, etc. 9. Nebulisation, if required 10. Tube feedings for ventilated babies: Initiate tube feeds once the baby is hemodynamically stable; abdomen is soft and not distended; increase feeds gradually. If neonates condition does not permit adequate enteral nutrition, trophic feeds may be administered. Withhold feeding for 4-6 hours prior to extubation 11. Weight records: Should be done daily or more often as required by clinical condition. However, it should be done with the help of either online weighing scale (ideally) or on a stand-alone weighing machine without adversely affecting the baby. COMPLICATIONS Mechanical ventilation can give rise to following complications. Therefore it is essential to prevent or minimize their sequelae. UPPER AIRWAY 1. Nasal septum necrosis 2. Palatal groove 3. Nasofacial cellulitis 4. Subglottic edema 5. Subglottic tracheal stenosis 6. Necrotizing tracheobronchitis LOWER AIRWAYS 1. CLD 49 2. 3. 4. 5. Air leaks Pulmonary haemorrhage Atelectasis Pneumonia EXTRAPULMONARY 1. ROP 2. Sepsis 3. IVH 4. PDA 5. NNEC ROLE OF ANALGESICS / SEDATIVES/ PARALYTICS Having an endotracheal tube in-situ, IV lines and other invasive monitoring, is stressful and painful to the baby. A smooth uneventful ventilation is more likely to occur if the baby is calm, comfortable and pain free. Such a baby synchronizes well with the ventilator and is less likely to fight the ventilator.[4] This can be ensured with the use of low dose analgesic infusions. Sedatives alone are not as effective as they do not reduce pain sensation. However, they may be used in conjunction with analgesics. It is better to use narcotic analgesics for comprehensive action. 1. Morphine: Supplied : Inj. 10mg per mL Dose : Bolus dose 0.1 0.5 mg /Kg . Repeat doses every 2 to 6 hrs. Infusion : 0.025-0.05 mg/Kg/hr after initial loading infusion of 0.1mg/Kg/hr. Maximum dose : 20 µg/Kg/hr. Side effects : Resp depression, decreased gut motility, urinary retention. 2. Fentanyl: Supplied : 0.05 mg/ mL in a 2mL vial. Dose : Bolus : 1-2 µg/Kg IV. IV to be administered over 3-5 min. Repeat dose : every 1-2 hrs Infusion : 1-2 µg/Kg/hr 3. Midazolam: Supplied: Inj 1 mg./ml in 2ml Dose : Bolus : 0.1 mg/Kg IV. Repeat dose : every 2-4 hrs. Infusion dose : 0.4-0.6 micrograms /Kg/min 4. Lorazepam: Supplied as: Inj 2mg/mL Dose : Bolus : 0.1 mg/Kg Repeat dose : every 2-4 hrs. IV Proceedings & Abstract Book 5. Pancuronium: Initial dose : 0.1 mg/kg Repeat dose : 1-4 hourly. It is not to be used for continuous infusion. 6. Vecuronium: Loading dose of 0.1mg/kg followed by 0.050.1 mg/kg/ hr. Paralytic agents should be used for the minimum possible duration. Side effects of paralysis: 1. Loss of spontaneous respiration in the case of accidental extubation. 2. V/Q mismatch. 3. Analgesics need to be given, as pain is not alleviated. WEANING When to start? Satisfactory blood gas levels pH > 7.25 PaCO2 = 40 - 50 torr PaO2 = 60-80 torr Stable baby at this levels for 6 24 hrs No respiratory distress No radiological complications Haematocrit > 35- 40 % Metabolically stable: calcium / magnesium /potassium / phosphate / nitrogen balance Transferring of respiratory load from machine to neonate should be in a careful and controlled manner with close observation How to execute? Various modes and sequence of execution available for weaning are: Low rate IMV - Extubation ± nasal / nasopharyngeal CPAP / BIPAP IMV - Patient Triggered Ventilation Extubation ± nasal / nasopharyngeal CPAP / BIPAP. Steps to be taken prior to extubation Nil orally for atleast 12 hours Stop sedatives / narcotic analgesics 24 hours prior to extubation Start methylxanthine in a < 1 kg and < 7 days old neonate Theophylline - 5 mg / kg / day Caffeine - 10 mg / kg / day 50 Start Dexamethasone @ 0.5 mg / kg / day; 24 hours prior to extubation and continue for 24 to 48 hours there after. It is usually started when there has been repeated intubations or when the baby has been ventilated for more than 5-7 days. Usual settings on which extubation is done: PIP - 15 PEEP - 4 FiO2: 0.25-0.35 Ventilatory rates: 20-30 EXTUBATION Has to be electively planned and executed. Preferably in the morning hours so that there is sufficient staff for after care. Attempt when electrolytes, acid base status are normal with a haematocrit of greater than 35%. Increase FiO2 prior to extubation Gently do endotracheal suctioning under direct vision with full asepsis. Do bag to tube ventilation prior to extubation and then come out with the tube after giving a positive pressure. Send the tip of the tube for culture and sensitivity POST EXTUBATION CARE Do gentle bag and mask ventilation for few times. Do gentle oropharyngeal suctioning. Give warm and humidified oxygen @ > 5 litres / min under hood while titrating FiO2 with the clinical condition. Change neonates position 2 hourly. Gently do chest physiotherapy using a nipple /cushioned soft face mask/cupped hands. No feeds for atleast next 12 - 24 hours CONCLUSION This write up primarily addresses conventional mechanical ventilation & should facilitate a relatively less experienced doctor to perform mechanical ventilation of neonates safely. However, in reality, mechanical ventilation requires the use of both science and art and is best learnt sitting next to the baby. It is important to remember that mechanical ventilation has to be carried INTERNATIONAL PEDIATRIC UPDATE 2004 out not in isolation but with comprehensive care of all the systems of a neonate, only then it will be successful with optimal intact outcome of a neonate. References: 1. Spitzer AR, Greenspan JS, Fox WW. Positive pressure ventilation: Pressure limited and time cycled ventilation. In: Goldsmith JP, Karotkin EH, editors.Assisted ventilation of the neonate.4th ed. Philadelphia: Saunders,2003;149-70 2. Beresford MW, Shaw NJ, Manning D: Randomised controlled trial of patient triggered and conventional fast rate ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2000 Jan; 82(1): F14-8 3. Mariani G, Cifuentes J, Carlo WA: Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 1999 Nov; 104(5 Pt 1): 1082-8 4. Bernstein G, Mannino FL, Heldt GP, et al: Randomized multicenter trial comparing synchronized and conventional intermittent mandatory ventilation in neonates. J Pediatr 1996 Apr; 128(4): 453-63. Acellular Pertussis Vaccines Dr. Rémy Teyssou, Epidemiology Senior Director, Medical Affairs Department, Sanofi-Aventis, Lyon In worldwide terms of morbidity and mortality, Pertussis (Whooping cough) is one the most important of the vaccine preventable diseases. In industrialized countries, pertussis incidence is higher in infants, adolescents and adults. In the developing world, millions of cases occur annually, mostly in children. The first pertussis vaccines were whole cell vaccines, prepared using bacterial cells harvested from cultures. The efficacy of these vaccines has been clearly demonstrated in clinical trials, through epidemiological surveillance systems and from clinical experience in countries where routine Pertussis vaccination was withdrawn which lead to dramatic increases in Pertussis disease incidence. In several countries, Pertussis vaccination was withdrawn following concerns over the reactogenicity of whole cell vaccines. Fever, drowsiness, fretfulness are the most frequent adverse events, while convulsion/ seizures and acute encephalopathy account respectively for 1 case per 1,750 children vaccinated and 1/100,000. These concerns directly lead to the development of a new generation of cellfree (acellular pertussis) vaccines, based on 51 purified antigenic components involved in the pathogenesis of B. pertussis infection. Five distinct virulence factors have been described and studied in the vaccine perspective1: Pertussis toxin (PT), which produces a wide range of physiological effects, such as T and B-lymphocyte stimulation, lymphocytosis, inhibition of neutrophil chemotaxis and monocytes migration. PT is a major contributor to the pathogenesis, and as such is a major component of all current acellular vaccines Filamentous hemagglutinin (FHA), which is hypothesized to interact with pertactin in establishing binding to respiratory tract epithelium. It may also facilitate the intracellular infection, stimulate suppressor T-cells. Fimbriae (Fim) 2 and 3, which promote attachment to monocytic cells and to the respiratory epithelium. These induce serotype-specific immunity. Pertactin (Prn), which is located on bacterial surface. It acts as an adhesin, probably in conjunction with FHA. Different acellular pertussis (acP) vaccines have been developed, including one (PT alone), two, three four or five of these Proceedings & Abstract Book components. Currently there are licensed formulations containing two (PT, FHA), three (PT, FHA, Prn) or five components (PT, FHA, Prn, Fim2 and Fim3). These acP vaccines are administrated in combination with other antigens: diphtheria and tetanus toxoids (DTacP). In many countries they are also administrated with additional antigens: Hepatitis B, inactivated polio vaccine and/ or Haemophilus influenzae b. Numerous studies have clearly established that adverse events following administration of acP are less severe and occur less frequently than with whole cell pertussis vaccines .1 All currently licensed acP vaccines have been confirmed to be effective in numerous clinical trials and surveillance studies. They have a similar range of efficacy, with only minor differences.2,3,4,5 However, efficacy is not the only approach for assessing the potency of the vaccine. Measuring the effectiveness represents a more pertinent alternative, as vaccine effectiveness describes the vaccine impact on disease when used under the real-world circumstances of medical and public health practice, rather than under the ideal conditions of a clinical efficacy trial. The ongoing Swedish surveillance program, which has been implemented since 1990, provides unique information about effectiveness of acP vaccines routinely used in this country (2 and 3 components) since their introduction in 1996 3. All children born since January 1st 1996, and continuing to live in Sweden, have been followed; each notified and confirmed case has been tracked by telephone contacts to document vaccination status and clinical course. The information gathered allows the calculation of incidence in vaccinated and nonvaccinated children and hence the vaccine effectiveness. The most recent available data on the two-component vaccines (PT, FHA) showed an effectiveness of about 91% after 2 doses, increasing to 98% after the third dose. In conclusion, acellular pertussis vaccines have proven high efficacy, and have superior safety profiles compared to the whole cell vaccines. Whatever the strategy implemented and the vaccine used, epidemiological surveillance warrants a long-term follow-up of the incidence and the effectiveness. References: 1. M. J. Corbel and D. K. L. Xing. Toxicity and potency evaluation of Pertussis vaccines. Expert Review Vaccines. 2004 ; 3 (1) : 89 101 Vaccine. 2003 ; 21 : 2015 - 2021 2. L. Gustafsson, H. Hallander, P. Olin, E. Reizenstein and J. Storsaeter. A controlled trial of a twocomponent acellular, a five-component acellular and a whole-cell Pertussis vaccine. New England Journal of Medicine. 1996 ; 334(6) : 349 355 4. F. Simondon, MP Preziosi, A. Yam, C. Toure Kane, L. Chabirand, I. Iteman, G. Sanden, S. Mboup, A. Hoffenbach, K. Knudsen, N. Guiso, S. Wassilak and M. Cadoz. A randomized double-blind trial comparing a two-component acellular to a wholecell Pertussis vaccine in Senegal. Vaccine. 1997; 15 : 1606 1612. 3. P. Olin, L. Gustafsson, L. Barreto, L. Hessel, T. C. Mast, A. Vanrie, H. Bogaerts; J. Storsaeter. Declining Pertussis incidence in Sweden following the introduction of acellular Pertussis vaccine. 5. S. Torvaldsen, J. M. Simpson and P. McIntyre. Effectiveness of Pertussis vaccination in New south Wales, Australia, 1996-1998. European Journal of Epidemiology. 2003; 18 : 63 69 52 INTERNATIONAL PEDIATRIC UPDATE 2004 Adverse Reactions to MMR Vaccines Dr. A. K Dutta, Director Prof. & HOD Pediatrics, Lady Hardinge Medical College, New Delhi Introduction Immunization is the most cost effective and widely used public health interventions. A higher standard of safety is generally expected of vaccines than other medical interventions since it is always given in healthy individuals to prevent diseases. This lower risk tolerance for vaccines translates into a need to investigate the possible causes of much rarer adverse events after vaccinations than would be acceptable for other pharmaceutical products. No vaccine is perfect in its safety and efficacy. As the incidence of vaccine preventable diseases are becoming less due to universal immunization, adverse vaccine reactions (true vaccine reactions) and those associated with vaccination only by coincidence, become increasingly frequent and prominent. World Health Organization Expanded Program on Immunization recommended in 1991 that all National Programs implement surveillance for adverse events following immunization. As the evidence of the vaccine preventable diseases are declining, more so in developed countries, there is a general trend to blame vaccines for the etiology of several diseases. In the United Kingdom whole cell pertussis vaccine fell into disrepute because of encephalopathy. However, the hypothesis has been proven to be not true. Similarly MMR vaccine especially Urabe strains has been incriminated to cause large number of aseptic meningitis syndrome. Autism and other neurological complications of MMR vaccine were in the headlines of several print and electronic media in the west. In Indian market several vaccine-manufacturing companies are marketing MMR vaccine with different strains. An attempt has been made in this review to analyze the possible adverse reactions of MMR vaccine containing different strains of measles, mumps and rubella vaccine. 53 Measles Vaccine Measles is a relatively safe vaccine irrespective of the strains used for its preparation either as monovalent or in combination (MMR). Fever with a temperature of more than 39.50C occurs in approximately 5-15% of cases. Fever usually develops 7-12 days after vaccination and is of relatively mild in nature. Occasionally, febrile seizure can cause in vaccine recipients. Rash occurs in approximately 5% of the cases 7-10 days after vaccination and is transient in nature and usually disappears in two days. Side effects following second dose of measles containing vaccines are generally less frequent than the first one, because most children would be immune from the initial vaccination. The Institute of Medicine in 1994 in USA after examining the possible adverse reactions of licensed vaccine observed that there is causal relationship between measles containing vaccine and thrombocytopenia, anaphylaxis and death. The incidence of thrombocytopenic purpura from MMR is estimated to be 1 per 30,000 doses. There are reports of documented death from vaccine strain viral infection in severely immuno-compromised children including AIDS. Severe progressive vaccine associated measles pneumonitis in a child with AIDS, 1 year after the dose is reported from U.S.A. The possible causal relationship of central nervous system involvement such as encephalitis and encephalopathy and MMR vaccination is debatable. There is inadequate data to accept or reject the hypothesis. The incidence of encephalopathy and encephalitis as observed by CDC in U.S.A. following measles containing vaccine was found to be 0.4 per million doses. This rate is lower than that noted for severe neurological disorders of unknown etiology in Proceedings & Abstract Book unimmunized children of the same age range. This suggests a chance temporal association rather than cause and effect for most cases. The National Childhood Encephalopathy study group however did find an increased risk of encephalopathy or prolonged convulsion within 7-14 days of vaccination, but none of the children had any serious permanent sequelae. There is very little or no evidence of SSPE following measles vaccination. The epidemiological data has not documented a direct risk from the vaccine. Other side effects which are attributed to measles vaccine are Gullain-Barre Syndrome, Reye syndrome, oculomotor palsy, optic neuritis, retinopathy, hearing loss, cerebellar ataxia, autism and inflammatory bowel disease. It is very difficult to determine whether these events are truly vaccine related or represent a chance temporal relation. Mumps Vaccine Mumps vaccines prepared by various laboratories in the world contain following strains e.g. Jeryl-Lynn, Leningrad-Zagreb, Leningrad-3, Urabe, Hoshino, Torri, Miyahara, Chiba, and Rubini. The most common adverse events to mumps vaccine are parotitis and low-grade fever, which occurs 10-14 days after vaccination. Transient rash, purpura and pruritis also have been reported following mumps vaccination. In one study, Parotid and or submaxillary swelling was observed in 1.6% of children receiving Jeryl Lynn strain and 1-2% in Urabe strain. Following Hoshino strain, parotid swelling was observed 14-24 days after vaccination. Assessment of adverse reaction following mumps vaccine is difficult to assess since MMR is a combined vaccine. However, there have been very rare reports of orchitis, arthritis, sensorineural deafness and acute myositis. There is a theoretical risk of diffuse retinopathy, joint disturbances and thrombocytopenia. Mumps and Aseptic Meningitis Natural mumps virus infection has a high incidence of aseptic meningitis. All the available mumps vaccine has been implicated to cause aseptic meningitis. However, the rates of this complication vary 54 according to the strains used in the vaccine. The Urabe strain as well as Leningrad-3 strains have been attributed the most for the causation of aseptic meningitis. In the United Kingdom, a total of 23 cases of aseptic meningitis following Urabe strain containing MMR vaccine (1 in 11,000 doses) raised a doubt regarding the safety of the strain in early eighties. The same vaccine was attributed to cause convulsion 15-35 days after vaccination in 1 of 2600 doses. Following this, Urabe strain has been withdrawn from use in several countries in the west. It is very difficult to attribute mumps vaccine for all cases of aseptic meningitis since coincidental aseptic meningitis after MMR vaccination may occur due to other viruses and even due to wild mumps virus. However, confirmation of the causative role of the vaccine virus can be made by definitive identification methodology of the mumps virus isolate as vaccine strain. There is a definite causal relationship between mumps vaccine and aseptic meningitis. Data regarding association of mumps vaccine and aseptic meningitis are available from United States, U.K., Canada, Germany, Japan and France where a meticulous surveillance system for adverse reactions of vaccination is practiced. The reported occurrence of aseptic meningitis following vaccination is a rare event and reported to be 1 in 1.8 million doses. In a nested casecontrol study, receipt of MMR within 30 days was not demonstrated to be risk factor for hospitalization for aseptic meningitis. In Germany, the reported incidence is 1 per million doses. The rates of aseptic meningitis from Japan using Hoshino, Torii, Miyahara and Chibha strains were found to be 1 in 1,20,000; 30,000; 20,000 and 5,000 respectively. Leningrad Zagreb strain is being used in India and Croatia. Reported incidence of aseptic meningitis as per WHO (weekly epidemiological report No. 45, 9th Nov. 2001) is 1 per 1,00,000 doses in Bahamas and 2 per 1,00,000 doses in Slovenia. This strain is widely used in India and since 1999; MMR vaccine has been introduced in Delhi States immunization schedule. No deaths have been reported from Delhi after administration of 500,000 doses of MMR vaccine containing L-Zagreb strain. There was one case of anaphylaxis and two cases of aseptic meningitis. The causal INTERNATIONAL PEDIATRIC UPDATE 2004 relationship of aseptic meningitis could not be ascertained. Urabe strain has been incriminated with aseptic meningitis in Japan and United Kingdom. In Japan the rate of aseptic meningitis following MMR Urabe strain was found to be 1 in 2,000 doses and isolation of vaccine virus in CSF in 1:9,000 cases. In Canada, the observed rate of meningitis following MMR was calculated to be 1 in 62,000 doses. In France, the rate of aseptic meningitis observed with Urabe strain manufactured by Pasteur Meriux and GlaxoSmithKline was 1: 28,400 and 1: 12,000 doses respectively. The Public Health Laboratory Services Surveillance from United Kingdom suggested a rate of 1 in 11,000 doses with Urabe strain and none with Jeryl Lynn strain. Brown and co-workers demonstrated that the strain isolated from cases of aseptic meningitis was one of two variants present in the Urabe vaccine. The meningitisassociated variant had a mutation from guanine to adenine at base 1081, which resulted in a glutamine to lysine change in amino acid 335 of the HN protein. In view of the controversy over Urabe strains association with aseptic meningitis WHO in 2001 stated that currently available mumps vaccine vary in terms of adverse reactions and protective efficacy but there is ample evidence that these vaccines are highly efficacious and safe. MMR vaccine with available strains can be safely introduced in the National Immunization program of any country. However, WHO policy recommends that Rubini strain should not be used and those previously immunized with this strain should receive one more dose of an effective mumps vaccine to ensure protection.(WHO position paper on Mumps Virus vaccines, weekly epidemiological report No. 45, 9th Nov. 2001) and incidence of radiculoneuritis, other neuropathies and thrombocytopenia. A review of adverse events in Canada observed an incidence of 0.3 per 1,00,000 doses for arthritis or arthralgia. The adverse reaction of joint involvement was found to be more with earlier strain of HPV-77 and Candehill vaccine. However, Polk and associates have reported an incidence of 13-15% arthralgia or arthritis with RA 27/3 strain of rubella vaccine. The mechanism of joint involvement is probably because of direct infection of the synovial tissue by the virus. Tingle and coworkers reported in their prospective study of 268 women in British Columbia following complications e.g. sore throat, cervical lymphadenopathy, rash, myalgia, parasthesia, arthralgia and arthritis in a large number of cases. The side effects of rubella vaccine in the form of mild rubella vary directly with age, being almost absent in infants and present up to 50% in women. A double blind study of vaccination with MMR in children revealed 1% incidence of arthropathy and little evidence of other reactions. Other complications e.g. polyneuropathy, optic neuritis and diffuse myelitis, transverse myelitis and Guillain-Barre syndrome have been reported following rubella vaccination. The complications are more with earlier HPV-77 and Candehill vaccines. However, cases of diffuse myelitis are reported with RA 27/3 strains. Thrombocytopenia is a known complication of natural rubella with an incidence of 1 in 3000 infection and following vaccination, the reported incidence is 1 in 3,00,000 vaccinees. Rubella vaccines have been noted to depress nonspecific cellular immunity transiently including tuberculin reaction, cell mediated immunity to Candida and delayed type of hypersensitivity to recall antigen. Rubella Vaccine The National Academy of Medical Sciences in U.S.A. in 1991 published the report of the committee in which four possible adverse effects of rubella vaccine e.g. acute arthritis, chronic arthritis, neuropathies and thrombocytopenia were described. The report found a definite causal relationship between RA 27/3 strains and acute arthritis and chronic arthritis in adult women. There is still insufficient evidence to indicate a causal relationship between use of vaccine Summary Although adverse side effects following MMR vaccine is well known, most of the reactions are of trivial and transient nature. Some of the adverse reactions are related to a particular strain in the MMR vaccine. However, the benefit of the vaccine far outweighs the side effects and therefore universal immunization with MMR vaccine is recommended for all infants in National Immunization Program. If the MMR vaccine is given early in life as primary immunization, 55 Proceedings & Abstract Book the adverse reactions are minimum. The present knowledge and review of the subject clearly indicates that for measles vaccine either Schwarz or E-Z strain can be safely used, for mumps Jeryl Lynn strain, Leningrad Zagreb or Urabe strain and for rubella RA 27/3 are the strains which can be incorporated. Universal immunization with MMR vaccine would prevent several million children deaths from measles, eliminate congenital rubella syndrome and ameliorate the misery of morbidity of mumps. References 1. Chen RT, Rastogi Se, Mullen JR, et al. The vaccine adverse event reporting system (VAERS). Vaccine 1994; 12 : 542-550. 2. World Health Organizaztion. Vaccine supply and quality. Surveillance of adverse events following vaccination. Wkly Epidemiol Rec 1996; 71 : 237242. 3. Report of a WHO scientific group on measles vaccine. WHO Technical Report Series 1963; 263 : 5-37. 4. Peltola H, Heinonen OP. Frequency of true adverse reactions to MMR vaccine. A double blind placebo control trial in twins. Lancet 1986; 1 : 939-942. 5. Isozaki M, Kuno Sakai H, Hoshi N, et al. Effects and side effects of a new trivalent combined MMR vaccine. J Exp clin Med 1982; 7 : 547-550. 6. Katz SL. Immunization with live attenuated measles virus vaccines. Five years experience. Arch Virus Forsch 1965; 16 : 222-230. 7. Griffin MR, Ray WA, Mortimer EA, et al. Risk of seizures after MMR immunization. Pediatrics 1991; 88 : 881-885. 8. Landrigan PJ, Witte JJ. Neurological disorders following live measles virus vaccine. JAMA 1973; 275 : 1459-1462. 9. Oski FA, Naiman JL. Effect of live measles vaccine on the platelet count. N Eng J Med 1956; 275 : 352-356. 10.Wilhelm DJ, Paegle RD. Thrombocytopenia purpura and pneumonia following live measles vaccine. Am J Dis Child 1967; 113 : 283-285. 11.Stratton K, Howe CJ, Johnson RB Jr. Adverse events associated with childhood vaccinations. 56 Evidence bearing on casuality. Washington DC. National Academy Press 1994. 12.Miller C, Miller E, Rowe K, et al. Surveillance of symptoms following MMR vaccine in children. Practitioner 1989; 233 : 69-73. 13.Nakayama T, Oka S, Komase K, et al. The relationship between the mumps vaccine strain and parolitis after vaccination. J Infect Dis 1992; 165 : 186-187. 14.Griffin MR, Ray WA, Mortimer EA, et al. Risk of seizures after MMR vaccination. Pediatrics 1991; 88 : 881-885. 15.Ueda K, Miyazaki C, Hidaka Y, et al. Aseptic meningitis caused by MMR vaccine in Japan. Lancet 1995; 346 : 701-702. 16.Miller E, Goldacre M, Pugh S, et al. Risk of aseptic meningitis after MMR vaccine in U.K. children. Lancet 1993; 341 : 979-982. 17.Peltola H. Mumps vaccination and meningitis. Lancet 1993; 341 : 994-995. 18.Tingle AJ, Chanter JK, Pot KH, et al. Post partum rubella immunization : Association with development of prolonged arthritis, neurological sequalae and chronic rubella viremic. J Infect Dis 1985; 152 : 606-612. 19.Tingle A, Mitchell L, Grace M, et al. Randomized double blind placebo controlled study on adverse effects of rubella immunization in seronegative women. Lancet 1986; 349 : 1277-1281. 20.Centre for disuse control. Adverse events following immunization. Surveillance Report No.1 19791982. US Dept. of Health and Human Services. Public Health Services. Atlanta CDC, August 1984. INTERNATIONAL PEDIATRIC UPDATE 2004 MMR Vaccines : Which One to Use? Dr. Y. K Amdekar, Consultant Pediatrician, Jaslok Hospital, Mumbai. MMR vaccine is available in combination of different strains. Each manufacturer stresses superiority of his brand and brings out points against other brands. This offers equal opportunities for physicians to learn worthiness of each combination. However contradictory claims by the industry confuse the practitioner to choose the ideal brand for routine use. Most of the times, half-truth is put forward by the industry and hence need for unbiased study to make right choice. Every vaccine in the market is assured to be reasonably safe and effective. There is no reason to believe one vaccine far superior than the other. But there are few considerations that may decide a vaccine more appropriate in our setting than another is. Ideal MMR vaccine is expected to offer protection against all three diseases to an acceptable extent. It should be adequately immunogenic to administer at the earliest age of susceptibility to ensure protection to all age groups of children. It should result in sustained immunity and should have capability of producing good booster effect on revaccination. It should be of course safe enough not to cause any serious side effects. Finally cost of the vaccine must be affordable to the majority. Vaccine for the rich is not a sound idea as poor feels obligatory to do the best for his child as well, at any cost. Edmonston-Zagreb Measles strain is shown to be more immunogenic in early infancy than Schwarz strain and is therefore an ideal vaccine to administer at 6 months of age. Immunity induced by EZ vaccine is also unaffected by previously administered vaccine and thus it is also ideal for revaccination. However, Schwarz vaccine induces higher antibody response amongst children with low levels of maternally transmitted antibodies. Antibody response induced by Moraten strain is as good. In general, different strains of Mumps 57 vaccine (Leningrad-Zagreb, Jeryl Lynn and Urabe) produce equal immune response, though it is claimed that side effects are least with Jeryl Lynn strain, particularly in reference to aseptic meningitis. However, unbiased studies have estimated incidence of vaccine induced aseptic meningitis to be as low as 0.8 per 100,000 doses. Moreover vaccine induced aseptic meningitis is a benign disease with complete recovery without treatment. In fact, mumps virus induced disease presents with encephalitis more than mere meningitis. Other side effects are minor and include parotitis, lymphadenitis and purpura. Cost factor is an important consideration in selecting an ideal vaccine. As of now, costeffectiveness of safe MMR vaccine is not in favor of its universal use. Developed world may consider even the smallest advantage good enough to change to new vaccine. It would be long before we could do that. The only worry in this game of vaccine manufacturers is the fact that industry would rule how we should behave and the obvious beneficiary may not be the child. Proceedings & Abstract Book Behavioural Diagnosis in Office Practice Dr. Gautam Koppikar, Consultant Pediatrician, Nasik. Developmental-Behavioural Paediatrics is an emerging subspeciality of Paediatrics, and in past, not much emphasis was given on this subject in undergraduate or postgraduate curriculum and teaching. However in office practice, behavioral diagnosis is an essential skill and it fully decides the choice of therapy and the outcome. Behavioral diagnosis is difficult, as it requires a thorough understanding of the diagnostic criteria. Also there is a need to periodically revise your diagnosis in view of the dynamic nature of developmentalbehavioural disorders. A thorough knowledge of co-morbid conditions is also essential for proper office diagnosis. The various diagnostic pitfalls, dilemmas and difficulties are illustrated in this talk in the form of various Case Scenarios. Dilemmas in Chronic Viral Hepatitis Sheena Sharma*, Anupam Sibal** *Dr. Med., Aerztliche Pruefung, LMU Germany, Research Fellow **Senior Consultant Pediatric Gastroenterologist and Hepatologist, Director Medical Services, Apollo Centre for Advanced Pediatrics, Indraprastha Apollo Hospital, New Delhi. Dilemmas in chronic viral hepatitis: Chronic viral hepatitis is an important life limiting liver disease requiring proper management and appropriate timing of treatment. Without treatment, there is a high risk of reactivated infection and development of hepatocellular carcinoma. Also, untreated patients form a reservoir for further spread of infection. On the other hand however, limited treatment options exist with side effects ranging from general clinical complaints to treatment resistance with virological rebound and exacerbation of hepatitis. The goal of treatment is to achieve viral clearance and normalization of elevated serum transaminases beyond the end of therapy. The most difficult questions confronted by the clinician are: who really needs to be treated and when. 58 Hepatitis B The natural history of hepatitis B in children varies from spontaneous viral clearance to prolonged latency and progressive liver damage. Therefore, the aim of treatment in children is prevention of complications in later life. Treatment indications for hepatitis B are HBsAg positivity, HBeAg positivity more than 6 months, active viral replication (HBV DNA >105 copies/ml) and elevated serum alanine aminotransferase (ALT) more than twice the normal value in patients older than 2 years. It has been demonstrated in multiple trials that better response is achieved when there is low viral replication (low HBV DNA level), severe histologic activity with high baseline serum ALT levels, ideally more than twice the normal value. Many times the biochemistry consisting of serum AST/ALT levels might be within INTERNATIONAL PEDIATRIC UPDATE 2004 normal limits and a liver biopsy is imperative to determine the histologic activity. A liver biopsy before treatment, although being an invasive procedure, is a relatively benign and low risk procedure, which provides an objective status of the liver for further management. While treatment with standard interferon alpha requires daily subcutaneous injections and shows immediate peaks followed by zero-levels, pegylated interferon has a constant serum concentration level and seems to provide better viral clearance than interferon alpha. Pediatric data on treatment with pegylated interferon in hepatitis B however, is not available. Lamivudine is a nucleoside analogue, which can be administered orally and is tolerated well. The initial hope for a better treatment option has been overshadowed by the increasing risk of YMDD mutation with duration of treatment. The ideal treatment time to attain viral clearance compromises with the risk of mutation. Due to fear of exacerbation of hepatitis after stopping treatment, the emergence of YMDD mutation and emergence of resistant mutant viruses, there has been an interest in opting for combination therapy consisting of interferon alpha or pegylated interferon with lamivudine. Not only does one hope to decrease the risk of lamivudine induced mutation, but also to gain from additional antiviral effects. Very few studies exist on combination therapy in children with no significant benefit in terms of viral response. No consensus on the most appropriate combination regimen exists till date. Follow up requires monitoring the virological response and should include serum transaminases, HBV DNA, HBeAg/ anti-Hbe every 1-3 months after cessation of therapy for the first year and annual determination of HBsAg. Hepatitis C The first dilemma is labeling a child as a case of chronic hepatitis C since the natural history and immunological response is very variable. While treatment goals are to eradicate hepatitis C virus by complete loss of HCV RNA from liver and serum, to decrease progression of liver disease as well as reduce frequency of hepatocellular carcinoma and improve survival, the time of initiating therapy poses a challenge. Patients with evidence of ongoing infection (HCV RNA postive), elevated transaminases more than twice the normal value and evidence of histological liver disease should be started on therapy. Direct correlation between HCV seropositivity and extent of liver disease is not always present and serum AST/ALT levels may in fact be normal in spite of histological evidence of inflammation. Although there is limited data on treatment of chronic hepatitis C in children, interferon alpha remains an important part of therapy. Combination therapy with interferon alpha and ribavarin are promising and pegylated interferon may increase further efficacy with clinical trials eagerly awaited. Given the limited treatment options and risks involved, treating children appropriately remains a challenge. References: 1. Chongsrisawat V, Poovorawan Y. Management of chronic hepatitis B and C virus infections. Indian J Pediatr 2002 Feb; 69(2): 149-54 2. Jara P, Bortolotti F. Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience on European children. J Pediatr Gastroenterol Nutr 1999 Aug; 29(2): 163-70 3. EASL International Consensus Conference on Hepatitis B (13-14 Sept.2002). J Hepatol 38(2003): 533-540 4. Craxi A, Cooksley WG. Pegylated interferons for chronic hepatitis B. Antiviral Res 2003 Oct; 60(2): 87-9. 5. Liaw YF. Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. J Gastroenterol Hepatol. 2002 Dec;17 Suppl 3:S333-S337 6. Schwarz KB. Pediatric issues in new therapies for hepatitis B and C. Curr Gastroenterol Rep. 2003 Jun;5(3): 233-9 59 Proceedings & Abstract Book A Novel Diagnostic Aid (ISABEL): Development and Preliminary Evaluation of Clinical Performance Padmanabhan Ramnarayana, Amanda Tomlinsona, Gautam Kulkarnia, Anupama Raob, Joseph Brittoa a Department of Paediatric Intensive Care, St Mary’s Hospital, London, UK b Department of Haematology, Watford General Hospital, Watford, UK Abstract Clinical diagnostic aids are relatively scarce, and are seldom used in routine clinical practice, even though the burden of diagnostic error may have serious adverse consequences. This may be due to difficulties in creating, maintaining and even using such expert systems. The current article describes a novel approach to the problem, where established textbook matter is used as the knowledge base for a pediatric diagnostic tool called ISABEL. The inference engine (Autonomy) utilizes advanced textual pattern-recognition algorithms to extract key concepts from textbook description of diagnoses, and generates a list of diagnostic suggestions in response to clinical features entered in free text. The system was developed over the course of months without significant manpower requirement. Development was an iterative process, relying on sequential evaluation of clinical performance to provide the basis for improvement. The usage of the system over the past 2 years, as well as results of preliminary clinical performance evaluation are presented. These results are encouraging. The ISABEL model may be extended to cover other domains, including adult medicine. Keywords: Decision support; diagnosis; evaluation studies; pattern recognition; diagnostic error Introduction: Biomedical knowledge has grown exponentially in the past few years, resulting in severe information overload for clinicians [1]; it is estimated that this problem will double every 20 years [2]. However, rapid growth has not affected all domains of 60 medical knowledge equally, information related to newer medical tests and treatment is constantly evolving, whereas traditional knowledge pertaining to clinical diagnosis has changed relatively little. Recent techniques that attempt to summarize latest treatment recommendations in line with changing medical evidence are now available, and are popular with clinicians [3][4], whereas systems that might assist in routine clinical diagnosis remain scarce. We know, however, that medical information relevant to making clinical diagnoses is constantly needed [5], and that this information need is fulfilled mainly by consulting textbooks [6]. We also know that errors related to misdiagnoses, or missed diagnoses, constitute a significant proportion of the preventable burden of medical error [7]. Some diagnostic errors may be due to errors of omission (failure to consider all clinically relevant diagnoses during initial workup). In addition, incorrect formulation of the clinical problem, as well as difficulty in extracting relevant information from textbooks quickly, whether paperbased or electronic, may contribute to diagnostic error. One reason why computerized diagnostic aids are scarce may be related to the difficulty of converting traditional medical knowledge into computer-readable form. Existing aids for internal medicine, such as DXplain, QMR and ILIAD [8][9][10], were developed over many years, involving the input of multiple experts to provide semiprobabilistic relationships between thousands of clinical features and hundreds of diseases. These tools were also developed to assist the clinician primarily during the rare entity of a diagnostic INTERNATIONAL PEDIATRIC UPDATE 2004 dilemma (clinical dead-end), by acting as oracles. As a result of this design, they often required the user to expend a considerable amount of time interrogating the system [11]. In order to regularly use such a standalone system in practice, a clinician had to be highly motivated, one reason why diagnostic decision support as a concept may not have captured clinicians interest. This paper aims to describe the development of a novel diagnostic aid called ISABEL (http://www.isabelhealthcare.com) [12][13][14], which utilizes unstructured information from standard textbooks to provide a set of diagnostic reminders for any clinical scenario, in response to clinical features entered in free text. In stand-alone format, it is intended to be used by clinicians in routine practice, in a negligible amount of time. An analysis of the systems performance is also described. Materials and Methods: Underlying knowledge base: Electronic text from 4 standard pediatric textbooks, provided by Elsevier Health Sciences, was used to populate a predesigned diagnostic tree comprising around 3500 diagnoses. This tree was based on the table of contents derived from one standard textbook (Nelsons Textbook of Pediatrics, 16th Edition). Figure 1 depicts part of this diagnostic tree. paediatric view Categories Allergic Disorders Bone and Joint Disorders Cardiovascular System Endocardium Diseases Acquired Heart Disease Cardiac Arrhythmias Congenital Heart Disease Diseases of the Myocardium Diseases of the Pericardium Diseases of the Peripheral Vascular System Heart Failure / Congestive Heart Failure Tumors of the Heart Children with Special Health Needs Digestive System Diseases of the Blood Figure 1- View of part of the ISABEL diagnostic tree 61 Electronic text pertaining to each diagnosis within the tree was copied from each of the textbooks into the ISABEL database, without any modifications, by one research nurse. Thus, unformatted text relating to the same disease, from different sources, was collated under one disease label. Where new disease labels were necessary to accommodate text from a new textbook, they were created within the same overall diagnostic tree model. Since there was no modification of the text involved, this entire process took less than 4 months for one researcher, for all 4 textbooks. Inference engine: Commercially available software was used as the inference engine (Autonomy, Autonomy Corporation, Cambridge, UK, www.autonomy.com). This software employs advanced pattern-recognition techniques on unstructured text to extract a documents digital essence, identifies and encodes the unique signature of key concepts within a document, and creates concept agents to match document profiles with similar ideas as the input text. The software utilizes Bayesian Inference and Shannons principles of information theory to generate its pattern-matching algorithms to enable sophisticated concept extraction from documents. By aggregating text related to one specific diagnosis under a single diagnostic label within the diagnostic tree, it was possible for the software to generate a unique signature of key concepts for each diagnosis, by using its concept extraction techniques. This signature was constantly modified with the addition of text from each additional textbook used to populate the ISABEL database. Search methodology: In response to a set of key clinical features for a patient (concepts), ISABEL utilized Autonomy to search the underlying database of text, and return all documents (diagnostic labels) whose concept signature matched that generated from the clinical features. Clinical features could be altered (by entering additional findings or deleting findings) to reflect a different concept signature, and thus alter the results of the search. Due to the nature of the search mechanism, only clinical features described in textual language were used to generate Proceedings & Abstract Book a concept signature (i.e numerical values, such as the age of the child, were not used). System architecture and delivery platform: In order to maximize the use of the system, and eliminate inequalities of regional distribution, ISABEL was delivered on the World Wide Web to all medical practitioners, after a short registration process. To this end, a website was created by DynamicWeb, UK using Javascript. The Autonomy Dynamic Reasoning Engine (DRE) was hosted on a dedicated ISABEL server, as was the database comprising the diagnostic tree, which could be construed as being the equivalent of multiple documents of text in html. At the front end, a free text box, into which the user could enter the clinical features of a patient, was created on a dedicated diagnostic tool webpage on the ISABEL website. On searching the database with these features, a list of all matching diagnostic labels (diseases) was returned. The maximum and minimum number of the diagnoses displayed on the results page could be varied by the developers of the system. Remodeling the search mechanism: Preliminary examination of the systems raw results by the medical team (consisting of three pediatricians) suggested four problems, which led to a remodeling of the underlying architecture of the ISABEL database. Since numerical values were not used in the generation of the concept signature, it became obvious that users had to specify the patients age group separate from the clinical features to avoid ageinappropriate diagnoses being displayed (such as neonatal meningitis for a 3 year old child) Due to the global audience, it was essential to take into account where the patient originated from, and to tailor diagnostic suggestions accordingly. Due to the free text (variable) nature of input, it was necessary to create an intermediate filter between the input and the DRE, whose main function was to convert non-medical terminology into medical terms. Since the primary function of the system 62 was to provide diagnostic reminders, each holding equal clinical value, it was felt that the degree of concept matching, as expressed by Autonomy, should not be used as the basis for the ordering of the diagnostic suggestions. These changes were achieved by tagging each of the diagnostic labels in the tree to specific age groups (newborn, infant, child and adolescent), and to specific regions of the world (e.g. North America, Western Europe etc., as per World Health Organization guidelines). This was done by the development team in 4 weeks. In addition, the intermediate filter to convert common non-medical terms into appropriate medical terms was developed specifically for ISABEL by the medical team in 4 weeks. Table 1 shows some common terms included in this filter. Table 1 Examples of terms included in the filter Lay terms & abbreviations Nad Hot, high temperature WBC Shut down, peripheries Medical translation Normal Fever, pyrexia White cell Shock, cold vasoconstriction Additional drop-down boxes were provided for the user to specify the age-group and the region, in addition to the existing free text box for clinical features. Diagnostic results were arranged into body systems to which they pertained (Asthma - Respiratory disorder), rather than in rank order of the degree of concept match. This facilitated a patho-physiological approach to the diagnostic process. Further information regarding each diagnosis in the suggestion list could be obtained by clicking on it text from Nelsons textbook was provided for reference. Figures 2 & 3 show how a set of clinical features entered in free text into the search box produce a set of diagnostic labels (with the preceding text: have you considered?) for the users attention. Measuring usage of the system on the Web: The complete system as described above was available on the Internet from June 2001. Usage statistics were used as indicators of the popularity of the system, INTERNATIONAL PEDIATRIC UPDATE 2004 Figure 3 Diagnostic suggestions arranged to reflect patho-physiological process involved Figure 2 Clinical features entered into free text box and were measured using analog 5.22. Data from July 2001 to date are provided in the results section. Preliminary estimates of the systems performance: Since the primary role of the system was to offer relevant significant diagnostic reminders for a variety of clinical scenarios in pediatrics in a negligible amount of time, preliminary testing of the performance of the system was based on examining if important diagnostic suggestions were offered, and how long it took to obtain results from the system. This testing was done by the developers of the system, rather than users, in a laboratory setting removed from clinical practice. Clinical data from 100 real patients, drawn from an unselected consecutive sample of children attending 4 emergency departments in the UK was used. These data consisted of age-group, initial clinical features (including results of available firstpass tests) and final discharge diagnoses. They were collected by clinicians working in these departments for the study, and were not modified by the developers in any way during testing. Cases were examined by a panel of two pediatricians, working together, who produced a bare minimum list of significant diagnoses that ought to have formed part of the examining physicians diagnostic work-up list to ensure clinical safety (gold standard). These clinical data were also entered into ISABEL by one research nurse, and the resultant diagnostic suggestion list was compared to the gold 63 standard list. The maximum number of suggestions was fixed at 15 for this study. Outcomes: Comprehensiveness ratio: mean value of match between the gold standard list and ISABELs list (expressed as a proportion). Relevance ratio: Ratio of matching gold standard diagnoses in the ISABEL list to the total number of diagnostic suggestions offered by ISABEL. Interrogation time: Time taken to enter clinical data into the system and generate a diagnostic suggestion list (on a 56 KBps modem connection) Results: Usage statistics: 25 GB of data was transferred in the period from July 2001-August 2003 (average/day: 32 MB). There were 9,168,147 successful page requests (average/day: 11,641); over 12,000 users registered to use the site in the specified period. Over a fifth of users accessed the system >5 times since registration. The entire National Health Service (NHS), UK was provided log-in free access via IP address recognition in mid2002; it then proved difficult to estimate the true number of users. This facility was also extended to cover many teaching hospitals in the US (over 10% of the registered users are currently US-based). Performance of the system: The panel provided gold standard diagnoses for all 100 cases. The median number of such diagnoses per case was 2 Proceedings & Abstract Book (range 1-4). ISABEL provided a maximum number of 15 diagnoses (minimum 10, mode 15). In 73/100 cases, ISABEL displayed all gold standard diagnoses (comprehensiveness ratio 1.0). In an additional 15/100 cases, at least half of the gold standard was present in the ISABEL suggestions (comprehensiveness ratio 0.50). The mean comprehensiveness ratio across all 100 cases was 0.81. Since the best raw relevance ratio in this study could only have been 0.27 (all 4 gold standard diagnoses matched in a set of 15 ISABEL diagnoses), a final relevance ratio was calculated (expressed as a proportion of 0.27). In this study, the mean final relevance ratio was 0.45 (95% CI 0.39-0.51). Over a 56KBps modem connection, ISABEL results took less than 1 sec to display in all cases. Time taken to enter clinical data into the system (interrogation time) was variable depending on the level of detail entered (range: 30 sec 2 min). Discussion: This paper describes the development and preliminary analysis of the performance of a diagnostic tool for pediatric medicine. We have shown that, using a novel technique to search an established medical knowledge base (textbooks), it is possible to deliver relevant diagnostic suggestions in a suitable format for physicians consideration. The system does not aim to provide probabilistically ranked diagnoses like other similar systems. We feel that organizing diagnostic suggestions in terms of pathophysiological causes is useful for the clinician. Further information on each diagnosis can be sought in the form of text from established medical textbooks. This approach empowers the user, and leaves the final decision making capacity in their hands (treating them as learned intermediaries) [15]. Other diagnostic systems have attempted to closely replicate the human processes involved in diagnostic decision making. They were intended to be expert systems, functioning at a level akin to a diagnostic consultant. Human efforts at making medical diagnoses involve, among others, some implicit method of assigning probabilities (a priori, as well as posterior) associated with clinical features, and reconciling patterns learnt or observed from clinical experience. However, this approach 64 has limitations low base-rate events, which have enormous clinical significance if missed, may be assigned lower probability estimates (common things are common) during clinical encounters leading to diagnostic errors of omission [16]. Furthermore, such errors may not result always from not knowing, but may be a result of the loss of a checklist function when busy or fatigued during clinical work [17]. It has been demonstrated that using checklists to process many medical tasks leads to improvement in clinical care [18]. In that sense, ISABEL was intended only as a reminder system, to prompt consideration of alternative diagnoses that may have been pushed down by clinicians in their rank order, either because they were uncommon or due to simple omissions. The development time involved to reach a working prototype of the system was only in the order of months, rather than years. The manpower required to achieve this level was also minimal (one research nurse, and a medical team to ensure quality control). Utilizing established and recognized knowledge bases and applying advanced textual pattern-recognition techniques to the matter contained within them is a novel approach, which ensures minimal manipulation of data by non-experts developing the system. It was apparent during the development of this system that this alone did not satisfy clinical requirements and expectations, and that further input by medical experts to fine-tune the raw output of the system was necessary. Previous attempts at developing diagnostic systems have taken many years and involved input from many medical experts. This point is clear from studying the Internist system, that later developed into the QMR system [19]. Textbooks also have established mechanisms to be kept up to date (although sometimes they may lag behind by roughly 2-3 years). Updates to the ISABEL system are easy: new text simply replaces the old text in the diagnostic tree. Keeping previously mentioned expert systems up to date was an arduous task that involved searching through the literature for new updates, and consulting with many medical experts. We used previously researched outcome measures to characterize the clinical performance of the ISABEL system. In comparison to four expert diagnostic INTERNATIONAL PEDIATRIC UPDATE 2004 systems tested previously by Berner et al in 1994, ISABEL performs well, with a comprehensiveness ratio of 0.81[20]. Testing the relevance ratio was also quite important: it reflects how focused the diagnostic suggestion list was. This is important, because users may reject a system that displays important diagnoses but also provides many other trivial possibilities, detracting from the value of the relevant suggestions. However, since our gold standard consisted of only a few diagnoses that were considered so clinically important that they could not be omitted, as opposed to all possible relevant diagnoses, our relevance ratios were small. For this reason, we also tested the performance of the system with varying numbers of maximum ISABEL diagnostic suggestions. A maximum of 10 diagnostic suggestions retained the comprehensiveness ratio >0.75, and improved the relevance ratio to 0.40. We have also shown that these encouraging results were obtained in a clinically negligible amount of time (<2 min), during which the system was interrogated. This is in contrast to other expert systems that may take an average of 22 min to interrogate [21]. Limitations: Limitations of system design include the fact that negative findings cannot be used to influence the diagnostic suggestions produced, and that diagnosis are not ranked in order of probability. Results from the usage statistics suggest that the system is popular, perhaps indicating that they find its advice useful [22], but a more comprehensive user survey is needed to determine usability issues. The clinical performance evaluation described is a preliminary study, and the case mix in the validation sample may not have been fully representative. In addition, results from an isolated examination of the system cannot be extrapolated to suggest the impact of the system on clinicians. It is important that this is assessed by means of different studies that focus on the impact of the system on diagnostic decision-making. Conclusions The ISABEL system promises a novel method of delivering clinically relevant diagnostic suggestions for a variety of clinical scenarios in pediatrics in a negligible amount of time. This model can be extrapolated to develop similar systems for adult medicine. Acknowledgments The authors would like to acknowledge the useful comments provided by Dr Jeremy Wyatt and Dr Paul Taylor during the development of the ISABEL system. We also remain thankful to Jason and Charlotte Maude, who were instrumental in setting up the ISABEL Medical Charity to support the development of the ISABEL system. References [1] Wyatt JC. Clinical Knowledge and Practice in the Information Age: a handbook for health professionals. London: The Royal Society of Medicine Press:2001. [2] Wyatt J. Uses and sources of medical knowledge. Lancet 1991:338:1368-72. [3] Brassey J, Elwyn G, Price C, Kinnersley P. Just in time information for clinicians: a questionnaire evaluation of the ATTRACT project. BMJ. 2001 Mar 3:322(7285):529-30. [4] Godlee F, Smith R, Goldmann D. Clinical evidence. BMJ. 1999 Jun 12:318(7198):1570-1. [5] Smith R. What clinical information do doctors need? BMJ 1996:313:1062-1068. [6] Ely JW, Osheroff JA, Ebell MH, Bergus GR, Levy BT, Chambliss ML, Evans ER. Analysis of questions asked by family doctors regarding patient care. BMJ. 1999 Aug 7:319(7206):35861. [7] Leape LL, Brennan TA, Laird N, Lawthers AG, Localio AR, Barnes BA, Hebert L, Newhouse JP, Weiler PC, Hiatt H. The nature of adverse events 65 in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991 Feb 7:324(6):377-84. [8] Barnett GO, Cimino JJ, Hupp JA, Hoffer EP. DXplain: an evolving diagnostic decisionsupport system. JAMA. 1987:258:67-74. [9] Miller R, Masarie FE, Myers JD. Quick medical reference (QMR) for diagnostic assistance. MD Comput. 1986 Sep-Oct:3(5):34-48. [10] Warner HR Jr. Iliad: moving medical decisionmaking into new frontiers. Methods Inf Med. 1989 Nov:28(4):370-2. [11] Graber MA, VanScoy D. How well does decision support software perform in the emergency department? Emerg Med J. 2003 Sep:20(5):426-8. [12] Greenough A. Help from ISABEL for paediatric diagnoses. Lancet. 2002 Oct 19:360(9341):1259. [13] Thomas NJ. ISABEL. Critical Care 2002; 7(1):99100. [14] Ramnarayan P, Britto J. Paediatric clinical decision support systems. Arch Dis Child. 2002 Proceedings & Abstract Book Nov:87(5):361-2. [15] Brahams D, Wyatt J. Decision-aids and the law. Lancet 1989;2:632-4. [16] Bornstein BH, Emler AC. Rationality in medical decision making: a review of the literature on doctors decision-making biases. J Eval Clin Pract. 2001 May:7(2):97-107. [17] Graber M, Gordon R, Franklin N. Reducing diagnostic errors in medicine: whats the goal? Acad Med. 2002 Oct;77(10):981-92. [18] Balas EA, Weingarten S, Garb CT, Blumenthal D, Boren SA, Brown GD. Improving preventive care by prompting physicians. Arch Intern Med. 2000 Feb 14:160(3):301-8. [19] Miller RA, Pople HE Jr, Myers JD. Internist-1, an experimental computer-based diagnostic consultant for general internal medicine. N Engl J Med. 1982 Aug 19:307(8):468-76. [20] Berner ES, Webster GD, Shugerman AA, Jackson JR, Algina J, Baker AL, Ball EV, Cobbs CG, Dennis VW, Frenkel EP, et al. Performance of four computer-based diagnostic systems. N Engl J Med. 1994 Jun 23:330(25):1792-6. [21] Friedman CP, Elstein AS, Wolf FM, Murphy GC, Franz TM, Heckerling PS, Fine PL, Miller TM, Abraham V. Enhancement of clinicians diagnostic reasoning by computer-based consultation: a multisite study of 2 systems. JAMA. 1999 Nov 17:282(19):1851-6. [22] Berner ES. Diagnostic decision support systems: how to determine the gold standard? J Am Med Inform Assoc. 2003 NovDec:10(6):608-10. Stressed School Child Dr. V.K. Mundra, Dr Anupama Shah Children are making news for the last few months Children who hang themselves or others Children who rape Children who fail exams and jump Others who master skills much beyond their age Children who answer quiz masters on TV And children who give up hope And as a chorus, conducted by the media, the stricken conscience of the thinking class cries out how society is tressing out the child Is it reality ? who is stressing which child ? who is hurting, who is doing the hurting? From children who protest not being allowed to wear mehendi, to children who are interviewed at the age of 3 yrs, is there a common thread? If the system is so cruel, how is todays Indian youth conquering the world? Arent these boys and girls who have stormed the superpowers also a product of this system? As America goes to elections it debates the loss of livelihood because of our keyboard invaders; whom India budgets for its economy, it counts the billions of dollars 66 repatriated by them for its foreign exchange reserves. Suddenly within a generation, the gates have opened , and horizons have changed. Shall we plan for the average or cater to the best? Doctors see those who fall by the wayside; those who succumbed to the infection, not those who have resisted it, those who wilted under the onslaught, not those who overcame it. We see the ill not the healthy. Is there a middle path? Can there BE a middle path? Atleast for children who attending tuitions in class II , for children at the receiving end of the highly touted quality time sparingly dispensed by the working mothers, for children getting their personalities rounded by the never ending chain of karate class, dance class , elocution class, for children living out the unfulfilled dreams of ambitious parents, for these children, do doctors offer hope? Can we as a group stand up and say STOP IT INTERNATIONAL PEDIATRIC UPDATE 2004 Growth Hormone Beyond Growth Hormone Deficiency Dr. Archana D. Arya, Consultant Pediatric Endocrinologist and Diabetologist, Centre for Child Health, Sir Ganga Ram Hospital, New Delhi. Human Growth hormone (hGH) was first used in 1950s to stimulate growth in children with hypopituitarism (1). It was obtained by purifying cadaveric pituitary extract, and hence the availability was limited. In 1985 the first case of CreutzfeldJacob disease was reported in a patient who had received growth hormone and subsequently more cases were reported. The preparation was banned and in the same year (2), the 192 amino-acid biosynthetic GH was approved by the FDA, USA. Since then there has been abundant supply of the recombinant hGH. Its growth promoting effect in children who do not have classical GH deficiency has been investigated in a large number of children. Now it is also being studied for its metabolic effects besides the effect on linear growth. The paradigm has shifted from GH replacement to GH augmentation therapy. The number of FDA approved indications has more than doubled in the last 5 years. This has made the decision about GH use for short stature, more complex. Data to support that improvement in height would improve psychological health is scarce, except in severe GH deficiency (3). Growth Hormone Physiology: Human growth hormone is secreted by the anterior pituitary gland under the influence of Growth Hormone Releasing Hormone (GHRH) and inhibitory somatostatin that are released by the hypothalamus. The secretion of GH is cyclical and pulsatile, and it is released in response to sleep, exercise and hypoglycemia. It is bound to GH binding protein in the circulation and has a short half life of less than 20 minutes. Hence to identify peaks, frequent sampling would be required. Due to the pulsatile secretion and short half life, GH response to pharmacological stimuli is used for judging adequacy of secretion. 67 GH mediates its effects through Insulin like Growth factor I (IGFI), which is a peptide secreted by the liver in response to stimulation by GH. It is bound in the circulation to IGF binding proteins (IGFBP) the most important one being IGFBP-3. IGF 1 levels correlate with the clinical state of GH deficiency, sufficiency or excess but do not exclusively reflect GH production because levels of IGF1 vary with age. IGF1 correlates better with bone age and puberty rather than chronological age. Poor nutrition and chronic disease may decrease the IGF1 levels. Effects Of Growth Hormone: The most apparent effect of GH is to stimulate linear growth in children before epiphyseal fusion occurs. Besides this it has a number of other metabolic effects: Anabolic (Cell proliferation & protein synthesis) Lipolytic (Decreases adipose tissue) Increases lean tissue Increases bone density Bolsters cardiac contractility Improves mood & motivation Increases exercise capacity Alters the carbohydrate metabolism INDICATIONS OF GROWTH HORMONE THERAPY: The FDA, USA, has approved the following indications of GH therapy: 1. Growth Hormone Deficiency: Growth Hormone has been used for GH deficiency (GHD) for almost 50 years now. The diagnostic criteria for GH deficiency have changed over the years as more and more children were tested. The gold standard for diagnosing GHD was to demonstrate inadequate GH stimulation with 2 pharmacological agents. GH level of < 10 ng/dl on provocative stimulation is Proceedings & Abstract Book suggestive of GH inadequacy. The Growth Hormone Research Society recently recommended measurement of IGF-1 and IGFBP3 in addition to provocative GH testing to identify children with abnormalities in the GH/IGF axis not detected by standard tests. Children with GH levels in the high subnormal range and with normal stimulated levels but low spontaneous secretion or low IGF-1 and IGFBP3 are now considered to have partial GH deficiency. Early initiation of treatment with GH, in cases with Growth Hormone deficiency results in normal adult height. (4) 2. Turner Syndrome: The longest trials of GH therapy, after GHD have been on girls with Turner syndrome. Turner syndrome (TS) occurs because of the complete deletion of an X chromosome or a part of one of the arms. Mosaicism may occur in this condition. 95-100% of these girls have growth retardation and untreated their height is about 143cms as reported from the western literature, which is about 20 cms less that their average height. Special growth charts are available for girls with Turner syndrome. These girls are usually not GH deficient. They gain about 4.4 cms/year, do not have a pubertal growth spurt because of hypogonadism and have some degree of GH resistance. GH therapy with or without anabolic steroids like oxandrolone accelerates growth in girls with TS (5). Studies have shown that the mean final height of girls with TS treated with GH was 150.4cms, which was about 8.4cms more than the expected average height and those treated with GH and oxandrolone was 152.1cm, which was 10.4 cms more than the predicted height without treatment.(6) At this time initiation of therapy is recommended as soon as females with TS have dropped below the 5th percentile of the normal female growth curve. This could be as early as 2 years of age. The recommended starting dose is 0.05mg/kg/ day. In older girls or those >8 years of age if therapy is started when short stature is extreme, concomitant administration of oxandrolone should be considered. 3. Chronic Renal Failure: Growth failure is often the presenting symptom of Chronic Renal Failure (CRF). The genetic height potential is usually not 68 attained in these children and the mean adult height is 2 standard deviations below the mean. Poor growth in children with CRF is due to non-endocrine factors like malnutrition, acidosis, and renal osteodystrophy and endocrine factors such as GH resistance suggested by exaggerated response on provocative stimulation, decreased levels of IGF1 and increased levels of IGFBP1.Despite dialysis, growth failure persists in these children and post transplant, growth rate may normalize, but no catch up growth is seen. Pharmacological doses of GH correct height deficit in most children with CRF before transplant. In a study of 38 children with CRF, GH treatment resulted in a final height that was 1.4 SD above standardized height at baseline and the mean final height of 50 non treated matched control children with CRF was 0.6 SD below standardized height at baseline. (7) Current information suggests no adverse effect of GH on the glomerular filtration rate. GH therapy is approved for treatment of children with growth failure associated with CRF, up-to the time of renal transplantation and it should be used in conjunction with optimal management of CRF. 4. Prader Willi Syndrome: Prader-Willi Syndrome (PWS) occurs due to deletion in chromosomal region 15q11-13. The incidence is1:10,000 -25,000 live births. This condition is typically characterized by hypotonia, hyperphagia leading to gross obesity, short stature that is often due to GH deficiency, hypogonadism and psychomotor retardation. GH therapy in these children results in growth rate increases similar to those seen in GH deficient children. In addition it improves the muscle tone, decreases the fat mass, increases the lean body mass and bone mineral density (8). Growth failure related to PWS is an approved indication for GH treatment. 5. Intrauterine Growth Retardation: Intrauterine growth retardation (IUGR) is defined as a birth weight or length, more than 2 SD below the mean. 3% babies are born with IUGR and 10% of these do not show catch-up growth. Growth retardation is assumed to be due to abnormality of the GH - IGF1 axis. Puberty invariably starts early in these children, compromising the INTERNATIONAL PEDIATRIC UPDATE 2004 growth potential further and resulting in a height that is below their genetic potential. This group includes children with dysmorphic features compatible with Russell Silver Syndrome. A number of studies indicate that administration of GH can normalize stature of short IUGR children who are not GH deficient during childhood and early puberty. (9) Effect of GH on final height still remains to be seen and will finally determine the efficacy and safety of use of GH in these children. 6. Idiopathic Short Stature: Idiopathic short stature (ISS) includes children with short stature that is not due to any known illness or GH deficiency. A recent study of 80 non GHD children treated with GH showed a mean increase in SD score for height from -2.7 to -1.4. The mean difference between the predicted adult height before treatment and achieved adult height among boys was 5.0 + 5.1 cm and 5.9 + 5.2 cm for girls. Only a few subjects in this study reached their mid-parental height (10). It seems that long term GH treatment of non-GHD children can lead to statistically significant increases in final height in some children. The FDA recently approved use of GH to treat children with ISS. Growth disorders, illnesses and metabolic conditions for which GH treatment has been investigated are: Familial short stature, Constitutional growth delay, Skeletal dysplasias, Syndromes (Noonans, Downs), Thalassemia Major, Xlinked hypophosphatemic rickets. Patients on chronic glucocorticoid therapy (Juvenile rheumatoid arthritis, Asthma), Cystic fibrosis, AIDS wasting, Post operative wound healing, Burns, Inflammatory bowel disease, Adult GH deficiency, Aging Dosage and Monitoring of GH Therapy: The dose of growth hormone used varies according to the condition being treated. Pharmacological doses are 0.07-0.1 u/kg/ day. It is given as a daily subcutaneous injection at night. Growth with daily dosing is better than with thrice weekly doses which were being used earlier. The preparation can be given with a pen device by the parents at home. Routine monitoring of thyroid functions, blood glucose, IGF1 and IGFBP3 during therapy is recommended. Cost of GH therapy is very high and is approximately RS. 20,000 per month for a child weighing 20kgs. Treatment should be continued till response to therapy is good or satisfactory height is achieved or till epiphyses fusion occurs. Side Effects of GH Therapy: Side effects of GH therapy are listed below. They are not encountered very often but monitoring for side effects must be done regularly. - Hypothyroidism - Pseudotumor cerebri - Slipped femoral capital epiphysis - Possible salt and water retention - Hyperinsulinemia - Growth attenuation from antibody formation In the past there had been a concern about recurrence of malignancy /occurrence of new malignancies in GH treated patients. Prolonged follow-up studies indicate that the rates of new leukemia in-patients without pre-existing factors who are treated with GH is not greater than the general population. There is also no risk of developing nonleukemic neoplasms or recurrence of malignancy in GH treated patients. The decision to treat or not to treat a patient with GH should be made judiciously after careful evaluation by an experienced pediatric endocrinologist. What can be done with Growth Hormone is not necessarily what should be done. References: 1. Raben MS. Treatment of a pituitary dwarf with human growth hormone (letter). Journal Clin. Endocrinol 1958: 18:901. 2. Underwood LE, Fisher DA, Frasier SD, et al. Degenerative neurologic disease in patients formerly treated with human growth hormoneReport of the Committee Growth Hormone Use of 69 the Lawson Wilkins Pediatric Endocrine Society, May 1985. J Pediatr 1985: 107:10. 3. Sandberg DE, McGillviray MH. Growth Hormone therapy in childhood-onset growth hormone deficiency; adult anthropometric and psychological outcomes. Endocrine 2000: 12(2); 173-182. Proceedings & Abstract Book 4. Allen DB. Childhood growth hormone deficiency: statural and psychological effects of long-term GH replacement. Endocrinologist 1998: 8:3S-7S. 5. Rosenfeld RG. Update on growth hormone therapy for Turners syndrome. Acta Pediatr Scand 1989 (suppl.) 356:103-108. 6. Rosenfeld RG, Frane J, Attie KM, et al. Growth Hormone therapy of Turners syndrome: beneficial effects on final height. J Pediatr 1998:132:319-324. 7. Haffner D. Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O. Effect of growth hormone treatment on the adult height of children with chronic renal failure. N Engl J Med 2000; 343(13):923-930. 8. Lindgren AC, Hagenas L, Muller J, Blichfeldt S, Rosenborg M, Brismar M, Ritzen EM. Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favorably. Acta Pediatr Scand 1998:87:28-31. 9. Sas T, Waal W, Mulder P et al. Growth hormone treatment in children with short stature born small for gestational age; 5-year results of a randomized, double blind, dose-response trial. J Clin Endocrinol Metab . 1999: 84:3064-3070. 10.Hintz RL, Attie KM, Baptista J, Roche A. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999: 340:502-507. The Skin as the External Marker of Illness in Children Assoc Prof Giam Yoke Chin, Senior Consultant, Pediatric Dermatologist, National Skin Centre, Singapore The skin presents with signs of diseases which are easily seen and a doctor can easily make a diagnosis. For the last decade, there has been advances in pediatric dermatology, genodermatoses and discovery of the genome and location of genes in diseases. This lecture will present a spectrum of pediatric dermatology, both common and some rare diseases, with the clinical approach and management, as far as possible. The following are presented: Neonatology: physiological skin problems, eg erythema toxicum neonatorum, nevus sebaceous 70 Diseases at birth: congenital ichthyoses, haemangiomas, the new classification, PHACE syndrome Common disorders: Atopic eczema, new approach and new calcineurin inhibitors Infections: eg molluscum contagiosum, use of imiquimoid, new biological response modifier. Autoimmune diseases: neonatal lupus erythematosus, dermatomyositis. Life threatening diseases: Steven Johnson disease Hair disorders: hypotrichosis Genodermatoses: erythrokeratodema, Nethertons syndrome INTERNATIONAL PEDIATRIC UPDATE 2004 Interpreting Laboratory Results for Diagnosing Infectious Diseases Dr. T. Jacob John One cannot imagine diagnosing and treating cardiac, renal or any other organ disorder without careful laboratory testing for diagnosis and follow up. But when it comes to infectious diseases (IDs) there is a tendency to treat without diagnosis, simply because a wide variety of antimicrobials are available. This is a vicious spiral low demand, low supply. Thus, when tests are required, facilities may not be readily available. When Laboratory facilities are available, some pediatricians rely too much on test results. Too many tests may be a source of additional income to the institution. A balance is essential. Norms of diagnosis with and without laboratory tests must be available to the practicing pediatrician. Laboratory diagnosis is essential both for clinical diagnosis of individual children as well as for public health needs of determining the cause of outbreaks. Sometimes we place undue reliance on laboratory results, without knowing that the quality of tests reagents and procedures may not be satisfactory. For these reasons, laboratory results must be interpreted taking into account all available pieces of information on the sick child or in the outbreak, as the case may be. Even when quality assured, laboratory tests have accuracy indices less than 100%. In most instances we live with this problem and occasionally even go wrong. On some infections we simply cannot afford to be wrong. HIV infection is one such. Here, stringent criteria have been established to make the laboratory results accurate. When in doubt, the result is not announced. The presentation will illustrate other situations in which results must be interpreted and also provide clues for the same. Kawasaki Disease Dr Sujata Sawhney, Consultant Paediatric Rheumatologist Centre for Child Health, Sir Ganga Ram Hospital, New Delhi. Introduction: Tomisaku Kawasaki saw his first case of an unusual 4-year-old child with fever and a rash in Tokyo in 1961. Over the next 6 years he saw 50 similar patients and published the first English report in 1974-a mere four decades ago. This disease was characterised by high fever, cervical lymphadenopathy, conjunctival injection, red tongue, fissured lips, erythema and swelling of hands and feet followed by periungual digital peeling. The association of these clinical manifestations, initially 71 called Mucocutaneous Lymph Node Syndrome is now recognised as Kawasaki disease (KD), the most common systemic vasculitis in childhood after HenochSchonlein purpura. Controversy raged in Japan over whether or not KD had any longterm cardiac sequelae, and carried on till 1970, when it was established that KD did cause coronary artery aneurysms. In fact, KD is a systemic vasculitis complicated by coronary and peripheral arterial aneurysms in 20% to 35% of untreated patients, and by myocardial Proceedings & Abstract Book infarction in a small proportion. In developed countries it is the most common cause of acquired heart disease in children and may also be a risk for adult ischemic heart disease. Prompt diagnosis is critical and the early administration of IVIG dramatically reduces the rate of coronary abnormalities to less than 5% of patients. Despite efforts over the last three decades, there is still no diagnostic test available for KD, and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high persistent fever. Epidemiology: Although KD has been reported all over the world, the disease is over expressed among Asian populations, especially Japanese. Nationwide epidemiological surveys indicate that the number of KD patients has gradually increased in Japan since the last 1960s. The annual attack rates are 120 to 150 cases per 100,000 children under 5 years, with 6000-8000 new cases annually. In US Caucasians the attack rate is 4 to 15 cases per 100,000. In Europe the annual reported incidence ranges from 3 to 8 per 100,000 children under 5 years. A recent analysis of hospital admission data in England shows that the incidence of KD among English children has increased between 1991 and 2000. It is possible that this reflects an increase in recognition rather than incidence. Etiology: The cause is unknown and a search for an infectious agent has not been successful to date. An infectious etiology has been long suspected as the disease has seasonal peaks, and many of the clinical features are similar to those of an infectious disease. The hypothesis that KD could be a super antigen disease has been widely debated. Immunopathogenesis: Activation of the immune system is a central feature of Kawasaki syndrome. Concentrations of many proinflammatory cytokines and chemokines, including tumour necrosis factor á (TNF á), interleukins 1, 6, and 8, are higher than normal during the acute phase of the disease. Activated monocytes/macrophages seem to have an important role in Kawasaki syndrome. These cells have been found in the vessel walls of patients who died and in skin biopsy samples from patients in the 72 acute phase of the disease. Clinical manifestations: KD is a systemic vasculitis predominantly affecting children less than 5 years of age. KD is rare in neonates, but if it occurs, it may follow a rapid and severe course. Infants may often present as atypical cases and commonly experience very severe inflammatory changes, especially vasculitic signs. In children older than 8 years of age, KD mainly affects male and Caucasian subjects; the diagnosis is frequently delayed in the acute phase, and the incidence of coronary artery abnormalities is higher than in younger children. The fever lasts for at least five days, but may persist for up to a month. The sub acute phase lasts for about a further month, with full recovery in most patients by day 50. The typical manifestations of KD are detailed in table 1. The child must have high fever lasting more than 5 days without reasonable explanation and unresponsive to antibiotics plus i) Bilateral non-exudative conjunctivitis. ii) Polymorphous exanthemata. iii) Bilateral non-suppurative cervical lymphadenopathy (at least one lymph node larger than 1.5 cm). iv) Changes of the extremities: peripheral edema, peripheral erythema, and periungual desquamation. v) Mucous membrane changes (i.e. injected or fissured lips, redness of pharynx, strawberry-like tongue). Fever of five days duration plus four of the five remaining criteria or the presence of fever and coronary artery aneurysms (CAA) detected on 2D- echocardiogram with three additional criteria are needed for the diagnosis of complete KD. Atypical KS is a term that has emerged in recent years. It is used for those children who have 1. Fever for at least five days 2. At least two of the diagnostic criteria for KS 3. Lab finding consistent with significant inflammation It has been reported that infants can present CAA without developing the classic diagnostic criteria, supporting the evidence that the disease is often under recognised or misdiagnosed. Atypical cases of KD are INTERNATIONAL PEDIATRIC UPDATE 2004 Kawasaki disease Diagnostic Criteria Fever Duration of 5 days or more plus 4 of the following Conjunctivitis Bulbar, non-suppurative, bilateral Lymphadenopathy Cervical >1.5cm Rash Polymorphous, non vesicles or crusts Changes of lips or oral mucosa Red cracked lips; strawberry tongue; diffuse erythema of oropharynx Changes of extremities Initial stage : erythema and edema of palms and soles. Convalescent stage : peeling of skin from fingertips Table 1 common (up to 10% of the total) and the diagnosis should be considered even without the full complement of diagnostic criteria. Kawasaki syndrome is usually self-limited. The signs and symptoms usually evolve over ten days and gradually resolve in most children even without any specific treatment. In untreated patients, Coronary Artery Aneurysms develop in 20%, and notably are clinically silent in most cases. They are recognized many years later, because of myocardial infarction or sudden death. The eye findings in KD could play a role in the earlier diagnosis and treatment; the presence of iridocyclitis and conjunctivitis provide additional support to the diagnosis in patients with incomplete KD. Ocular evaluation is usually mild and bilateral, sometimes associated with keratic precipitates, and resolves within 2-8 weeks without any sequelae. Slit-lamp examination may be useful in helping to differentiate KD from diseases that closely mimic the condition, such as streptococcal and staphylococcal toxin-mediated diseases and drug reactions. Digital peeling, a useful diagnostic hint, usually occurs 10-15 days from the onset of typical fever even in children who had received IVIG. A long-term follow-up of patients with KD has reported recurrent episodes of skin peeling for several years after the disease recovery. It has been reported only in patients with complete KD and its significance and mechanisms are still unknown. It may also be observed in a number of other conditions caused by infectious agents and their toxins. Since the clinical criteria of KD present sequentially, and often the interval between 73 the appearance of fever and the development of all clinical manifestations may be longer than 1 to 2 weeks, it often is a diagnostic dilemma for the clinician. Other causes of the non-specific symptoms can be difficult to exclude. In these patients KD should be suspected in the presence of high fever of unknown origin lasting more than 4 to 5 days, and IVIG should be administered even before diagnostic criteria are satisfied. Two signs that could help physicians in the diagnosis, even though it is not included in the diagnostic criteria are 1. Irritability present in the majority of children with KD that can be related to aseptic meningitis. 2. The appearance of erythema and induration at sites of BCG immunizations as a useful early diagnostic sign. In many cases the clinical features of KD are not all present on any given day. The challenge for the clinician lies in the ability to exclude diseases that closely resemble KD, but need entirely different treatment (for example disease caused by staph/strep toxin) Specific features of KD that confuse the clinician are as follows: 1. Sterile pyuria misdiagnosed as urinarytract infection 2. Cerebrospinal-fluid pleiocytosis misdiagnosed as aseptic meningitis or partially treated bacterial meningitis 3. Rash misdiagnosed as viral or drug eruption 4. Cervical lymphadenopathy misdiagnosed as bacterial adenitis. Complications that occur in Kawasaki disease are detailed in table 2 Differential diagnosis: The differential diagnoses include the following conditions; they are detailed below along with the main features that help to differentiate the illness from KD. 1. Streptococcal infections : a. Scarlet fever: extensive lymphadenopathy, no conjunctivitis b. Toxic shock syndrome: Very sick child, often with shock even at presentation 2. Staphylococcal infections Initial erythema of skin, in later stages there are bullae on the skin, no mucosal involvement Proceedings & Abstract Book List of complications in Kawasaki disease Irritability and aseptic meningitis Gallbladder hydrops Diarrhoea Hepatitis Otitis media Pancreatitis Myositis Pericarditis Aneurysm formation leading to peripheral gangrene, cerebral infarction and cardiac aneurysm. Table 2 3. Other viral infections: a. Measles: Very similar in initial stages. Usually generalized lymphadenopathy, in KD more than half have a solitary lymph gland. Desquamation in measles does not affect the palms and soles. b. Rubella: Usually patients have generalized lymphadenopathy, and low grade fever c. Epstein Barr infections: Older child, sore throat, and lymphadenopathy. d. Influenza A, and Influenza B: Fever duration 3-5 days, upper respiratory tract symptoms 4. Mycoplasma pneumoniae: Rarely is there any conjunctival involvement, erythema of the hands and feet, and oral involvement. 5. Stevens Johnson syndrome: Erythema multiforme, erosive mucosal lesions, rash fades in ten days 6. Systemic onset juvenile idiopathic arthritis: High fevers, evanescent rash, serositis, organomegaly and arthritis. Differential diagnoses for children who fail to respond to IVIG are: Polyarteritis nodosa, systemic onset JIA and malignancies. Laboratory findings Recommended investigations in Kawasaki disease are detailed in table 3 Laboratory findings in patients with Kawasaki disease include raised white cell count with neutrophilia, changing to lymphocytosis by the end of the first week. By day 14 there may be a hypochromic anaemia and thrombocytosis. A moderate-high increase of serum 74 concentration of liver enzymes may occur in the early stage, unrelated to aspirin administration. Urinalysis may show leukocytes and erythrocytes but no bacteria. CSF contains increased numbers of WBC, mainly lymphocytes, as expression of aseptic meningitis. Lipid profile alterations occur in the early phase including decreased levels of highdensity lipoprotein (HDL), and cholesterol, and increased levels of triglycerides. Low HDL levels may persist over months to years after the acute phase, and may have a correlation with Coronary artery aneurysms. Cardiac investigations: All children with typical or suspected KD have to be closely monitored by electrocardiogram (EKG) and twodimensional echocardiography (2D-echo). The EKG may reveal arrhythmia, myocardial dysfunction and ischemia. 2D-echo is useful in detecting coronary artery dilation and aneurysms. Ultrasound may reveal aneurysms and other changes in peripheral arteries. The high-risk groups for coronary artery disease are infants younger than 6 months of age, and older children with very high platelet count, high ESR and fever lasting for more than 2 weeks. Cardiac monitoring includes 2D-echo at onset and six to eight weeks after onset of the disease. However, in order to detect possible coronary alteration not observed at the first evaluation, a third 2D-echo study at 14 days has also been suggested. In patients with CAA, close follow-up by echocardiography is mandatory in order to evaluate the size of aneurysms and to detect the formation of thrombus. EKG and 2D-echo studies need to be tailored to single patient depending on the size of CAA. Children with giant aneurysms (diameter greater than 8 mm) require stress testing to define myocardial function. Because of the risk of coronary stenosis in these patients, coronary angiography is also recommended. Cardiac monitoring reveals that about 50% of mild CAA normalise within two years, while 5-year follow-up shows a complete regression of all CAA. Unfortunately, giant aneurysms persist in most patients over time and may evolve in severe stenosis, myocardial infarction, and even death. The mortality rate has completely changed after the introduction INTERNATIONAL PEDIATRIC UPDATE 2004 List of investigations to exclude Kawasaki disease CBC, and film ESR and CRP Blood culture ASOT LFT, urea, creatinine Clotting screen, auto antibody screen Urine routine for hematuria, and proteinuria Auto antibody screen Viral titres: Adeno, Parvo, EBV, CMV. ECG, ECHO, X-Ray Chest PA. Table 3 of IVIG, and in Japan it is reported as low as 0.14 %. Treatment: It was only in1983 that Japanese investigators reported that children with KD treated with IVIG had quicker resolution of fever, and had fewer coronary artery abnormalities than historical controls. A multi center, open-level, randomized trial in the USA showed that children treated with IVIG and high-dose aspirin had significantly faster resolution of fever and other inflammatory markers than children treated with high-dose aspirin alone. In addition the rate of coronary-artery abnormalities among children with normal echocardiography at study entry was significantly lower for those assigned IVIG and aspirin than for those assigned aspirin alone (3% vs. 15% 7 weeks after treatment). Thus a single dose of 2gm/kg IVIG infused over 12 hours is now the standard therapy for Kawasaki disease. An epidemiological survey of more than 5000 patients in Japan treated with 2 g/kg IVIG showed that patients treated before day 6 of illness had fewer cardiac complications at 1 month after onset of the syndrome than those treated later in the course of the illness. Any child with Kawasaki disease, who has evidence of persisting inflammation, including fever or high concentrations of inflammatory makers with or without coronary - artery abnormalities, should be treated even if the diagnosis is made after illness day 10. Administration of live virus vaccines (measles, mumps, and rubella, or varicella) should be deferred for at least 11 months after IVIG administration owing to reduced immunogenicity of the vaccine related to 75 passive antibodies in the IVIG preparation. Aspirin is used to reduce inflammation and to inhibit platelet aggregation in children with Kawasaki syndrome, although it has no effect on development of coronary-artery aneurysms. Currently, high doses of aspirin (80-100 mg/kg daily divided into four doses) are used in the acute inflammatory stage of the disease. There is no consensus on the dose of aspirin used early on in these patients with recent recommendations suggesting using 30-50mg/kg/day, and others advocating no role at all. If aspirin is used in the acute phase, the dose is reduced once the patient has been afebrile for 3-7 days, to a single daily dose of 3-5 mg/kg. This antiplatelet dose is continued for 4-6 weeks, until the concentrations of all inflammatory markers have returned to normal and no coronary-artery damage has been noted by echocardiography. Treated of persistent of recrudescent fever: 10-15% of children diagnosed with Kawasaki syndrome and treated with high-dose aspirin and 2 g/kg IVIG will have persistent or recrudescent fever. If fever persists after the first dose of IVIG the following steps should be taken: 1. Reconsider the diagnosis of the Kawasaki syndrome 2. If it is the diagnosis give a second dose of IVIG 2 g/kg 3. If after the second dose of the IVIG the fever persist consider the following options: a. Pulsed intravenous methylprednisolone b. Cyclophosphamide plus prednisone c. Monoclonal antibodies to TNFα Treatment of cardiovascular complications: The aims of therapy in-patients who have coronary-artery aneurysms are to prevent thrombosis and the myointimal proliferation that lead to stenosis. The treatment modalities available are: 1. Low-dose aspirin (3-5 mg/kg daily) for small to medium aneurysms (<8 mm). 2. Antiplatelet agents (eg, clopidogrel ) 3. Low-molecular-weight heparins, and warfarin in the long-term management of children with gaint aneurysms. A dedicated pediatric cardiologist should Proceedings & Abstract Book carefully follow up all patients with cardiovascular complications. It is important for these children to be followed up well into adult hood, for the blood pressure to be monitored, stress testing undertaken, and sport activities to be supervised on the individual bases. The question remains whether Kawasaki syndrome is a risk factor for accelerated atherosclerosis in adulthood. A registry and structured follow-up study should be established in each country so that investigators can to collect data to address the unanswered questions about long-term outcome for children, with Kawasaki syndrome. Conclusion: Kawasaki syndrome may contribute to the burden of adult cardiovascular disease. Until a diagnostic test is devised, children may continue to be misdiagnosed and suffer preventable morbidity and mortality. Like in many rheumatological conditions the best cure for Kawasaki syndrome would come with more research in to the etiopathogenesis of this sometimes-fatal childhood affliction. References: 1. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatr 1974:54:271-6. 2. Han RK, Silverman ED, Newman A, McCrindle BW. Management and outcome of persistent or recurrent fever after initial intravenous gamma globulin therapy in acute Kawasaki disease. Arch Pediatr Adolesc Med 2000:154:694-9. 3. Maury CP, Salo E, Pelkonen P. Elevated circulating tumor necrosis factor-? in patients with Kawasaki disease. J Lab Clin Med 1989:113:651-4 4. Petty RE, Cassidy JT. Kawasaki Disease. In: Cassidy JT, Petty RE editors. Textbook of pediatric Rheumatology, 4th ed. Philadelphia: WB Saunders Company, 2001: 580-94 5. Newburger JW. Kawasaki disease: who is at risk? J Pediatr 2000: 137:149-52 6. Hsieh YC, Wu MH, Wang JK, Lee PI, Lee CY, Huang LM. Clinical features of atypical Kawasaki disease. J Microbiol Immunol Infect 2002; 35: 57-60 7. Stanley TV, Grimwood K. Classical Kawasaki disease in a neonate. Arch Dis Child Fetal Neonatal Ed 2002: 86 (2): F135-6 8. Stockheim JA, Innocentini N, Shulman ST. Kawasaki disease in older children and adolescents. J Pediatr 2000: 137: 250-2 9. Brogan PA, Bose A, Burgner D, Shingadia D, Tulloh R, Michie C, Klein N, Booy R, Levin M, Dillon MJ. Kawasaki: an evidence based approach to diagnosis, treatment, and proposals for future research, Ann Rheum Dis 2002; 86: 286-290 10.Wright DA, Newburger JW, Baker A, Sundel RP. Treatment of immunoresistant Kawasaki disease with pulsed doses of corticosteroids. J Pediatr 1996: 128:146-9. Safer Antipyretics Dr. C. P. Bansal Is it really an issue? Certainly a BIG YES! Because, Antipyretics is The Most Commonly Prescribed Group among pediatricians. Nearly every prescription of ours has one or the other antipyretic. Fever is the presenting symptom in nearly 80% of pediatric patient in every setup OPD, Indoor or in emergency room. Therefore we must be concerned about the safety profile of the members of this group. Temperature Regulation is done by a thermostat in the hypothalamus where equilibrium between Heat Production and Heat Loss is maintained. 76 Certain Normal Values of Temperature: Normal Oral Temp at 6 A.M. 37.2o C (98.9o F ) 4-6 P.M. 37.7 o C (99.9o F) Variation 0.5 o C (0.9 o F) 1 o C Rectal Temp. = 0.6 o C (1.0 o F) > Oral Temp. I would like to discuss this topic in two heads 1] Antipyretics are safe or unsafe riskbenefit analysis of the use of the group as such. 2] Which member of the group is best suited to infants and children out of available INTERNATIONAL PEDIATRIC UPDATE 2004 options? The risk-benefit ratio of antipyretics: The dictum that antipyretics are uniformly beneficial and safe in febrile illnesses may not be entirely true [1]. Some negative impacts from using antipyretics for common disease, viral shedding was found to be prolonged a bit in rhinovirus infected volunteers [2,3,4], duration of parasitaemia was found to be increased mildly [5] specially in Malaria [6]. Thus it has been opined by some that antipyretic therapy actually does more harm than benefit. After several such studies now enough evidence exists to warrant even more research into this topic and to cause clinicians to consider that the risk-tobenefit ratio of these medications may not be as favorable as once thought. [1]. Few studies have also concluded that antipyretics suppress polymorphonuclear activity. HARMFUL EFFECTS OF FEVER 1. Fever poses a threat of convulsions. 2. Children are exposed to the risk of Metabolic Acidosis & Heat stroke 3. Children feel discomfort (parents also feel discomfort) in a febrile state as their blood pressure and respiration rate both are increased and this causes irritation. 4. During fever appetite is lost i.e. kids become anorexic and due to excessive evaporative loss of water also become thirstier leading to dehydration. 5. Studies have proved that in febrile state O2 Consumption is increased and by an estimate the increase is 13% for every degree rise of temperature. 6. Increased requirements of calories and of fluid in fever can be well expected. 7. Finally a depression of Mental Activitydelirium/stupor can be dangerous outcomes of high fever Heat Stroke. However a recently published study concludes that the antipyretic drugs at recommended doses do not suppress polymorphonuclear function in vitro [7]. Thus treating Fever especially in children becomes our responsibility and duty, at least to bring comfort to the patient and parent. The settling of the first part makes the second part the Safety of Antipyretics all the more important. 77 Possible Options 1. Physical Methods 2. Antipyretic Agents ; Aspirin (Non selective cox inhibitor) Acetaminophen (Paracetamol) Ibuprofen (Propionic Acid) Nimesulide (Cox 2 inhibitor) Mefenamic Acid (Anthranalic Acid Derivatives) 3. Alternating Antipyretics 4. Combination of Antipyretics 1. Physical Methods Tepid sponging and fanning have been effective in the earlier phase only. This lowering of temperature is present only till these are continuously done, as they neither reset the thermostat nor they interfere with the chemical mediators of fever. Further, many studies have concluded that the main aim of the antipyretic therapy is to bring comfort to the patient and when temperature is high or is rising, tepid sponging is always an act of discomfort to the patient. Thus it is not advisable. However some authors recommend that a combination of physical therapy such as tepid sponging and Paracetamol [8] is best way of controlling temperature, as till the effect of PARACETAMOL comes tepid sponging lowers the temperature. Others are cold drinks, cold water or saline enema, more fluid, comfortable, airy environment. 2. Antipyretics A. ASPIRIN : Aspirin is the most widely used and is probably one of the oldest drug, with more than 80 billion tablets consumed a year, in the United States alone, as well as being listed as the active ingredient for more than 50 other drugs. Records show it was in use more than 2,000 years ago. Yet full implications of the effects of this drug are still to be realized. Aspirin is commonly known as The Wonder Drug. When we were students every prescription of our worthy consultants used to contain Aspirin. Its therapeutic effects were so good that even today in clinical use the effect of Paracetamol or any other antipyretic or analgesic are judged as effect equivalent to aspirin. But when its association with the Reyes Syndrome and other serious side effects on blood and on gastric mucosa Proceedings & Abstract Book were confirmed, its use as antipyretic was abandoned. B. PARACETAMOL : It has a clinical standing and a safety profile of more then 50 years. It is today the most popular home medicine. Its analgesic (pain relief) and antipyretic (fever relief) effects are comparable to those of aspirin. There are virtually no groups of people who should not take it. Interactions with other treatments are not a problem. At the recommended dosage there are virtually no side effects. It is suitable for small children and the elderly. It can be taken by those sensitive to aspirin. It is well tolerated by patients with peptic ulcers. Dosage: Previously it was 10mg/kg then came recommendations of 15mg/kg (4 hrly) Maximum 90mg/kg day, recently it has been postulated that initial dose of 30mg/kg with a maintenance dose of 15mg/kg brings about better antipyresis [9]. Toxic dose is 150mg/kg only possible by homicidal/suicidal intentions and that too in elderly. However, there has never been a problem of serious accidental overdose with paracetamol in the under fives. [10, 11] The Paracetamol toxicity is treated with - Nacetylcysteine (NAC) (Parvolex). Mechanism of Action: As with many medicines, the effectiveness of Paracetamol was discovered without knowing how it works. Over 100 years after it was first discovered, we are now learning its mechanism of action which makes paracetamol such an effective and useful medicine. Paracetamol has no significant action on COX-1 and COX-2, this explains its lack of anti-inflammatory action and also, more importantly, its freedom from gastrointestinal side effects typical of NSAIDs. Recent research (13) has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in 78 the brain and spinal cord, which is selectively inhibited by paracetamol, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the effectiveness of Paracetamol in relieving pain and reducing fever without having unwanted gastrointestinal side effects. Paracetamol And Asthma Paracetamol is not known to be linked with asthma. Indeed, Paracetamol is the preferred analgesic for asthma sufferers, because NSAIDs are much more likely to precipitate asthma attacks and are to be avoided by asthma sufferers. [14] C. IBUPROFEN : Ibuprofen is a non-steroidal antiinflammatory drug with established analgesic, anti-inflammatory and antipyretic properties. Dose 7.5 Mg/Kg to 10 Mg/Kg6-8 Hrly, Max. 40 Mg /Kg /Day Ibuprofen was first approved in the UK in February 1969 and has been one of the most heavily prescribed non-steroidal antiinflammatory drugs (NSAIDs) since then. It was launched in the UK as an over-thecounter (OTC) medicine, in 1983 and is now widely used in self-medication. A switch to General Sales List (GSL) status in the UK was obtained in January 1996. A large safety study involving 84,000 children showed a similar safety profile for ibuprofen and paracetamol[12,15] . As antipyretics it has not been preferred over Paracetamol because 1. It is thought to have less antipyretic property 2. Its association with asthma. 3. Renal side effects & complications. Thus it was supposed to be relatively slightly more toxic then Paracetamol. However few recent (all dependable Randomized Control Trials or Double Blind) studies have proved it to be better than Paracetamol. [16,17,18,19,20]. It is found to be longer acting, yielding significantly better antipyretic effect after four hrs of initial dose than paracetamol. But it is a fact that its antipyretic activity is, if not better, then at least equal to paracetamol by all. Maximum reduction of temperature occurs 3-4 hours after administration, has a greater half life INTERNATIONAL PEDIATRIC UPDATE 2004 then Paracetamol so 8 hourly convenient doses are possible. [21,22] Ibuprofen has clear edge over Paracetamol in conditions like flu like syndrome, URIs, Otitis Media, Pneumonias, Septic Arthritis and all other inflammatory febrile conditions. The next allegation on Ibuprofen about its association with asthma & renal complications (as other NSAIDs) has also been negated by recent authenticated studies [23,24]. Its safety in children below two years of age has also been documented [25] D. NIMESULIDE : Nimesulide was introduced in 1985 in Italy, in India in the early nineties and soon became the best selling anti-inflammatory drug. There are over 150 Nimesulide brands available in the market and are often prescribed to bring down high fever in children and as an anti-inflammatory drug amongst elders. Ironically, Nimesulide world over is only prescribed for musculo-skeletal pains. This could be the main reason why no multinational drug firm has launched this drug in India. The product has combined sales in excess of Rs 270 crore annually. The reasons for this tremendous take off by the drug are its potent anti-inflammatory effect, better compliance & wide range of formulations. Properties of the Nimesulide - Nimesulide is a non-steroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties and a specific mode of action, similar to selective COX 2 inhibitor. It is weak inhibitor of Prostaglandin synthesis and also inhibits leukocyte function. - Its dose is 2.5mg/kg and can be given twice a day Maximum dose is 5mg/kg. - It is generally well tolerated by the children - Nimesulide is currently marketed in 50 countries. It is available as tablets, suppositories and topical gel. In some countries also oral drops and oral suspension are/were on the market. I would like to discuss the controversy about Nimesulide in a bit detail. Though Nimesulide is a preferential COX-2 inhibitor and therefore, assumed to be safer 79 in clinical use, its gastrointestinal tolerance has not been proven to be superior to other NSAIDs because various epidemiological studies give little weight to the hypothesis that selective inhibition of COX-2 may have a sparing effect on the GI Tract [26,27]. Why the current controversy? Nimesulide was aggressively promoted in India and attained the top position as antipyretic in private practice. But recently the status of Nimesulide has become questionable following reports of fatal adverse drug reactions (ADR). The National Pharmacovigilance Centre (CNF, Portugal) from 1993 to 99 [28] received 17 ADR reports of Nimesulide, which included ;- skin (five), hepatic (four), peripheral edema (two), stomatitis (two), paraesthesia (one), thrombocytopenic purpura (one), irritability (one) and headache/reduced visual acuity in (one). From the hepatic ADRs, two, which occurred in children, were compatible with Reyes syndrome and both resulted in fatality. Also seen was one case of cholestasis and another of liver enzyme elevation and coagulopathy, the later being fatal. Another report informed three cases of fixed drug eruptions with Nimesulide [29]. Nimesulide induced liver injury usually presents with hepatocellular necrosis or cholestasis. Many cases of Nimesulide induced hepatotoxicity (some even fatal) have been reported [30 to 47]. Patients with liver toxicity typically revealed features of hypersensitivity i.e. an increase in blood and tissue eosinophilia. This indicates that both immunological and metabolic idiosyncratic reactions can be involved as the pathogenetic mechanism of Nimesulide induced liver disease. Neonatal renal failure following the use of nimesulide has been reported [48]. Even if the risk of hepatotoxicity is small and fatality rare, nimesulide use for fever particularly in children cannot be justified when safer alternatives like p aracetamol and ibuprofen are available. We all should be aware of the fact that due to its toxicity, ADRs and suspected danger, Nimesulide has never been licensed for use in developed economies like US, Canada, UK, Australia, New Zealand and Scandinavian countries. Small countries like Portugal, Israel and our Proceedings & Abstract Book neighbors Sri-Lanka and Bangladesh have shown the guts and grit to withdraw the drug. Nimesulide was withdrawn in 2002 by the innovator, Boehringer from Spain and Finland. The European Union has recently issued a precautionary advice on the marketing of this drug following serious complications after its use. Medical activists highlighted the rampant misuse and overuse of Nimesulide, and its ADRs leading to fatalities in children through various media, including cable TV. Letters appeared in press warning the Nimesulide users of its toxicity [49]. It is a matter of great concern that while other countries have banned the sale of this drug, the Drug Controller-General of India (DCGI) merely ordered a review of this drug. The DCGI has gone on record to admit that due to powerful commercial interests, it might be difficult to get objective answers even from doctors. True to the anticipated fears, Delhi Medical Association has declared Nimesulide safe [50] Criticizing this act of DMA, leading pediatricians and neonatologists of India have questioned the validity of this survey from merely fifty doctors of Delhi who gave clean chit to Nimesulide. Editor of Monthly Index of Medical Specialties (MIMS) has rightly pointed that ADR monitoring is not done by any professional body of doctors in the world [51]. Industrial interests surely prevail over professional ethics and obligations. Not surprisingly, to the tune of DCGI, Delhi High Court has issued a clean chit to nimesulide in response to the PIL filed by a true medical activist. This judgment and the decision of the DCGI were mainly based on the IAP declaration it is as safe or unsafe as other which again is based on just one study conducted in Delhi. This certainly has earned a bad name for IAP [51] in the leading news papers of the country. However as against this judgment of Delhi High Court; recently The European Medicine Evaluation Agency (EMEA) has disallowed the use of Nimesulide by children below the age of 12 years in all its member-countries. They have reached this conclusion only after a 16-month long review of the controversial drug by experts drawn from European Union member states [52]. Following this decision, India is the only country where nimesulide is being marketed for use not only by 80 children, but also by infants below the age of one year [52]. Result of this Controversy: Despite the clearance from the DCGI and High Court and despite the intense lobbying from the drug manufacturers, the outcry of media and activist doctors have made the common practioner of India genuinely worried and they are now gradually shifting away from Nimesulide [52]. Hereunder are some figures that will prove this statement It had a growth rate of seven % in October 2002 and is now degrowing at minus 1%. Faster negative growth rates are predicted in the coming months, according to experts. In comparison to October 2002, the sale of two most popular brands of pediatric tablets declined by 52.4 % and 44 % respectively. The pediatric suspensions of these two brands witnessed a decline of 22 % and 29 % respectively. According to a survey by AC NielsenORG-MARG, annual turnover figure for Nimesulide in Oct. 2002 was at Rs 200 crore. It declined by 20 % by March 2003; further sales went down by around 17 % in June 2003. Birth Story of Nimesulide [53] It is very important to know the origin and background of this drug. Nimesulide has been developed and licensed by Helsinn Healthcare SA, Switzerland, which acquired the exclusive worldwide rights for the drug in 1976. 1. Nimesulide was discovered by 3M Pharmaceuticals, an American manufacturer at St. Paul, Minnesota, United States. Therefore the origin of the molecule is United States, where it is not approved. 2. 3M Riker - the parent company of 3M Pharmaceuticals - It sold the molecule to a private company in Switzerland called Helsinn. Helsinn, instead of launching Nimesulide in Switzerland, licensed the drug to Boehringer in Italy where it was launched in 1985. In Italy, it is licensed for use only in musculo-skeletal inflammation and accompanying pain (not as an anti-pyretic). Its use in children below 6 years is prohibited. 3. Nimesulide was launched in Switzerland, INTERNATIONAL PEDIATRIC UPDATE 2004 the home country of Helsinn, in 1995 i.e. 10 years after Italy.Based on the human data from Italy, the Swiss Government permitted its use in adults only. Its use in children below 12 years is prohibited. Some other Facts [54] : 4. Everyone connected with pharma business around the world knows that introducing new molecules in USA, Britian, Australia, Denmark etc. is not very easy while it is not very difficult in Italy and Brazil. 5. Today Nimesulide is licensed for use in fewer than 40 countries. In other words its use is not permitted in over 150 countries. 6. India is the ONLY country on earth where Nimesulide drops were marketed for use in neonates and infants. The only two countries where nimesulide is permitted in children are Italy and Brazil and even there its use is prohibited below 12 and 3 years of age respectively. 7. As per Rule 122 (E) of the Drugs & Cosmetics Act read with Schedule Y, all drugs require mandatory prior permission from Drugs Controller, India (DCI). Fresh permission is required if a new formulation of approved drug is to be launched such as sustained release etc. In India only two formulations are approved i.e. 100mg tablet and 50mg/5ml suspension. The following formulations are being marketed without the permission from Drug Controller of India50mg tablets for kids, 25mg/ml drops, 200mg tablets, 400mg tablets, 100mg EF tablets, 100mg MD tablets. Even when one company obtains permission for any formulation, another company needs fresh DCI approval if introducing the same drug within 4 years. Over 170 companies in India are marketing nimesulide single ingredient formulations without mandatory DCI approval. 8. ALL fixed-dose combinations of Nimesulide with other agents such as Paracetamol, Diclofenac, Tizanidine etc are being marketed without mandatory DCI approval. This fact has been admitted by DCI in reply to a question in Loksabha on 20-08-2000. India is the ONLY country on earth where Nimesulide with other agents is being marketed. 9. The retail price of Nimesulide for 10 tablets ranges between Rs. 14.50 to Rs. 81 29. It is not the cheapest analgesic or antipyretic. It is about 200 to 400% more expensive. Besides, the basic cost price of 10 tablets of Nimesulide 100mg is Rs. 1.80. As per ORG-MARG data, no other NSAID has such a huge profit margin. 10. Several laboratory, animal and human studies in Canada and USA have shown that Nimesulide is partially, but not fully, COX-2 Selective. Besides, NIMESULIDE INHIBITS COX-1 MUCH BEFORE AND AT MUCH LESSER SERUM LEVELS. Thus it is not gastro-protective. This was one of the reasons for aborting an attempt to get USFDA approval in 1998. 11. All studies submitted to DCI in India by manufacturers of Nimesulide were sponsored and financed by Helsinn many of them actually written by Helsinn employees. Equipotent single dose of Antipyretics [55] Paracetamol, 10 -15 mg/kg, 4-6 Hrly Ibuprofen 8-10 mg/kg 6 -8 Hrly, and Nimesulide is 2.5 mg/kg 12 Hrly Therefore in practice, practically, underdosing of Paracetamol and overdosing of Nimesulide becomes unavoidable and hence parents and physicians feel that Paracetamol does not work while Nimesulide never fails - This has resulted in overuse of Nimesulide, which has nearly replaced Paracetamol in clinical practice. Strong and often unethical marketing practices have contributed to such a scenario. Considering practical issues beyond Nimesulide as an antipyretic is best avoided. Alternating Antipyretics: It has been a common practice to use two different antipyretics with full therapeutic dose alternating both of them in one patient in a particular febrile episode this is not an ethical practice [56, 57, 58, and 59]. If need arises then the same antipyretic should be used again this makes PARACETAMOL a preferable Antipyretic as it can be repeated after 4 hours while ibuprofen after 6 hrs however it again keeps nimesulide as it can only be repeated after 12 hours. This practice can lead to confusion in parents and chances of toxic overdose increases further chances of renal complications are Proceedings & Abstract Book increased especially if child is dehydrated. 4. Combination of Antipyretics Combinations of antipyretics (fixed dose) are totally irrational. They result in doubling of the dose. Further no two Antipyretics have similar frequency of administration thus their administration together is unethical .The practice of combining them with other agents like metoclopromide with an idea to potentiate their effect is also not evidence based. Conclusions 1. We should do not let Fever Phobia rule our mind. 2. Treat Fever above 101F 3. Physical methods are of limited value and are discomforting to child. 4. Ibuprofen is coming up as still better then Paracetamol 5. Nimesulide as Antipyretic should better be avoided. 6. Use one Antipyretic in proper recommended doses and in recommended intervals if needed. References 1. Mackowiak PA, Plaisance KI. Benefits and risks of antipyretic therapy. Ann N Y Acad Sci 1998: 856: 214223. 2. Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L . Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990: 162:12771282. 3. Stanley ED, Jackson GG, Panusarn C, Rubenis M, Dirda V. Increased virus shedding with aspirin treatment of rhinovirus infection. JAMA 1975: 231:12481251. 4. Doran TF, De Angelis C, Baumgardner RA, Mellits ED. Acetaminophen: more harm than good for chickenpox? J Pediatr 1989: 114:10451048. 5. Plaisance KI, Kudaravalli S, Wasserman SS, Levine MM, Mackowiak PA. Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. Pharmacotherapy 2000: 20:14171422. 6. Meremikwu M, Logan K, Garner P. Antipyretic measures for treating fever in malaria (Cochrane Review). The Cochrane Library, Issue 2, 2002. Oxford: Update Software: 2002. 7. Polymorphonuclear leukocyte functions in children. Int Immunopharmacol. 2002 Oct;2(11):1599-602. 8. Chandra J, Bhatnagar SK. Antipyretics in children Indian J Pediatr. 2002 Jan:69 (1):69-74. 9. Treluyer JM, Tonnelier S, dAthis P, Leclerc B, Jolivet-Landreau I. Antipyretic efficacy of an initial 30-mg/kg loading dose of acetaminophen versus a 15-mg/kg maintenance dose. Pediatrics 2001 Oct;108 (4):E73. 10. Guidelines for the management of acute Paracetamol overdosage 2003 NPIS 11. Thomas SH. L. et al. Paracetamol poisoning in the North East of England: presentation, early management and outcome, Hum. & Exp. Tox. (1997), 16: 495-500. 12. Lesko SM, Mitchell AA. An assessment of the safety of paediatric ibuprofen JAMA 1995; 273 (12): 929-931 13. Chandrasekharan NV et. al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression, Proc. 82 Natl. Acad. Sci. USA, 2002, 99:13926-13931. 14. National Asthma Campaign; Fact sheet 09. 15. http://www.ibuprofen-foundation.com/whatibuprofen/story.htm 16. Perrott DA, Piira T, Goodenough B, Champion GD.Efficacy and safety of acetaminophen vs ibuprofen for treating childrens pain or fever: a meta-analysis. Arch Pediatr Adolesc Med. 2004 Jun;158(6):52 17. Goldman RD, Ko K, Linett LJ, Scolnik D. Antipyretic efficacy and safety of ibuprofen and acetaminophen in children. Ann Pharmacother. 2004 Jan; 38 (1):146-50. 18. Wahba H. The antipyretic effect of ibuprofen and acetaminophen in children. Pharmacotherapy. 2004 Feb;24(2):280-4 19. Purssell E. Treating fever in children: Paracetamol or ibuprofen? Br J Community Nurs. 2002 Jun:7 (6):316-20. 20. Int J Clin Pract Suppl. 2003 Apr;(135):9-12. Autret-Leca E. Tours University Hospital, France A general overview of the use of ibuprofen in paediatrics. 21. Van Esch A, Van Steensel-Moll HA, Steyerberg EW, Offringa M, Habbema JD, Derksen-Lubsen G. Antipyretic efficacy of ibuprofen and acetaminophen in children with febrile seizures. Arch Pediatr Adolesc Med. 1995 Jun; 149 (6): 632-7. 22. Kauffman RE, Sawyer LA, Scheinbaum ML . Antipyretic efficacy of ibuprofen vs acetaminophen.. Am .J Dis Child. 1992 May; 146 (5): 622-5. 23. Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics. 2002 Feb; 109 (2): E20. 24. Lesko SM, Mitchell AA. Renal function after shortterm ibuprofen use in infants and children. Pediatrics. 1997 Dec;100 (6):954-7. 25. Lesko SM, Mitchell AA . The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics. 1999 Oct;104 (4):e39 26. Jouzeau JY, Terlain B, Abid A, Nedelec E, Netter P. Cyclooxygenase isoenzymes : how recent findings affect thinking about nonsteroidal antiinflammatory drugs. Drugs 1997; 53: 563-82. INTERNATIONAL PEDIATRIC UPDATE 2004 27. Dr.Chandra.M.Gulhati, Essentialdrugs.org 18 Mar 2003 05:18:00 -0500 (EST) 2003 Jul 5; 327(7405): 18-22. Comment in: BMJ. 2003 Nov; 27(7422) :1050-1 28. World Health Organisation. Nimesulide Adverse Reactions reported to the CNF. WHO ADR Newsletter 1999: 2:6. 42. Dumortier J, Borel I, Delafosse B, Vial T, Scoazec JY, Boillot O. Subfulminant hepatitis associated with Nimesulide treatment requiring liver transplantation [Article in French] Gastroenterol Clin Biol. 2002 Apr; 26(4): 415-6. 29. Cordeiro MR, Goncalo M, Fernandes B. Nimesulide: Fixed drug eruption: 3 case reports. Contact Dermatitis 2000; 43:307. 30. Nimesulide-induced hepatitis and acute liver failure. Weiss P, Mouallem M, Bruck R, Hassin D, Tanay A, Brickman CM, Farfel Z, Bar-Meir S. Isr Med Assoc J. 1999 Oct; 1(2): 89-91 31. Sbeit W, Krivoy N, Shiller M, Farah R, Cohen HI, Struminger L, Reshef R. Nimesulide-induced acute hepatitis. Ann Pharmacother. 2001 Sep; 35(9):1049-52. 32. Van Steenbergen W, Peeters P, De Bondt J, Staessen D, Buscher H, Laporta T, Roskams T, Desmet V. Nimesulide-induced acute hepatitis: evidence from six cases. J Hepatol. 1998 Jul;29 (1):135-41. Comment in: J Hepatol. 2000 Jan; 32(1):174. 33. Rodrigo L, de Francisco R, Perez-Pariente JM, Cadahia V, Tojo R, Rodriguez M, Lucena MI, Andrade RJ. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation.. Scand J Gastroenterol. 2002 Nov; 37(11):1341-3. 34. Liver toxicity due to Nimesulide is well known, but to our knowledge the occurrence of haemolytic anaemia has not been related to this drug previously. For these reasons, Nimesulide has been restricted or removed from the market in several countries in recent months. 35. Weiss P. Nimesulide-induced hepatitis and acute liver failure. Isr Med Assoc J. 1999 Nov;1(3):221 36. Merlani G, Fox M, Oehen HP, Cathomas G, Renner EL, Fattinger K, Schneemann M, Kullak-Ublick GA. Fatal hepatoxicity secondary to Nimesulide. Eur J Clin Pharmacol. 2001 Jul;57(4):321-6. 37. Ferreiro C, Vivas S, Jorquera F, Dominguez AB, Espinel J, Munoz F, Herrera A, Fernandez MJ, Olcoz JL, Ortiz de Urbina J. Toxic hepatitis caused by Nimesulide, presentation of a new case and review of the literature. [Article in Spanish] Gastroenterol Hepatol. 2000 Nov;23 (9):428-30. 38. Schattner A, Sokolovskaya N, Cohen. Fatal hepatitis and renal failure during treatment with Nimesulide. J. Rehovot, Israel. J Intern Med. 2000 Jan; 247 (1):153-5. 39. Tejos S, Torrejon N, Reyes H, Meneses.Bleeding gastric ulcers and acute hepatitis: 2 simultaneous adverse reactions due to Nimesulide in a case [Article in Spanish] M. Rev Med Chil. 2000 Dec;128 (12):1349-53. 40. Ozgur O, Hacihasanoglu A, Karti SS, Ovali E Nimesulide-induced fulminant hepatitis. Turk J Gastroenterol. 2003 Sep;14(3):208-10. 41. Traversa G, Bianchi C, Da Cas R, Abraha I, MennitiIppolito F, Venegoni M. Cohort study of hepatotoxicity associated with Nimesulide and other non-steroidal anti-inflammatory drugs. BMJ. 83 43. Montesinos S, Hallal H, Rausell V, Conesa F, Lopez A. Nimesulide-induced acute hepatitis. [Article in Spanish]. Gastroenterol Hepatol. 2001 Apr; 24 (4): 219-20. 44. Rodrigues de Oliveira J, Correia J, Silvestre F, Meirelles A, Bernardo A. Severe acute hepatitis probably induced by Nimesulide [Article in French]. Gastroenterol Clin Biol. 2000 May; 24(5): 592-3. 45. Gallego Rojo FJ, Fernandez Perez F, Fernandez Perez R, Porcel A, Blas JM, Diez F. Nimesulideinduced hepatotoxicity. [Article in Spanish]. Rev Esp Enferm Dig. 2002 Jan: 94(1): 41-2. 46. Papaioannides D, Korantzopoulos P, Athanassiou E, Sinapidis D. Nimesulide-induced acute hepatotoxicity. Indian J Gastroenterol. 2003 NovDec;22(6):239 47. Perez-Moreno J, Llerena Guerrero RM, Puertas Montenegro M, Jimenez Arjona MJ.Gastroenterol. Nimesulide toxic hepatitis in pregnancy [Article in Spanish] Hepatol. 2000 Dec;23(10):498-9. 48. Balasubramaniam J. Nimesulide and neonatal renal failure. Lancet 2000;355: 575. 49. Thawani V. Nimesulide, a dangerous drug. The Hitavada (Nagpur) 2002 Oct 15; 8. 50. Jain K . Doctors question IMA survey on Nimesulide. Times of India (Mumbai) 2003 Jan 14; p 1. 51. http://www.hinduonnet.com/thehindu/2003/08/ 17/02hdline.htm 52. h t t p : / / w w w. e x p r e s s h e a l t h c a r e m g m t . c o m / 20030915/pharmanews03.shtml EMEA,ban: Nimesulide market slips further 53. http://www.dermagic.100megas.com/year2004/ March04.html#question2, 54. http://www.essentialdrus.org/ Dr. Chandra M. Gulhati, Editor, MIMS 55. Amdekar Y.K. Rational Use of Antipyretics. Indian Pediatrics 2003; 40:541-544 56. Mayoral CE, Marino RV, Rosenfeld W, Greensher J. Alternating antipyretics: is this an alternative? Pediatrics 2000; 105: 1009-1012. 57. Carson SM. Alternating acetaminophen and ibuprofen in the febrile child: examination of the evidence regarding efficacy and safety. Pediatr Nurs. 2003 Sep-Oct;29 (5):379-82. 58. Diez Domingo J, Burgos Ramirez A, Garrido Garcia J, Ballester Sanz A, Moreno Carretero E. Use of alternating antipyretics in the treatment of fever in Spain. [Article in Spanish ] An Esp Pediatr. 2001 Dec; 55(6):503-10. 59. Rosefsky JB. Alternating antipyretics: is this an alternative? Pediatrics. 2001 Nov;108(5):1236-7 Proceedings & Abstract Book Long-Term Benefits of Breastfeeding Dr. Armida Fernandez, Retired Prof of Neonatology & Ex Dean, LTMG Hospital & L.T.M.M College, Sion, Mumbai Human milk is the ideal food for a baby and provides all the nutrients necessary for growth and development. Extensive research has documented compelling evidence that the benefits of breastfeeding continue through infancy, childhood & adulthood. This article will highlight the longterm benefits of breastfeeding for the baby and the mother. In addition to proteins, carbohydrate and fats necessary for the growth of the baby, breast milk is replete with protective factors and bioactive substances, which enhance the development of the gut and play an important role in immuno-protection of the baby. Besides the active role of breast milk, alternatively early introduction of artificial milks and foods increases the risk of chronic disease in adulthood. Evidence suggests that breastfeeding reduces the risk of insulin dependent diabetes mellitus, childhood cancer, obesity & inflammatory bowel disease. There is also evidence to suggest that breastfeeding improves intelligence and cognitive functions particularly in preterm babies. The protective effect of breast milk on long term diseases is probably related to the abundance of bioactive factors including secretory antibodies, leucocytes, lipids, carbohydrates as well as other anti inflammatory agents & compounds that modulate the immune response such as prostaglandins, hormones enzymes, cytokines and growth factors (1) The breastfed baby is also protected by the absence of large foreign proteins before gut closure, before the development of oral tolerance and before immune system maturation. Besides a breastfed baby is also protected against infection & inflammation. There may be critical window period for exposure to certain proteins for children with certain risk profiles that increases the risk for autoimmune disease. 84 Insulin Dependent Diabetes Mellitus (IDDM) IDDM is an autoimmune disease determined by a complex of factors both genetic and environmental in origin. The risk of developing IDDM in childhood may be influenced by infant feeding practices. The relationship of IDDM to breastfeeding was first described by Borch-Johnson in 1984 when he reported an increased risk of IDDM in children who were breastfed for less than three months. (3) There is sufficient data available today relating feeding practices to IDDM (4) (5). Complex biochemical, hormonal, anti-microbial and antiinflammatory substances present in human milk influence the development of the gastro intestinal tract and the developing immune system, much of which is in the gut. Introduction of artificial feeds in the first three to six months increases the risk of IDDM in genetically susceptible children by providing early exposure to foreign proteins and depriving the infants from the complex immuno- activity of breast milk (6) Factors associated with increase risk of IDDM in genetically susceptible infants include a) Breastfeeding duration of less than three months b) Early introduction of cows milk c) Early introduction of solids A meta analysis of case control studies carried out by Gerstein demonstrated (4) the relationship of breastfeeding for less than 3 months and the development of IDDM. (7). There was a much stronger correlation in children who developed IDDM before four years of age. Celiac Disease Celiac disease is an auto immune enteropathy resulting from a genetic susceptibility and dietary exposure to gluten. INTERNATIONAL PEDIATRIC UPDATE 2004 Studies indicate that the incidence of celiac disease decreased in those babies who were breastfed when gluten was introduced (8)(9). There was a delayed onset of the disease in those who were breastfed for a longer duration and babies who were exclusively breastfed. Childhood Cancer A number of case controlled studies have found an association between artificial feeding and increased risk of childhood cancers i.e lymphoma and leukemia (10) (11) (12) There is also experimental evidence that has shown apoptosis of cancer cells in human milk. This is a result of selective activity of multi meric ± lactalbumin which is described as potent Ca++ at elevating and apoptosis inducing agent with broad yet selective cytotoxic activity. Normal cells are not affected. This protein most abundant in human milk is created in the acid environment of the gastro-intestinal tract. Inflammatory Bowel Disease & Ulcerative colitis and Chrons disease The causes of these diseases remain unclear and are probably multi factorial. Available case control studies suggest that inflammatory bowel disease was less likely in babies who were breastfed as compared to controls (14) (15) Hypothesis relate association to the protective action of breastfeeding against gastro intestinal infections and the early development and maturation of the gut. Obesity There is increasing evidence relating early infant feeding practices to obesity (16). Case control studies in an adolescent clinic showed a significantly high risk for obesity in those infants who were not breastfed (17). Bioactive substances in breast milk may influence adi pocyte differentiation and proliferation. The infants ability to regulate intake differs between babies who are breastfed and artificially fed which may alter later regulation of food intake that may result in obesity. Breastfeeding and Neurodevelopment Breastfed children have a better neurodevelopment outcome (18, 19). A number of factors could be responsible which include biological, nutritional, genetic 85 or a combination of factors. There is some evidence that supports a nutritional role. Breast milk contains Docohexanoic & arachnadoic acids, long chained polyunsaturated fatty acids. Large quantities of these are used in the growing brain of the fetus and the neonate. The placenta is a source of fatty acids in the fetus. After birth, baby is dependent on the LCFA present in human milk. This is particularly relevant to the preterm baby who has been born early. Photo receptor membranes in the retina also have highest concentration of DHA. Maturation of visual system may be affected in preterm babies who have not received breast milk. A meta analysis of various studies on cognitive outcome in babies showed a higher score in breastfed babies starting as early as two months which continued through childhood at 10-15 years of age (20). Duration of breastfeeding correlated with development and cognitive outcome. Lucas long-term study of preterm babies showed a significantly higher IQ in preterm babies who had received breast milk (21) Atopy & Asthma Atopic disease is a common health problem. Environmental exposure in early infancy may be particularly important for sensitization and later development of atopy probably because of physiological immaturity of the immune system. As in other immune disorders breast milk has a protective role in atopic disease. Studies have shown that prolonged breastfeeding is prophylactic against atopic disease throughout childhood & adolescence (22). Other long-term benefits for the baby Breastfeeding also offers protection against otitis media, attributed to the factors present in breast milk itself or the harmful effects of bottle-feeding. Studies have shown that this protective effect is related to duration of breastfeeding and lasts for a year after breastfeeding has stopped. (24) A systematic review of studies on the effects of infant feeding on cholesterol in infancy childhood, adolescence & adulthood concluded that breastfeeding is associated with increase in Total Cholesterol & Low Density Lipoproteins in infancy but with lower levels in adulthood. This suggests long-term benefits of breastfeeding for cardiovascular health (25) Proceedings & Abstract Book Long-term benefits of Breastfeeding for the Mother Hormones of breastfeeding aid in adjustment to mothering, conservation of energy and in subsequent nutrient recovery. Long-term benefits include decreased risk of pre-menopausal breast cancer epithelial cancer of the ovary and reduced risk of spinal and hip fractures after menopause. The relative risk of pre-menopausal breast cancer decreases with the duration of breastfeeding (26,27). Initiation and physiological completion of breastfeeding during two to seven months postpartum is associated with decrease in ovarian cancer. (28) Clinical studies show bone loss during lactation and paradoxically positive effects References (1) Goldman A.S The immune system of human milk: Anti microbial, anti inflammatory & immunomodulating properties Pediatr Infect Dis J 1993; 12: 664 69 (2) Breastfeeding and chronic disease in childhood & adolescence Davis M.K, PCNA 2001; 48:125-141 (3) Borch-Johnsen K, Joner G, Mandrup-Poulsen T, et al: Relation between breast-feeding and incidence rates of insulin-dependent mellitus: A hypothesis Lancet 2:1083, 1984 (4) Scott Fw: Cow milk and insulin-dependent mellitus: Is there a relationship? Am J Clin Nutr 51:489, 1990 (5) Norris JM, Scott FW: A meta-analysis of infant diet and insulin-dependent diabetes: Do biases play a role? Epidemiology 7:87, 1996 (6) Harrison LC, Honeyman MC: Cows milk and Type 2 daibetes: The real debate is about mucosal immune function. Diabetes 1999; 48:1501-03 (7) Gerstein H.C: Cowss milk exposure and Type I diabetes mellitus. Diabetes Care 1994; 17:34 (8) Challacombe DN, Mecrow IK, Elliot K, et al: Changing infant feeing practices and declining incidence of celiac disease in West Somerset. Arch Dis Child 77:206, 1997 (9) Ivarsson A, Persson LA, Nystrom L, et al: Epidemic of coeliac disease increased in Swedish children. Acta Pediatr 89:165, 2000 (10) Grufferman S, Davis MK, Ambinder RF, et al: A protective effect of breast-feeding on risk of Hodgkins disease in children. Pediatr Perinat Epidemiol 12:A13, 1998 (11) Mathur GP, Gupta N, Mathur S, et al: Breastfeeding and childhood cancer. Indian Pediatrics 30:651, 1993 (12) Davis M.K Review of the Evidence for an association between Infant Feeding & Childhood Cancer Int. I. Cancer 1998; 11: 29-33 (13) Svensson M, Hakansson A, Mosserberg A-K, et al: Conversion of á-lactalbumin to a protein inducing apoptosis. Proc Natl Acad Sci 97: 4221, 2000 (14) Corrao G, Tragnone A, Caprilli R, et al: Risk of inflammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: A nationwide case control study. Int J Epidemiol 27397, 1998 (15) Koletzko S, Sherman P, Corey M, et al: Role of infant feeding practices in development of Crohns disease in childhood. Br Med J 298:1617, 1989 (16) Von Kries, Koletzko B, Sauerwald T etal. Breastfeeding & obesity: cross sectional study BMJ 1999; 319:147- 86 of significantly longer periods of breastfeeding resulting in less bone fractures. Hormonal control of calcium and bone regulation results in a short-term negative effect but a long-term positive effect.(29) For centuries breastfeeding was a norm as replacement foods were not available. With the advent of formula milk, the practice of breastfeeding was eroded as these milks served as a nutrient replacement. Thirty years of rigorous and positive research has led has to the rediscovery of breastfeeding as an evidence based health intervention which has immediate positive preventive health effects for the mother & infant as well as compelling long-term benefits that impact their health throughout life. 50 (17) Kramer Ms: Do breastfeeding and delayed introduction of solid foods protect against subsequent obesity. J. of Pediatr 1981; 98:883 (18) Lanting CI, Fidler V, Huisman M et al. Neurological differences between 9 year old children breast milk or formula milk as babies. Lancet, 1994 12; 344: 1319 22 (19) Horwood L.J et al. Breastfeeding & later cognitive and academic outcomes. Pediatrics 1998; 101:9 (20) Anderson JW, John stone BM, Remley DT: Breastfeeding one cognitive development. A meta analysis. Am J of Nat 1999; 30: 33-38 (21) Lucas A, Morley R, Cole TS: Randomised trial of early diet in preterm babies and later intelligence quotient BMJ 1998. 28; 317:1481 - 7 (22) Saarinen U.M, Kajosaari M 1. Breastfeeding as prophylaxes against atopic disease; prospective followup study until 17 years Lancet 1995; 346: 1065 69 (23) Breastfeeding and acute otitis media. Sassen M.L, Brand R, Grate Jan. Am. J of Otolaryn 1994:15; 351357 (24) Tule DN, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in Greater Boston: a prospective, cohort study. J Infect Dis. 1990; 161: 806-7 (25) Infant feeding and blood cholesterol: a study in adolescents and a systematic review. Owen CG, Whir cup PH, Odoki K et al. Pediatrics, 2003; 111: 921-922 (26) Enger S, Ross R, Paganini-Hill A, et al: Breastfeeding experience and breast cancer risk among postmenopausal women. Cancer Epidemiol Biomarkers Prev 7:365-369, 1998 (27) Nduati R, John G, Mbori-Ngacha D, et al: Effect of breastfeeding and formula feeding on transmission of HIV-1: A randomized clinical trail. JAMA 283:1167-1174, 2000 (28) Rosenblatt KA, Thomas DB: WHO collaborative study of neoplasia & steroid contraceptives: Lactation & risk of epithelial ovarian cancer Int J Epidemiol 1993; 22: 192-197 (29) John E.M, Whittemore AS, Harry R, Itnyre J. Collaborative ovarian cancer group. Characteristics relating to ovarian cancer risk 1993; 85: 142 -47 (30) Cumming RJ, Klinberg R.J Breastfeeding & other reproductive factors & the risk of hip fractures in elderly women Int J of epidemiology 199; 22:90