national journal of medical research

Volume 6 │ Issue 4 │ Oct – Dec 2016 │ Page: 296 - 357

Print ISSN: 2249 4995

eISSN: 2277 8810

NATIONAL JOURNAL OF MEDICAL RESEARCH

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print ISSN: 2249 4995│eISSN: 2277 8810

NATIONAL JOURNAL OF MEDICAL RESEARCH │ Volume 6│Issue 4│ Oct – Dec 2016

NATIONAL JOURNAL OF MEDICAL RESEARCH Official Publication of National Association of Medical Research

Print ISSN: 2249 4995

Online ISSN: 2277 8810

EDITORIAL BOARD

Chief Editor Dr. Viren Patel MD (Pathology), USA

Associate Editor

Dr. Sunil Nayak MD (Community Medicine), Patan, Gujarat

Executive Editor Dr. Harsh Shah, MD (Skin & VD)

Associate Executive Editor Mr. Bhaumik M

Members

Dr. Chirag Mehta MS (ENT), Palanpur Dr. Mehul Gosai, MD (Pediatric), Bhavanagar

Dr. Deepak Agrawal, MD (Pathology), Agra Dr. N K Gupta, MS, MCh (CTVS), PGDHHM, Lucknow

Dr. Deepak Parchivani PhD (Biochem), Bhuj Dr. Praful J. Dudharecha MD (Medicine), Rajkot

Dr. Deepak Shukla MD (Medicine), Surat Dr. Rajesh Solanki, MD (TB & Chest), Ahmedabad

Dr. H. R. Jadhav, MS (Anatomy), Ahmedabad Dr. Gunvant Kadikar MD (Ob. & Gy.), Bhavnagar

Dr. Hitendra Desai MS (Surgery), Ahmedabad Dr. Indira Parmar, MD (Pediatric), Vadodara

Dr. Kaushik Kadia MS (Surgery), Patan Dr. Rudresh Jarecha, DMRE, DNB (Radio.), Hydrabad

Dr. Uma Gupta, MD (Ob. & Gy.), Lucknow Dr. Suprakash Chaudhury, MD (Psychi.), PHD, Ranchi

Dr. Shalini Srivastav MD (PSM), Greater Noida Dr. Vani Sharma, MD (Ob. & Gy.), Himachal Pradesh

Dr. K. M. Maheriya MD (Pediatrics), Ahmedabad Dr. Gurudas Khilani, MD (Med & Pharmac), Patan

All the views expressed in the articles are personal views of the authors and not the official views of the National Journal of Medical Research or the Association. The Journal retains the copyrights of all material published in the issue. However, reproduction of the published material in part or total in any form is permissible with due acknowledgement of the source as per ethical norms.

The journal is indexed in Index Copernicus International, Scopemed, DOAJ, WHO HINARI, IndexScholar, IndMedica, NewJour, eJManager, Medical Journal Links, Research Bible, Universal Impact Factor, etc.

CORRESPONDENCE

Mr. Bhaumik M., Associate Executive Editor, NJMR Email: [email protected], Mob: 8140975850 PUBLISHER MedSci Publications National Journal of Medical Research (Reg. No. 24-022-21-48410) C-43, Umiya Bunglows, Bhadreshwar, Hansol, Ahmedabad – 382475.

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Open Access Journal NATIONAL JOURNAL OF MEDICAL RESEARCH

Volume 6│Issue 4│ Oct – Dec 2016 print ISSN: 2249 4995│eISSN: 2277 8810

NATIONAL JOURNAL OF MEDICAL RESEARCH

Volume 6│Issue 4│Pages 296 – 357│Oct - Dec 2016

Table of Content

Review Article

Re-Irradiation in Head and Neck Cancers: A Wise Selection from Available DataRubu Sunku, Vikas Kantilal Jagtap ...........................................................................................................................296 - 300

Original Article

Correlation between Ficat-Arlet and Mitchell’s Staging for Avascular Necrosis of Femur Head Saurabh Goyal, Purvi Desai, Devyani Ambadekar, Simranjeet Singh .................................................................301 - 304

Microbiologic Spectrum of Acute and Chronic DacryocystitisAbha Gahlot, Shashi Prasad, Manisha Singh, Bhargav Kotadia, Saloni Garg ....................................................305 - 308

Attenuation of Haemodynamic Response during Laryngoscopic Intubation with FentanylDinesh Thakur, Nirav S. Chauhan , Rahul Ramchandani, Himanshu Shah .......................................................309 - 312

Evaluation of Activities of Serum Gamma Glutamyl Transferase and Adenosine Deaminase in Preeclampsia – A Case Control Study

Rajeshwari R Patil, Archana S Choudhari ................................................................................................................313 - 315

Role of Fiberoptic Bronchoscopy in Non-Resolving PneumoniaRajesh Kumar Balakrishnan, Gyanshankar P Mishra, Shivhari V Ghorpade .....................................................316 - 320

A Comparative Study of Intravenous Methyl Prednisolone Versus Dexamethasone in Management of Patients with Posterior Scleritis

Shashi Prabha Prasad, Abha Gahlot, Nimrita Nagdev, Preeyam Biswas, Bhargav Kotadia, Kanisha Jethwa ...........................................................................................................................................................................321 - 324

Transportation of injured force personnel by Air – Merit & DemeritsDinesh Thakur, B. K. Mehta .....................................................................................................................................325 - 327

Comparing Clinical diagnosis and Laboratory Diagnosis in Paediatric Patients of Acute Viral Hepatitis in Ahmedabad, Gujarat

Ekta A Dalal, Gaurav Vishal .....................................................................................................................................328 - 331

Study of Adverse Drug Reaction in Anaesthesia Practice Rachana Gandhi, Ila Patel, Alka Shah ......................................................................................................................332 - 335

Renal Cell Carcinoma : MRI and Histopathological Subtype CorrelationRahul H Sharma, Hinal R Bhagat, Yash N Jardosh, Pradip K Anand ................................................................336 - 339

A Study of the Association between Patterns of Eye Drop Prescription and Medication Usage in Glaucoma Subjects

Punit Singh, Raghunandan Kothari, Ruta Shah, Shrey Rayajiwala, Aakash V Patel, Roshni Patel ..................340 - 343

Role of Random Urinary Protein to Creatinine Ratio in Mild PreeclampsiaManoj C Lokhande, Avinash N Jadhao ...................................................................................................................344 - 348

Open Access Journal NATIONAL JOURNAL OF MEDICAL RESEARCH

Volume 6│Issue 4│ Oct – Dec 2016 print ISSN: 2249 4995│eISSN: 2277 8810

Topical Proparacaine 0.5% Anaesthesia : Pain Management and Intraoperative Corneal Epithelial Edema in Phacoemulsification Catract Surgery

Shashi Prabha Prasad, Gira Raninga, Minal Doulatramani, Saurabh Ashtamkar, Asim Naik ..........................349 - 353

A Study of Adjuvant Concurrent Chemo-Radiotherapy with Capecitabine in Adenocarinoma Stomach Vishesh Gumdal, Manika Batra, Prakash Chitalkar, Rakesh Taran, Prashant Kumbhaj, Deepak Singla ........354 - 357

NATIONAL JOURNAL OF MEDICAL RESEARCH print ISSN: 2249 4995│eISSN: 2277 8810

NJMR│Volume 6│Issue 4│Oct – Dec 2016 Page 296

REVIEW ARTICLE

RE-IRRADIATION IN HEAD AND NECK CANCERS: A WISE SELECTION FROM AVAILABLE DATA Rubu Sunku1, Vikas Kantilal Jagtap2 Author’s Affiliations: 1Registrar, 2Assistant Professor, Dept. of Radiotherapy, Dr. B Borooah Cancer Institute, Guwahati Correspondence: Dr Vikas Kantilal Jagtap Email- [email protected]

ABSTRACT

Recurrence of cancer within radiation field is the most dreaded news after curative radiation therapy in head and neck cancer patients. Surgical treatment of these sites is always challenging, which becomes worse after radiation. With the introduction of conformal modalities, the chances of re-irradiation of recurrent cancer are being explored for many years now. In spite of increased use of reirradiation there are not much published criteria or guidelines in these groups of patients. The objective of this literature review is to identify the most commonly used patient selection criteria, radiation doses, fields, impact of newer technology and outcomes in terms of local control and survival.

Keywords: Re-irradiation, Chemoradiation, Recurrent, Head and neck cancer

INTRODUCTION

Even today, more than 2/3rd of patients of head and neck cancers will present in advanced stage. Almost half of these patients will have recurrence after radical treatment.1. In Radiation Therapy Oncology Group (RTOG) experience, previously irradiated patient has 1% per year risk of second malignancy.2 Currently, the treatment of choice in these patients is surgery. Vari-ous options such as salvage surgery, radiotherapy, chemotherapy, chemoradiation or palliative treatment are prescribed as per the stage, local extent and time since last radiotherapy. Addition of post-op radiation to salvage surgery remains controversial. Re-irradia-tion in previous radiation field for a recurrent tumor or second malignancy was earlier considered unsafe and toxic.1 Chemotherapy alone in this setting gives median survival of only 5 to 9 months.3 Therefore, if disease is unresectable, definite re-irradiation with or without chemotherapy is offered. Even though the chance of cure is low, it has to be weighed against the risk of toxicity because there are no other better treat-ment options available.

Prognostic factors for recurrent or secondary head and neck cancer

Patient’s selection and individualization of treatment is very important in management of recurrent head and neck cancer. Theoretically recurrent tumors or second malignancy in same fields will have a poor prognosis. Selection of patients with better prognosis and giving them best possible treatment plan is essen-

tial. De Crevoisier et al, in the study on role of re-irra-diation, found that the only two factors affecting the risk of death is surface and volume of second radiation field. Overall survival rate of patients irradiated with an area less than 125 cm2 or a volume less than 650 cm3 was higher than that of the patients treated with an area more than 125 cm 2 and a volume more than 650 cm3 (P = .08 and P = .03, respectively).4 This find-ing was also shown by Chen et al, in his study where in a multivariate model, the investigators found that the re-irradiation volume is the only factor inde-pendently associated with death. In subset of patients with tumors <27 cm3, the 2-year local control rate was 80%.5,6 Surgery followed by postoperative RT showed better 5yrs survival (49%) than definite RT (20%) with p value of 0.003 in a retrospective study by Hoeberts et al, but selection bias cannot be ruled out.7

Some studies showed that second primary tumor has better prognosis than recurrent disease. This can be explained by presence of resistant clonogen in recur-rent case which has survived previous radiation and proliferated over the time.1 A normogram to assess the prognosis of these patients was developed by Tan-vetyanon T et al, where various prognostic factors like performance status, co-morbidity, tumour bulk, iso-lated neck recurrence were considered for prediction in the normogram. It predicts the probability of death within 24 months of re-irradiation.8 Minimum of at least 6 months interval from previous radiotherapy is taken as inclusion criteria for re-irradiation by most of the authors.4 In RTOG 9610, patients who had gap interval of more than 3 years between two sessions of



radiation had 1 yr survival of 48% compared to 35% in patients with interval less than 3 years. Patients re-ceiving re-irradiation within 6 months to 1 year after previous radiation had survival of only 5.8 months which is comparable to chemotherapy only.9 Pre-ex-isting comorbidities and organ dysfunction are im-portant prognostic factors for patients undergoing reirradiation. For those with comorbidities and organ dysfunction, reirradiation largely serves as a palliative therapy.

Risk factors and contraindications against re-ir-radiations

Although patient’s performance status, age, tumor bulk and many other disease and treatment related fac-tors has to be kept in mind. But he most important factor which influence response to re-irradiation is in-terval since previous radiation. Longer duration from previous radiation has less chance of developing se-vere toxicity and higher chances of response to re-ir-radiation.5 Severe toxicity to previous radiation is a major contraindication to re-irradiation. Thorough evaluation to assess for pre-existing sequelae of previ-ous radiation should be done before considering the patients for re-irradiation. Occurrence of osteoradi-onecrosis (ORN) as such is a contraindication for re-irradiation. Presence of cartilage necrosis and edema of arytenoids, which places patient in high risk of as-piration and airway closure, should be ruled out.5 Ra-diation myelitis is another limiting toxicity, which is a contraindication for radiation of any organ in the vi-cinity of spinal cord. Using conventional fractiona-tion, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively.10 Carotid blowout is a rare but fatal complication due to re-irra-diation. In patients treated in a continuous course with 1.8–2-Gy daily fractions or 1.2-Gy twice daily frac-tions, rate of carotid blowout was 1.3%.11 Chen et al has also reported that patients with more than 3 years from previous RT, KPS (Karnofsky Performance Score) 90-100%, tumor volume < 30 cm3 and previ-ous RT dose less than 50 Gy were associated with lower risk of Toxicity compared to patients with less than 1 years from previous RT, KPS < 70, tumor vol-ume > 60 cm3 and previous RT dose > 60 Gy of radi-ation.5 Similarly Jae Y. Lee et al has shown in his study that shorter intervals to re-irradiation (<20 months) and larger re-irradiated PTVs (>100 cm3) were inde-pendent predictors of developing severe long-term toxicity in multivariable analysis. Probability of being free of severe toxicity was 94% in patients having smaller PTVs and longer disease free survival.12

Treatment considerations

Current management of recurrent head and neck can-cer is dependent on its resectability. Surgery remains the first choice of treatment in resectable non meta-static lesions.5 Complete resection gives long term sur-vival of 25% to 45% in these patients. However even

after complete resection with negative margins, these patients have very high local failure rates of upto 59 %.13 There was a trend for decreased LRC among those with close/positive margins, and significantly worse prognosis in those with ECE and bone invasion despite adjuvant reirradiation, suggesting treatment intensification may be warranted for select patients with high-risk pathologic features. De Crevoisier et al reported 4-year survival of 43% and 5-year disease free survival of 26% in patients who had positive mar-gins and/or lymph node involvement with extracap-sular extension.4 Considering these results, the Groupe d’Etude des Tumeurs de la Tête et du Cou (GETTEC) and the Groupe d’Oncologie Radiothéra-pie Tête et Cou (GORTEC) conducted a phase III phase randomized trial to address this issue. Previ-ously irradiated patients, were randomized to observa-tion or re-irradiation (60 Gy over 11 weeks; 2 Gy/day) with chemotherapy (concomitant 5FU + hy-droxyurea) after macroscopic surgical resection. Both local control and disease-free survival were improved in patients receiving postoperative re-irradiation and chemotherapy. However, there was no difference in overall survival.14 Vinita Takiar et al has shown that LRC (Locoregional control) benefit with concurrent chemotherapy seems even more pronounced when added to adjuvant reirradiation compared with adju-vant reirradiation alone with corresponding 5-year LRC rates of 56.7% versus 31.4% (P=0.001). Survival and toxicity were not affected by the use of adjuvant concurrent chemotherapy, nor did the type of chem-otherapy influence clinical outcomes.15

Role of definitive re-irradiation was evaluated by two prospective randomized trials RTOG 9610 and RTOG 9911. In RTOG 9610, Spencer et al showed that definitive radiotherapy combined with concur-rent chemotherapy with 5 FU and hydroxyurea is fea-sible with acceptable toxicity. Median survival and es-timated 1 yr survival was higher in secondary cancer (19.8 months and 54.2% respectively) in comparison to recurrent cancer (7.7 months and 38.4% respec-tively).9 In RTOG 9911, Paclitaxel and Cisplatin were given with split course radiation therapy. Median sur-vival was 12.1 month and estimated survival at 1 yr and 2 yrs were 50.2% and 25.9% respectively. 16 Phase III randomized trial by Tortochaux et al did not show any improvement in overall survival in patient receiv-ing re-irradiation with concurrent 5FU and hy-droxyurea in comparision to single agent methotrax-ate alone in palliative intent cases.17 However, many questions remain unanswered regarding the optimal delivery of Re-RT and the best Chemotherapy agents, as well as questions regarding selection criteria of pa-tient in order to achieve maximum benefit from radi-otherapy or combination chemoradiation.

Inclusion of lymph nodal region at risk in radiation field, still remain inconclusive. In most of the studies, radiation field included only gross tumour volume



with margin for clinical target volume. The margin given to GTV depends on radiotherapy technique em-ployed, either 3DCRT, IMRT or IGRT. Margin varied from 5mm to 2 cm to obtain CTV.4,9,18,19 In some studies CTV margin was reduced to as low as 1 mm when critical organ such as spinal cord and brain stem came in vicinity.10,11 Dose prescribed in re-irradiation remains controversial. Higher re-irradiation dose are shown to give better response. In study by Salam et al, 3-year overall survival and locoregional control rate of patients who received re-radiation dose of > 58 Gy was 30% and 56%, as compared to 6% and 33% in patients who received doses of < 58 Gy.20 Some ex-perimental data showed that head and neck can toler-ate cumulative dose of upto 130 Gy, and dose of spi-nal cord should be limited to 50 Gy.6,21 At present rec-ommended dose for re-irradiation in various studies are 60-70 Gy.6 Newer treatment modality, such as IMRT (Intensity Modulated Radiation Therapy) or IGRT (Image Guided Radiation Therapy), improves precision, therefore improve therapeutic ratio. Lee et al reported that IMRT has offered possibilities for ap-plying re-irradiation more safely with greater local control. They reported a 2-year disease free survival of 52% vs 20% in patients who underwent IMRT and patients who did not.22 Image guided Radiotherapy improves tumour localization and reduces positioning errors.

Effects of advanced treatment modalities on head and neck re-irradiation

Technical advancement gives us independence to im-prove conformity and precision, although risk of omission should always be taken into consideration. SBRT (Stereotactic radiotherapy) provides higher conformal dose distribution with greater sparing of normal organs, therefore allowing delivery of higher radiation dose in shorter time. Stereotactic radiother-apy and radiosurgery are emerging as very good alter-native to surgery in recurrent head and neck cancer. Roh et al reported an 80% response rate after 30 Gy (range 18–40 Gy) in 3–5 fractions administered using the Cyber-Knife system. A 2-year survival rate of 30.9% and a treatment death rate of 2.9% were re-ported.23 In study by Unger et al, patients treated with Stereotactic radiosurgery, the 2-year OS and locore-gional control (LRC) rates were 41% and 30%, respec-tively. Higher total dose, surgical resection, and naso-pharynx site were significantly associated with im-proved locoregional control. Surgical resection and nonsquamous histology were associated with im-proved OS.24 Rwigema et al did a review study on 85 patients who received SBRT with mean dose of 35 Gy. Those patient receiving dose < 35 Gy had lower local control as compare to those receiving > 35 Gy at 6 months (P=0.014). Local control and overall sur-vival at 2 yrs was 48.5% and 16.1% respectively.25 Sim-ilarly Proton beam therapy is a newer approach used in some centres with facilities available. Advantage of

proton beam over photon beam is that it relatively spares normal tissue proximal to tumor, while rapid dose fall off spares normal tissue distal to tumor providing potential for dose escalation. In a multi-in-stitute report by Romesser et al, 92 patients were re-irradiated with Proton beam radiotherapy (PBRT). The median dose was 60.6 CGy (Cobalt Grey Equiv-alent). Freedom from distant metastasis and overall survival at 1 year was 84% and 65.2% respectively, with acceptable acute and late toxicity.26

Guidelines and recommendations:

Although there are many articles to investigate the role of reirradiation in recurrent or second primary Head and Neck cancers, very few gives the overall insight to the actual use of the published data for selecting pa-tients in clinical practice.1 As per the available clinical data1 and review of literature the following points need to be given a thorough consideration before se-lecting the patients for reirradiation.

A. Patient Related Factors:

Good Performance status is the most important fac-tor required for patient to complete radiation with radical intent. Presence of any co-morbidity which can hamper treatment tolerance or response should be as-sessed before decision is taken for radiation.

Co morbidities which might lead to compromise on radiation dose or compliance and treatment interrup-tion should be evaluated before radiation.

Sequelae to previous radiation are a contraindication to further radiation, such as patients with osteoradi-onecrosis, fistula, radiation myelitis, sever fibrosis or trismus should not be considered for radical reirradi-ation.

B. Treatment and Tumor Related factors:

Time since last radiation not only predicts radiation response but also give us idea about possible toxicity. Interval less than 6 months criteria since last radiation is exclusion in almost all re-irradiation studies. Time interval of more than 3 yrs is shown to give significant benefit when compared with less than 3 yrs. It takes minimum of 6 months for appearance of late reaction; therefore it is recommended to have at least 6 months interval since last radiation and preferably 1 year (con-sidering the radioresistant tumor clone present after RT, 6 months might be very less time to actually con-sider radiotherapy again).

Radiation dose: Higher radiation dose increases tumor cell kill, therefore increasing probability of cure. Most of the studies done till now suggest that radiation dose should be kept atleast 58-60 Gy or more to achieve significant survival advantage.



Previous treatment with Conventional technique or conformal technique, Cobalt or Linear Accelerator, use of tissue compensator which might influence the toxicity profile should be checked. In developing countries like India where due to resource limitations many patients are treated with cobalt machines and without tissue compensators the pre-existing toxicities and OAR (oragans at risk) doses may hamper the reir-radiation dose. Although cumulative dose of 110-120Gy and spinal cord doses less than 50Gy should be considered as limit. Data regarding the other OAR like bone and soft tissue, vasculature is sparse.

Radiation Technique: Conformal radiation delivery techniques like IMRT, Stereotactic radiotherapy, Tomotherapy, Cyberknife, Gamma Knife, Proton Beam radiotherapy etc. etc. improves the radiation dose delivery by improving precision of radiation. These modalities allow increase in radiation dose and conformity to the tumor while sparing the normal sur-rounding tissue, hence gives opportunity to overcome relative radio resistance in previously radiated tissues.

Radiation field size area or volume is one of the most important prognostic factors. In some studies, it was the only relevant factor effecting radiation response. It is recommended to keep field size or contouring volumes to be as small as possible. CTV margins might be reduced to less than 5 mm with conformal techniques. Limited tumor volume increases cure rate and improve toxicity profile, therefore patient with negative neck node should not receive unnecessary elective neck node irradiation. Data suggests area less than 125 cm2 or a volume less than 650 cm3 and tu-mour volume <27 cm3 are good predictors.

Although there is no cut off volume to select patients, we recommend that large volume involving multiple subsites should be avoided as they are unlikely to ben-efit from reirradiation but it’s recommended to use case wise clinical judgment in these group of patients.

In patients who underwent surgery the post op RT should be considered for margin positive and extrac-psular disease or PNI positive patients along with con-current chemotherapy.

Use of concurrent chemotherapy should be consid-ered in patients with good performance score.

Adequate supportive care before, during and after the course of treatment is very important factor in getting good compliance to the treatment.

CONCLUSION

Significant number of patients treated for advanced head and neck cancer presents with recurrence. Some survivors may also present with second primary tu-mors. In patients who presents with inoperable non

metastatic recurrence or second primary, re-irradia-tion with or without chemotherapy remains the only option for cure. Even in patients who have surgically resectable disease, post op radiation seems to improve survival, especially in patients who have high risk fea-ture in post operative histopathology. Toxicity due to cumulative dose is an important factor to be kept in mind. It becomes necessary to weigh the possible ben-efit of re-irradiation against toxicity or death oncolo-gists in selecting the patients for re irradiation wisely. Reirradiation with or without chemotherapy should be administered in well selected patient, to improve loco regional control, progression free survival and overall survival at the same time maintaining a good quality of life.

REFERRENCE

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2. Cooper JS, Pajak TF, Rubin P, et al. Second malignancies in patients who have head and neck cancer: Incidence, effect on survival and implications based on the RTOG experience. Int J Rad Oncol Biol Phys 1989; 17:449–56.

3. Wong S, Machtay M, Li Y. Locally recurrent, previously irra-diated head and neck cancer: Concurrent re-irradiation and chemotherapy, or chemotherapy alone? J Clin Oncol 2006; 24:2653-8.

4. De Crevoisier R, Bourhis J, Domenge C, Wibault C, Koscielny S. Full-Dose Reirradiation for Unresectable Head and Neck Carcinoma: Experience at the Gustave-Roussy Institute in a Series of 169 Patients. J Clin Oncol 1998; 16:3556-62

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6. Chen AM, Farwell DG, Luu Q, et al. Prospective trial of high dose reirradiation using daily image guidance with intensity modulated radiotherapy for recurrent and second primary head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011; 80:669–76.

7. Hoebers F, Heemsbergen W, Moor YS, Lopez M, Klop M et al. Reirradiation for head-and-neck cancer: delicate balance between effectiveness and toxicity. Int J Rad Oncol Biol Phys 2011; 81:e111–e118.

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ORIGINAL ARTICLE

CORRELATION BETWEEN FICAT-ARLET AND MITCHELL’S STAGING FOR AVASCULAR NECROSIS OF FEMUR HEAD Saurabh Goyal1, Purvi Desai2, Devyani Ambadekar1, Simranjeet Singh1 Author’s Affiliations: 1Resident, 2Associate Professor, Department of Radio-diagnosis and Imaging, Government Medical College and New civil Hospital, Surat, Gujarat Correspondence: Dr. Saurabh Goyal Email: [email protected]

ABSTRACT

Introduction: Avascular necrosis (AVN) of the femoral head is an increasingly common cause of musculoskel-etal disability, and it poses a major diagnostic and therapeutic challenge. Surgical management involves joint preserving surgeries in early stages of disease and joint replacement procedures in advanced stage disease. Thus, pre-operative staging is of utmost importance in deciding the appropriate treatment option.

Objective: The objective of the study was to stage avascular necrosis involving head of femur according to Ficat-Arlet (using X-RAY and MRI features) and Mitchell staging (using MRI features) and to study the corre-lation amongst the above mentioned staging systems.

Methodology: X-RAY and MRI images of thirty patients having Avascular Necrosis of femur head (23-bilateral and 7-unilateral) were studied retrospectively and staged according to Ficat-Arlet and Mitchell staging.

Results: Most of the Ficat-Arlet stage I and stage II joints (early stage) had Class A signal on MRI and most of the Ficat-Arlet stage III and stage IV joints (advanced stage) had class B or class C signal on MRI. Most of the affected joints with class A signal in the necrotic core had early stage disease while those with class B or class C signal had advanced stage disease.

Conclusions: Our study suggests that Mitchell’s MRI staging for Avascular necrosis involving head of femur may have prognostic significance and Mitchell’s MRI staging may be used in surgical decision making (joint preservation versus joint replacement).

Keywords: Avascular Necrosis, AVN staging, Mitchell staging, Ficat-Arlet staging, femur head

INTRODUCTION

Avascular necrosis, also referred to as aseptic necrosis, osteonecrosis or ischemic necrosis is used to indicate cellular necrosis of bone and marrow elements.1, 2 The term “avascular necrosis” is used to refer to these changes when they occur in the epiphyseal region or subchondral bone.1 Osteonecrosis of the femoral head is a disabling clinical entity that usually leads to destruction of the hip joint.3 A number of joint salvag-ing treatment options are available if early diagnosis can be achieved, replacement of the hip joint is the last resort for pain relief and function.3 Although bone scintigraphy using single photon emission computed tomography (CT) may be nearly as accurate as MRI, MRI offers a more specific diagnosis in the patient who presents with hip pain of uncertain etiology.4 The reactive interface between infarcted bone and viable bone could be identified on MRI as a low signal inten-sity band.5 On conventional radiographs the reactive interface appeared as a lucent zone on the plain films.5

The necrotic volume of hips with bone marrow oe-dema was significantly larger than those without bone

marrow edema.6 Joint preserving surgeries (such as core decompression) are performed in early (stage I/II) and joint replacement in advanced stages (stage III/ IV).7 The results of core decompression may be poor in general and may have an unpredictable effect on disease progression.8 A quantitative system for staging avascular necrosis may allow more accurate evaluation of progression or resolution and better comparision of different methods of management.9 It is most important to diagnose the disease as early as possible, to establish the prognosis before collapse and to chose effective measures to prevent progres-sion to painful arthritis.10,11 The extent and location of the necrotic portion as well as the Ficat stage can be used as predictors for the result of core decompres-sion in osteonecrosis of the femoral head.12,13 Because it is easily understood and clinically relevant, the Ficat classification is currently one of the most widely used classification scheme.14

The objective of the study was to stage avascular ne-crosis involving head of femur according to Ficat-Ar-let (using X-RAY and MRI features) and Mitchell



staging (using MRI features) and to study the correla-tion amongst the above mentioned staging systems. As preoperative staging for Avascular Necrosis of the femoral head is of utmost importance in deciding the management of the patients, studying the correlation between the commonly used classification systems may help the surgeon in deciding the surgical proce-dure as and when required.

METHODOLOGY

The retrospective study was carried out in New Civil Hospital, Surat, from July to November 2016, involv-ing thirty subjects, first thirty cases of Avascular Ne-crosis of Femur Head with both X-RAY and MRI rec-ords were included in the study, there was no direct communication with the subjects and no interven-tions were carried out as per the guidelines of the eth-ical committee. X-RAY and MRI images of thirty pa-tients having Avascular Necrosis of femur head (23-bilateral and 7-unilateral) were studied retrospectively and findings were noted down as present /absent in the following format. Plain films- usually anteroposte-rior (AP) and frog lateral views, are used in staging AVN.

X-RAY features in Avascular Necrosis involving head of femur include Osteoporosis, Sclerosis, Sub-chon-dral radiolucent line due to sub-chondral bone frac-ture - Crescent sign, Sub-chondral cystic changes, Loss of spherical weight bearing dome, Partial col-lapse of head & Secondary osteoarthritis.15

MR Imaging : Imaging protocols for evaluation of pa-tients with AVN include T1- or PD-weighted images and contrast-enhanced T1- weighted fat-suppressed images, a T1-weighted axial localizer and coronal im-ages are acquired with either a T1- and T2-weighted spin-echo sequence, an FS PD FSE sequence, or a STIR (FSE STIR) sequence, sagittal plane imaging may be helpful in defining early changes of cortical flattening associated with subchondral collapse, STIR sequences, which negate yellow marrow–fat signal, provide excellent contrast for the detection of marrow replacement, fluid, and necrotic tissue. 1

General MR characteristics of AVN include the fol-lowing:

A hypointense peripheral band (primarily granula-tion tissue and to a lesser extent sclerosis) outlining a central region of bone marrow represents the re-active interface between necrotic and reparative zones, as seen on T1-weighted images. 1

There may be associated bone marrow edema of head and neck of the femur. 1

A joint effusion may be seen and is hypointense on T1- weighted images and hyperintense on FS PD FSE images. 1

A wedge-shaped subchondral infarct may also be seen. FS PD FSE images allow further characteriza-tion of AVN, but determination of the percentage of femoral head volume involved requires the use of at least two imaging planes. In the double-line sign there is a combination of a hypointense periph-eral border (sclerosis) and a hyperintense inner bor-der (granulation tissue) visualized on FS PD FSE images. AVN may exist in the absence of a double-line sign. Hyperintense effusion and marrow edema require characterization with FS PD FSE se-quences.1

All the affected hip joints were staged according to ‘FICAT-ARLET’ system using X RAY and MRI fea-tures and clinical symptoms and according to Mitch-ell’s staging using type of MRI signal in the necrotic core. Data was tabulated in a series of tables, graphs and charts. Correlation amongst the above staging sys-tems was studied. Fischer’s exact test was used to compute a P value and to see statistical significance.

Table 1: Ficat-Arlet system uses a combination on plain radiograph and MRI features1, 16

Stage X-RAY MRI

0 Normal Normal I Normal or minor osteopenia Edema II Mixed osteopenia and/or sclerosis

and/or subchondral cysts, without any subchondral lucency (crescent sign)

Geo-graphic defect

III Crescent sign and eventual cortical col-lapse

Same as x-ray

IV End stage with evidence of secondary degenerative change

Same as x-ray

Table 2: Mitchell MRI staging based on the sig-nal characteristics of the necrotic core 1, 16

Class T1 T2 Definition

A Bright Intermediate “fat” signal B Bright Bright “blood” signal C Intermediate Bright “fluid” or “edema” signal D Dark Dark “fibrosis” signal

Selection and description of participant: First thirty cases from the month of July – 2016 with both X-RAY and MRI records were included in the study.

RESULTS

A total of thirty patients were included in the study. Twenty three patients were males and seven were fe-males. Twenty three patients had bilateral disease and seven patients had unilateral disease. Total numbers of positive hip joints were 53. All the affected hip joints were staged according to ‘FICAT-ARLET’ sys-tem using X-RAY and MRI features. All the patients were also staged according to Mitchell’s staging using



type of MRI signal in the necrotic core. Seven patients had unilateral affection. Out of the rest 23 patients who had bilateral affection, 15 had unilateral com-plaints and the contralateral hip joint findings were in-cidental. Seven patients had underlying sickle cell dis-ease, two patients were in renal failure, two patients were post traumatic, while a cause could not be found in the rest of the patients.

Table 3: Predisposing factors for AVN (n=30)

Predisposing Factors No. (%)

Sickle Cell Disease 5 (16.67) Trauma 2 (6.67) Renal Failure 2 (6.67) Unknown 21 (70.0)

Out of seven patients with unilateral disease, none had stage I disease, two had stage II and stage III disease each and three had stage IV disease. Five out of the patients who had unilateral disease, had advanced dis-ease at presentation (Stage III and IV).

Fischer’s exact test was used to compute a P value. The two-tailed P value was less than 0.0001 and the association of Stage I-II with Mitchell’s Class A was found extremely statistically significant. Similarly, the association of Stage III-IV with Mitchell’s class B/C was also found statistically significant. 29/36 (approx-imately 75 %) affected joints with early stage disease (stage I or stage II) had class A signal on MRI. 14/17 (approximately 82%) affected joints with advanced stage disease (Stage III or stage IV) had class B or class C signal on MRI. 12/16 (75 %) hips with Ficat-Arlet stage I are Mitchell class A. 17/23 (73.9 %) hips with Ficat-Arlet stage II are Mitchell class A. 5/7 (71.4 %) hips with Ficat-Arlet stage III are Mitchell class B. 4/7 (57.1 %) hips with Ficat-Arlet stage IV are Mitchell class C. Mitchell class D shows no correlation with Fi-cat-Arlet stages. Most class A joints (29/30) are either Ficat-Arlet stage I or II. Most class B or C joints are either Ficat-Arlet stage III or IV.

Out of the five patients with sickle cell disease, four had bilateral disease and one had unilateral disease. Three patients with bilateral disease had stage I or stage II disease and most of the hip joints affected had class A signal on MRI. Other two patients had ad-vanced stage of disease (Stage IV) and the affected hip joints had class B or class C signal on MRI. All the affected hip joints in sickle cell patients with Class A MRI signal had early stage of disease (Stage I or II) and most of the affected joints with class B or class C signal had advanced disease (Stage IV).

Table 4: Correlation between FICAT-ARLET and Mitchell MRI staging (N=56) FICAT-ARLET

Stage

No. (%) Mitchell’s MRI

class

No. (%)

Stage I Stage A

A 12 (22.64) I 12 (22.64)

B 0 II 17 (32.07)

C 1 (1.89) III 1 (1.89)

D 3 (5.66) IV 0

Sub – Total 16 (30.19) Sub – Total 30 (56.60)

Stage II Stage B

A 17 (32.07) I 1 (1.89)

B 2 (3.77) II 1 (1.89)

C 1 (1.89) III 5 (9.43)

D 0 IV 2 (3.77)


Stage III Stage C

A 1 (1.89) I 1 (1.89)

B 5 (9.43) II 1 (1.89)

C 3 (5.66) III 3 (5.66)

D 1 (1.89) IV 4 (7.55)


Stage IV Stage D

A 0 I 3 (5.66)

B 2 (3.77) II 0

C 4 (7.55) III 1(1.89)

D 1 (1.89) IV 1 (1.89)


Table 5: Correlation between Ficat-Arlet and

Mitchell MRI staging in Sickle Cell Disease pa-

tients (N=9)

FICAT-ARLET Stage

No. (%) Mitchell’s MRI class

No. (%)

Stage I Stage A A 3 (33.33) I 3 (33.33) B 0 II 1 (11.11) C 0 III 0 D 1 (11.11) IV 0 Sub –Total 4 (44.44) Sub – Total 4 (44.44)

Stage II Stage B A 1 (11.11) I 0 B 0 II 0 C 1 (11.11) III 0 D 0 IV 1 (11.11) Sub – Total 2 (22.22) Sub - Total 1 (11.11)

Stage III Stage C A 0 I 0 B 0 II 1 (11.11) C 0 III 0 D 0 IV 2 (22.22) Sub – Total 0 Sub – Total 3 (33.33)

Stage IV Stage D A 0 I 1 (11.11) B 1 (11.11) II 0 C 2 (22.22) III 0 D 0 IV 0 Sub – Total 3 (33.33) Sub – Total 1 (11.11)

DISCUSSION

Class A signal in the necrotic core on MRI is associ-ated with early stages of disease while class B or class C signal in the necrotic core is associated with ad-vanced stage of disease.



Mitchell DG, Rao VM, Dalinka MK, Spritzer CE, ALAvI AB, Steinberg ME, Fallon MI, Kressel HY also produced similar results, in their study the central region within the rim was isointense with marrow fat on both T1W and T2W sequences in 20 (71%) of 28 lesions uncomplicated by fracture (stages I-II) but in only four (14%) of 28 stage III-IV lesions.17

Mitchell DG, Steinberg ME, Dalinka MK, Rao VM, Fallon M, Kressel HY also produced similar results, in their study the reactive interface between live and dead bone at the periphery of AVN lesions had a char-acteristic MRI appearance that facilitated diagnosis. Lesions that were isointense with fat on both the se-quences had an earlier roentgenographic stage and less severe symptoms than did lesions that were less in-tense than fat.18

Possible explanation for the similar results is that MRI provides pathophysiologic information that is differ-ent from information obtained from conventional methods.

Our study suggests that Mitchell’s MRI staging for Avascular necrosis involving head of femur may have prognostic significance and Mitchell’s MRI staging may be used in surgical decision making (joint preser-vation versus joint replacement).

CONCLUSION

Most of the Ficat-Arlet stage I and stage II joints had Class A signal on MRI and most of the Ficat-Arlet stage III and stage IV joints had class B or class C sig-nal on MRI.

Most of the affected joints with class A signal in the necrotic core had early stage disease while those with class B or class C signal had advanced stage disease.

Thus, class A signal in the necrotic core is mostly as-sociated with early stage disease while those with class B or class C signal are associated with advanced stage disease.

Hence Ficat-Arlet and Mitchell’s MRI classes may be used in deciding the treatment plan (joint preservation v/s joint replacement) in a patient.

REFERENCE

1. Stoller DW, Sampson T, Bredella M. Magnetic Resonance Imaging in Orthopaedics and Sports Medicine, 3rd ed. Phila-delphia: Lippincott Williams & Wilkins; 2007. p. 121-134.

2. Arlet J. Atraumatic necrosis of the femoral head: general re-port. InBone circulation and vascularization in normal and pathological conditions 1993 (pp. 235-240). Springer US.

3. Malizos KN, Karantanas AH, Varitimidis SE, Dailiana ZH, Bargiotas K, Maris T. Osteonecrosis of the femoral head: eti-ology, imaging and treatment. European journal of radiology. 2007 Jul 31;63(1):16-28.

4. Bluemke DA, Zerhouni EA. MRI of avascular necrosis of bone. Topics in Magnetic Resonance Imaging. 1996 Aug 1;8(4):231.

5. Beltran J, Burk JM, Herman LJ, Clark RN, Zuelzer WA, Freedy MR, Simon S. Avascular necrosis of the femoral head: early MRI detection and radiological correlation. Mag-netic resonance imaging. 1987 Jan 1;5(6):431-42.

6. Ito H, Matsuno T, Minami A. Relationship between bone marrow edema and development of symptoms in patients with osteonecrosis of the femoral head. American Journal of Roentgenology. 2006 Jun;186(6):1761-70.

7. Beltran, Javier, et al. "Core decompression for avascular ne-crosis of the femoral head: correlation between long-term re-sults and preoperative MR staging." Radiology 175.2 (1990): 533-536.

8. Markel DC, Miskovsky C, Sculco TP, Pellicci PM, Salvati EA. Core decompression for osteonecrosis of the femoral head. Clinical orthopaedics and related research. 1996 Feb 1;323:226-33.

9. Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular necrosis. Bone & Joint Journal. 1995 Jan 1; 77(1):34-41.

10. Arlet J. Nontraumatic Avascular Necrosis of the Femoral Head: Past, Present, and Future. Clinical orthopaedics and related research. 1992 Apr 1;277:12-21.

11. Steinberg ME. Diagnostic imaging and the role of stage and lesion size in determining outcome in osteonecrosis of the femoral head. Techniques in Orthopaedics. 2001 Mar 1;16(1):6-15.

12. Seiler JG, Christie MJ, Homra L. Correlation of the findings of magnetic resonance imaging with those of bone biopsy in patients who have stage-I or II ischemic necrosis of the fem-oral head. J Bone Joint Surg Am.1989 Jan 1;71(1):28-32.

13. Yoon TR, Song EK, Rowe SM, Park CH. Failure after core decompression in osteonecrosis of the femoral head. Inter-national orthopaedics. 2001 Feb 1;24(6):316-8.

14. Incavo SJ, Pappas CN. Diagnosis and classification of avas-cular necrosis of the hip. InSeminars in Arthroplasty 2004 Jul 31 (Vol. 15, No. 3, pp. 140-144). WB Saunders.

15. Radiographic Findings in Avascular Necrosis (AVN) of the Femoral Head. Available at: http://eradiology.bidmc.har-vard.edu/LearningLab/musculo/Prabhakar.pdfAccessed on Dec 10, 2016

16. Berquist TH. MRI of the Musculoskeletal System, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 238-58

17. Mitchell DG, Rao VM, Dalinka MK, Spritzer CE, ALAvI AB, Steinberg ME, Fallon MI, Kressel HY. Femoral head avascular necrosis: correlation of MR imaging, radiographic staging, radionuclide imaging, and clinical findings. Radiol-ogy. 1987 Mar;162(3):709-15.

18. Mitchell DG, Steinberg ME, Dalinka MK, Rao VM, Fallon M, Kressel HY. Magnetic Resonance Imaging of the Is-chemic Hip: Alterations Within the Osteonecrotic, Viable, and Reactive Zones. Clinical orthopaedics and related re-search. 1989 Jul 1;244:60-77.



ORIGINAL ARTICLE

MICROBIOLOGIC SPECTRUM OF ACUTE AND CHRONIC DACRYOCYSTITIS Abha Gahlot1, Shashi Prasad1, Manisha Singh2, Bhargav Kotadia3, Saloni Garg4 Author’s Affiliations: 1Professor, 2Senior Resident, 3Junior Resident, 4Intern, Dept. of Ophthalmology, D.Y. Patil Medical College, Pune Correspondence: Dr Manisha Singh Email: [email protected]

ABSTRACT

Introduction: The aim of this study is to report the microbiological spectrum of dacryocystitis and the antibi-otic sensitivity patterns of the organisms. It was a prospective study done at Department of Ophthalmology, Dr. D. Y. Patil Medical College and Hospital, Pimpri, Pune in 2015 on 42 cases of dacryocystitis.

Methodology: Patients were diagnosed with dacryocystitis and on the presence of a pus-filled lacrimal sac and peri lacrimal tissues for acute dacryocystitis. Chronic dacryocystitis patients were diagnosed by ROPLAS Test and sac syringing and were reviewed for demographic and microbiological profile.The culture results, organisms isolated, and their antibiotic sensitivity were studied.

Results: In this study 42 clinical samples were evaluated, among them 33(78.5%) were culture positive and rest were reported as no growth 9(21.5%). Among all positive growth, Staphylococcus aureus encountered as the commonest isolate (56%) followed by Streptococcus pneumoniae (2%) among the Gram-positive organisms .In the Gram-negative organisms, Escherichia coli (23%) followed by Pseudomonas aeruginosa (17%) was seen. Gram-positive organisms were commonly sensitive to flouroquinolones, penicillins and vancomycin whereas gram-negative organisms were sensitive to aminoglycosides.

Conclusion: Gram-positive and Gram-negative organisms were predominant in this study. The result has sig-nificant bearing on the treatment of patients and also when mass cataract surgeries are being performed.

Keywords: Epiphora, Dacrocystitis, Bacteriology INTRODUCTION

The mucosa of the lacrimal sac is known to be very resistant to infection. However, this resistance is com-promised by distal obstruction of the nasolacrimal duct1 and causes infection of the lacrimal sac. Dacro-cystitis might present in two forms. Acute dacryocys-titis is an acute inflammation of the lacrimal sac and presents as tenderness and erythema of the overlying tissues and 23% of eyes might present with lacrimal abscess1,2. Chronic dacryocystitis is not only more common than acute dacryocystitis but also has several stages of presentation like epiphora, mucoid dis-charge, conjunctival hyperaemia and chronic conjunc-tivitis1. This different presentation may be because of geographical variation in the microbiology of acute and chronic dacryocystitis and also different nasal pa-thologies which seem to play a crucial role in develop-ing dacryocystitis.3,4

There has been growing noise about changing trends in the microbiologic spectrum of dacryocystitis and where initial studies have shown Gram positive iso-lates predominantly in most studies, some recent stud-ies suggested an increasing frequency in gram negative organisms.5

Knowledge of the presence of nasolacrimal obstruc-tion and the potential organisms inoculated is there-fore of paramount importance before planning any in-traocular procedure because of the potential risk of endophthalmitis especially in a country like India where we still need to fill a huge lacunae in the number of cataract surgeries.

METHODOLOGY

This is a prospective study and we included patients with acute and chronic dacryocystitis who underwent microbiological evaluation presenting between 1st May 2015 to 30th June,2015 at Dr D Y Patil Medical Col-lege, Pimpri,Pune.

The study was performed with the agreement of ethics committee and in accordance with the ethical guide-lines of the hospital. Written informed consents were obtained from all participants.

Patients were examined by an ophthalmologist, and cases of dacryocystitis were identified and categorized as acute or chronic, based on their history, signs and symptoms. Acute dacryocystitis was diagnosed in pa-tients with pain, redness, and swelling in the lacrimal sac area(Fig1). Chronic dacryocystitis was diagnosed



in patients with persistent epiphora and regurgitation of mucoid or mucopurulent material on pressure over the sac area or during irrigation of the lacrimal drain-age system.

All cases of pseudoepiphora and epiphora caused by diagnoses other than nasolacrimal duct obstruction, patients with any history of previous infection, maxil-lofacial surgery, or maxillofacial trauma and the pa-tients who had received any topical or systemic anti-biotics for the past one week during their visit to the hospital were excluded.

Procedure of Sample Collection: The collection of the samples was performed by applying pressure over the lacrimal sac and allowing the purulent material to reflux through the lacrimal punctum, or by irrigating the lacrimal drainage system with sterile saline and col-lecting the sample from the refluxing material. The samples were collected with sterile cotton wool swabs, ensuring that the lid margins or the conjunctiva were not touched(Fig 2). The first swab was used for Gram staining and potassium hydroxide mount and second was immediately inoculated into culture media like blood agar, chocolate agar, MacConkey, Nutrient agar, Sabaurauds Dextrose Agar(Fig 3). Blood agar and chocolate agar were incubated at 37°C, while SDA was incubated at 25°C. The plates were observed daily for the presence of any growth up to 7d. The isolated organisms were identified by using standard procedures. Colony characteristic was noted down. Gram staining was done to identify whether the or-ganism grown was Gram-positive or Gram-negative. The organisms were further identified to genus and species level depending on motility and biochemical reaction. Also antibiotic susceptibility testing was done.

Antimicrobial Susceptibility Tests: The standard-ized Kirby-Bauer disc diffusion test of the Clinical and Laboratory Standards Institute was used for testing. The media used was Muelle rHinton agar for non-fas-tidious organisms. 5% Sheep Blood agar was added to Mueller-Hinton agar for fastidious organism and it was read after 16-18 hours. Inoculum turbidity was adjusted to 0.5 McFarland turbidity tube. A lawn cul-ture was made on the surface of medium using sterile cotton swabs and antimicrobial discs were applied. The plates were incubated for 18-24 hours for non-fastidious and under 5% CO2 for 24-48 hours at 37 degree Celsius for fastidious organisms. The zone of inhibition was measured and reported as susceptible or resistant. For detection of Methicillin resistant Staphylococcus aureus, oxacillin disc (10 microGram) was used on Mueller-Hinton agar containing 2% so-dium chloride.

Statistical Analysis: Chi-square (χ2) distribution was used to test the qualitative distribution. A pvalue <0.05 was considered as a significant association be-tween the variables which were tested.

RESULTS

The result depicts that majority of cases were in age group of 50-60 years followed by 40-50 and 60-70 i.e. 45.23%,38.11%, 16.66% respectively.(Table 1)

Table 1: Age wise distribution of study partici-pants (N=42)

Age(years) No.(%)

40-50 16 (38.11) 50-60 19 (45.23) 60-70

7 (16.66)

It was observed that females 27(64.3%) were more af-fected than males 15 (35.7%). Out of 42 patients, 33(78.6%) had positive growth and 9(21.4%) had no growth. Out of 33 positive isolates, 21(63.63%) were Gram-positive and 12(36.36%) were Gram-negative.

Table 2: Growth Pattern wise distribution of cases in study group (N=42)

Growth No. (%)

Yes 33 (78.6) Gram Positive 21 (50.0) Gram Negative 12 (28.6)

No 9 (21.4)

Table 3 shows that most common organism isolated was staphylococcus aureus ,positive 18cases(55%), followed by E. Coli positive in 7 cases(21%), followed by Pseudomonas aeruginosa positive in 5 cases(15%), followed by streptococcus pneumonia positive in 3 cases(9%)

Table 3: Percentage of organisms isolated (N=33)

Organism Isolated No. (%)

Staphylococcus Aureus 18 (55) Escherichia Coli 7 (21) Pseudomonas Aeruginosa 5 (15) Streptococcus Pneumoniae 3 (9)

DISCUSSION

DACRYOCYSTITIS is an infection of lacrimal sac secondary to obstruction of nasolacrimal duct. In our study majority of patients were in the age group of 50-60(43.2%) followed by 40-50(38.2%), and 60-70(16.6%). Madhusudhan et al 6 2005-10 had an av-erage age of 46.5 years in their study. Prakash R. et al 7 in 2012 studied 86 patients of both congenital and acquired dacryocystitis. Of 86 patients majority (35%) were in the age group of 4-60 years, of which most were in between ages 31-45years.



Table 4: shows the noted antibiotic sensitivity pattern of isolates

Antibiotic Staphylococcus Aureus

Escherichia Coli

Pseudomonas Aeruginosa

Streptococcus Pneumoniae

Total

Ciprofloxacin(5mcg/disc) 14 2 1 17 Cefuroxime 10 1 11 Gentamycin(10mcg/disc) 4 1 3 3 11 Erythromycin(15mcg/disc) 7 1 8 Cotrimazole(25mcg/disc) 6 6 Ofloxacin (5mcg/disc) 1 1 2 Azithromycin(15mcg/disc) 0 Amikacin(30mcg/disc) 2 1 1 1 5 Cefotaxim(30mcg/disc) 1 1 Vancomycin(30mcg/disc) 7 2 9 Clindamycin(2mcg/disc) 10 2 1 13 Amoxycillin(20/10mcg/disc) 0 Oxacillin(1mcg/disc) 5 5 Imipenem(10mcg/disc) 4 2 6 CAT(30/10mcg/disc) 5 4 9 Norfloxacin(5mcg/disc) 1 1 2 Ampicillin(10mcg/disc) 1 1 2 CAC(30/10mcg/disc) 2 1 3

Total 66 17 16 11 110

Table 5: Resistance pattern of Bacteriological isolates

Antibiotic Staphylococcus Aureus

Escherichia Coli

Pseudomonas Aeruginosa

Streptococcus Pneumoniae

Total

Ciprofloxacin 4 1 5 Cefuroxime 8 5 2 15 Gentamycin 1 3 4 Erythromycin 10 10 Cotrimoxazole 1 1 2 Ofloxacin 1 2 3 Azithromycin 0 Amikacin 1 1 Cefotaxim 1 1 Vancomycin 0 Clindamycin 5 1 1 7 Amoxycillin 1 1 Oxacillin 9 1 10 Imipenem 1 1 CAT 1 1 Norfloxacin 3 1 4 Ampicillin 1 1 2 CAC 1 1 2 4

Total 42 18 7 4 71

Our study is more or less comparable to theirs having 38.2% of cases under the age group of 40-50 years. Slight variation maybe due to the geographical and liv-ing conditions of the patients and their occupation. The study was predominant by female subjects (64.3%) as compared to male subjects (35.7%). The female to male ratio was 1.8:1 which correlated with the findings of Assefa et al in which the female pre-ponderance was 62.7%.

In the present study chronic dacryocystitis was the most frequently encountered clinical type (76.2%) fol-lowed by acute dacryocystitits (23.8%) and no case of congenital dacryocystitis. This was probably because of limitation of time and lower incidence of congenital dacryocystitis. This was more or less similar to the

study carried out by Prakash et al 7 in which 63.7% cases were of chronic dacryocystitis followed by 25% of acute dacryocystitis and 11.25% of congenital dacryocystitis. The most common Gram-positive or-ganisms isolated worldwide include Staphylococcus aureus (worldwide), Streptococcus pneumoniae (Af-rica), and S. epidermidis (USA). Among the Gram-negative isolates, there is a variable predominance like that of Haemophilus influenzae (Middle East), Pseu-domonas aeruginosa (North India and USA), Esche-richia coli (Europe), and Corynebacterium diphtheriae (China). Sun et al.8 from China and Brook and Frazier 9 from USA, although reported Staphylococcus isola-tion as the most common, however, found fungus in



8% (n = 100) and 5% (n = 62) of their isolates, re-spectively. With Staphylococcus aureus being the commonest isolate across most studies, focus has been on the increasing incidence of community-ac-quired methicillin-resistant Staphylococcus aureus and the challenges it is likely to post in the future in terms of antibiotic resistance and treatment. Microbiologic spectrum of acute dacryocystitis has been studied in 23 patients by the American Society of Ophthalmic Plastic and Reconstructive Surgery ASOPRS 10, and it was found that 78.3% of the isolates were Gram-pos-itive and 21.7% were Gram-negative. Among the Gram-positive isolates, Staphylococcus aureus was the most common organism noted, accounting for 50% of all the Gram-positive isolates. Among the Gram-negative organisms, there was no preponder-ance of any organism with equal incidence of isolates of Pseudomonas aeruginosa, Fusobacterium, and Stenotrophomonas maltophilia.

In our study 42 clinical samples were evaluated, among them 33(78.5%) were culture positive and rest were reported as no growth 9(21.5%). Among all pos-itive growth, Staphylococcus aureus encountered as the commonest isolate (56%) followed by Streptococ-cus pneumoniae (2%) among the Gram-positive or-ganisms and in the Gram-negative organisms, Esche-richia coli (23%) followed by Pseudomonas aeru-ginosa (17%). As it has been also common in many of similar studies, Gram-positive bacteria accounted for higher isolation rate (63.3%) with comparability of Kebede et al. 11 reported in Addis Ababa, Ethiopia which showed 62.6% Gram-positives and 37.4% Gram-negatives and Prakash et al. 2 which showed of 94 isolates, 61 (64.89%) were Gram-positive organ-isms and 33 (35.11%) were Gram-negative organisms. Interestingly, the current findings and previous re-ports by Kebede et al. were also in line with most sim-ilar studies.11,12 However, unlike the ASOPRS group, our Gram-negative profile was very different with Escherichia coli and Pseudomonas aeruginosa, ac-counting for 23% and 17% of all the Gram-negative isolates, respectively (n=12).

The antibiotic susceptibility pattern varies from region to region community. This is because of emergence of resistant strains as a result of indiscriminate use of an-tibiotics. In our study most of the isolates of Staphy-lococcus aureus were sensitive to ciprofloxacin (82.9%), followed by cefuroxime (60.9%) and clindamycin (58.5%). In case of Streptococcus pneu-moniae, gentamycin shows highest sensitivity (100%) followed by vancomycin (66.6%). The sensitivity among Escherichia coli were highest for ceftazidime-tazobactum (CAT) (70.1%), followed by imipenem (64.1%). Most of the isolates of Pseudomonas aeru-ginosa showed utmost sensitivity to ceftazidime-tazo-bactum (CAT) (80%) followed gentamycin (60%).

Unexpectedly a single isolate was resistant to Amox-ycillin and Ampicillin, as a result, the emergence of amoxicillin and ampicillin resistance Staphylococcus aureus in this teaching hospital may pose therapeutic problems, and therefore the empirical antibiotic treat-ment should be avoided and rather performing anti-microbial susceptibility testing is highly needed.

In this study, the limitations were time and the num-ber of patients. For better outcome, a larger study population should be undertaken for a longer period of time, to know the microbiology and to select effec-tive drugs of choice for dacryocystitis.

REFERENCES

1. Ali MJ, Joshi SD, Naik MN, Honavar SG. Clinical profile and management outcome of acute dacryocystitis: two dec-ades of experience in a tertiary eye care center. Semin Ophthalmol. 2015 Mar;30(2):118-23.

2. Ali MJ, Motukupally SR, Joshi SD, Naik MN. The microbio-logical profile of lacrimal abscess: two decades of experience from a tertiary eye care center. J Ophthalmic Inflamm Infect. 2013;3(1):57.

3. Mills DM, Bodman MG, Meyer DR, Morton AD., 3rd ASOPRS dacryocystitis study group The microbiologic spec-trum of dacryocystitis: a national study of acute versus chronic infection. Ophthal Plast Reconstr Surg. 2007;23(4):302–306.

4. Bharathi MJ, Ramakrishnan R, Maneksha V, Shivakumar C, Nithya V, Mittal S. Comparative bacteriology of acute and chronic dacryocystitis. Eye (Lond) 2008;22(7):953–960.

5. Chaudhry IA, Shamsi FA, Al-Rashed W. Bacteriology of chronic dacryocystitis in a tertiary eye care center. Ophthal Plast Reconstr Surg. 2005;21(3):207–210.

6. Madhusudhan, Yanti Muslikan, Nabilah Ismail, Adil Hussein. Microbiological aetiology of acute dacryocystitis Sains Malay-sia, Kelantan Malaysia. Journal of Acute Disease (2012):31-34

7. Prakash R., Girish Babu R.J., Nagaraj E.R., Prashanth H.V., JayashreeS. Shah A Bacteriological Study of Dacryocystitis Journal of Clinical and Diagnostic Research. 2012 May (Suppl-2), Vol-6(4): 652-655

8. Sun X, Liang Q, Luo S, Wang Z, Li R, Jin X. Microbiological analysis of Chronic dacryocystitis. Ophthalmic Physiol Opt. 2005 May;25(3):261-3.

9. Brook I, Frazier EH. Aerobic and anaerobic microbiology of dacryocystitis.. Am J Ophthalmol 1998; 125(4): 12.

10. Mills DM, Bodman MG, Meyer DR, Morton AD 3rd, ASOPRS Dacryocystitis Study Group. The microbiologic spectrum of dacryocystitis: a national study of acute versus chronic infection. Ophthalmic Plast Recon-strSurg.2007;23(4):302–6

11. Kebede A, Adamu Y, Bejiga Y. Bacteriological study dacryo-cystitis among patients attending in Menelik Hospital, Addis Ababa, Ethiopia. Ethiop Med J. 2010 Jan; 48(1):2933 13.

12. Mandal R, Banerjee AR, Biswas MC, Mondal A, Kundu PK,

Sasmal NK. Clinicobacteriological study of chronic dacryo-

cystitis in adults. J Indian Med Assoc. 2008;106(5):296–8



ORIGINAL ARTICLE

ATTENUATION OF HAEMODYNAMIC RESPONSE DURING LARYNGOSCOPIC INTUBATION WITH FENTANYL Dinesh Thakur1, Nirav S. Chauhan2, Rahul Ramchandani3, Himanshu shah2 Author’s Affiliations: 1Associate Professor, 3Resident, Dept. of Anesthesiology, GMERS Medical College Sola, Ahmed-abad;2Consultant, Ahmedabad, Gujarat Correspondence: Dr Dinesh Thakur Email: [email protected]

ABSTRACT

Introduction: Identified as a depth-of-anesthesia-dependent influencing factor, endotracheal intubation has been suggested to be one of the most invasive stimuli in anesthesia, particularly during induction3 and after tracheal intubation. The objective of the study was to find a safe and effective means of attenuating the cardio-vascular response to laryngoscopy and tracheal intubation.

Methodology: S.A.L Hospital and Medical institute and KESAR SAL Medical College and Research Institute, Ahmedabad during 2008-2010 in 100 patients, divided in two groups having 50 patients in each group. One group received intravenous fentanyl while other group termed as control group received intravenous normal saline. The following hemodynamic variables were considered for study: changes in heart rate and comparison of the controlled group with the group who received fentanyl; & changes in systolic arterial pressure and dias-tolic arterial pressure in the fentanyl treated group in comparison to the control group.

Results: At induction both the groups were observed to have a 5% decrease in heart rate in comparison to basal levels. At intubation, however, the fentanyl group had a highly significant mean heart rate at 12% below the control group (P≤0.0001). Highly significant attenuation of systolic blood pressure was observed in the fentanyl group with a 10% average lower value than the control over all measured points. As with SBP, high attenuation of the DBP pressor response to intubation in the fentanyl group was observed at all measured times – on average 10% greater attenuation than the control group.

Conclusion: In conclusion, fentanyl attenuated the cardiovascular response to laryngoscopy & intubation, and was more effective in attenuating these responses. DBP was maintained in the fentanyl group. No patient man-ifested any ischemic ECG changes so fentanyl is safe in patients of ASA physical status I/II.

Keywords: Laryngoscope, Tracheal Intubation, Fentanyl, Systolic Blood Pressure, Diastolic Blood Pressure

INTRODUCTION

Identified as a depth-of-anesthesia-dependent influ-encing factor1, endotracheal intubation has been sug-gested to be one of the most invasive stimuli in anes-thesia2, particularly during induction3 and after tra-cheal intubation.3,4

Significant changes in blood pressure and heart rate are known to occur during laryngoscopy and tracheal intubation5 following induction of anaesthesia. The exact mechanisms of the pressor response are not known, but have been associated with both sympa-thetic2,4 and parasympathetic responses4, which may include symptoms such as increased plasma catechol-amine concentrations6,7, increased blood pressure and increased heart rate.

The methods to attenuate the response to the reflex stimulus of laryngoscopy and intubation have in-

cluded Deep anaesthesia with intravenous / inhala-tional agents; Topical / I.V. lignocaine8; Narcotics, in-travenous / topical vasodilators; and Adrenergic blockers and calcium channel blockers.4

The objective of the study was to find a safe and ef-fective means of attenuating the cardiovascular re-sponse to laryngoscopy and tracheal intubation.

METHODOLOGY

Following institutional approval by the ethical com-mittee at S.A.L. Hospital and Medical Institute, Ah-medabad (Gujarat, India) informed consent to partic-ipate in this study was obtained from 100 patients. The study population consisted of randomly selected ASA physical status I/II, male/female adults between the ages of 20 and 60 years, scheduled for elective surgical procedures.



Patients having pre-existing systemic disorders, is-chemic heart disease, hypertensive heart disease, dia-betes mellitus, bronchial asthma, previous myocardial infarction, renal disease, cerebrovascular insufficiency or association with any co-morbid disease were ex-cluded from the study.

Each patient was randomly assigned to one of two double-blind study groups by closed enveloped method: the Fentanyl group received a single 2 μg/kg IV bolus in the round dose of 20μg/10kg of fentanyl diluted to 10 ml (20μg/ml) with normal saline 5 min prior17 to laryngoscopy and intubation (n=50) and the control group received the same volume of IV bo-lus of normal saline according to weight (n=50). Ob-server was not aware of the drug given. Heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded via a GE multi-channel monitor for each patient. Then baseline/be-fore induction HR, SBP and DBP levels were taken.

After recording baseline HR, SBP and DBP levels, the study drug (2 μg/kg of fentanyl diluted to 10 ml with normal saline) or the control placebo (10 ml normal saline) was administered by using double blind study and patients were pre-oxygenated for 5 min via a face-mask with Bain circuit. Patients were induced with Inj. Propofol 2mg/kg intravenously followed by succinyl-choline 1 mg/kg intravenously. Intermittent positive pressure ventilation with 100% 02 was given and at induction readings of HR, SBP and DBP were taken.

After the onset of complete relaxation, Laryngoscopy and Intubation were performed and at laryngoscopy readings of HR, SBP and DBP were taken. Upon bi-lateral, equal air entry confirmation, the endotracheal tube was fixed and the patients mechanically venti-lated using a Bain system. Following recovery from suxamethonium, atracuriumbesylate 0.5mg/kg was given intravenously for maintaining muscle relaxation and traces of inhalation anesthetic agent was contin-ued. Immediately after intubation at 1,2,3,4,5,10 and 15 minutes interval heart rate, systolic pressures and diastolic pressures were recorded. Any adverse clinical event occurring during the study period was recorded e.g. arrhythmia, cardiac arrest.

Statistical analysis: Statistical analysis of patient’s gen-der, age and weight for both the fentanyl and control groups are reported. Intra- and inter-group analysis for HR, SBP and DBP were statistically evaluated us-ing unpaired t-tests where P<0.05 was considered sig-nificant, and P<0.001 highly significant.

RESULTS

The mean age of the patients in Group 1 is 36.9 and in Group 2 is 36.1.The calculated P value is 0.68, which suggest that the observed difference is not sig-nificant at 95% confidence limit. It indicates the study

is age matched, and samples are drawn from the same population.

Table 1: Characteristics of study participants

Variable Group 1 Group 2

Age(yrs) 20-30 19 16 31-40 10 16 41-50 18 15 51-60 3 3 Age (Mean ± SD) 36.9 ± 10.4 36.1 ± 9.5

Gender Male 33 31 Female 17 19

Weight(kg) 40-50 3 5 51-60 26 25 61-70 21 20 Weight (Mean ± SD) 58.7 ± 4.6 58.3 ± 5.2

ASA Grade I 42 43 II 8 7

The mean age of the patients in Group 1 is 36.9 and in Group 2 is 36.1.The calculated P value is 0.68, which suggest that the observed difference is not sig-nificant at 95% confidence limit. It indicates the study is age matched, and samples are drawn from the same population.

There are 33 males and 17 females in Group 1 and 31 males and 19 females in Group 2. The calculated Chi square value is 0.043, which is not significant at 5% level of significance. It indicates that the study is sex matched and samples are drawn from the same popu-lation.

The mean weight of the patients is 58.7±4.6 kgs in Group 1 and 58.3±5.2 kgs in Group 2 as shown in Table 1. The calculated P values 0.684, which suggest that the observed difference is not significant at 95% confidence limit. It indicates the study is age matched, and samples are drawn from the same population.

ASA physical status I in Group 1 and Group 2 was 42 and 43 respectively, while ASA status II in Group 1 and Group 2 was 8 and 7 respectively. There was no statistical difference among both the groups, p value=0.78(>0.05) by Chi square test.

Table 2: Comparison of Basal vitals (mean)

Group HR SBP DBP SPO2

1 76.9±6.1 122.1±4.9 78.9±4.6 99.7±0.5

2 76.3±4.8 123.3±2.5 79.5±2.6 99.6±0.5

p-

Value

0.58 0.12 0.42 0.32



Table 3: Comparison of Heart rate, Systolic BP (SBP) and Diastolic BP (DBP) at different interval

Group Before induction

Induction Laryngoscopy and intubation

Intubation 1 min 2 min 3 min 4 min 5 min 10 min 15 min

Heart Rate (mean) 1 76.9 74.9 76.9 76.3 78.1 77.0 78.9 77.9 80.1 79.1 81.1 2 76.3 73.9 85.8 87.6 87.4 90.1 89.7 88.8 89.6 87.2 89.2 p –Value 0.57 0.36 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Percent difference between measured HR levels and basal values 1 0.00 -2.60 0.00 -0.78 1.56 0.13 2.60 1.30 4.16 2.86 5.46 2 0.00 -3.1 12.5 14.8 14.5 18.2 17.6 16.5 17.5 14.3 16.9

SBP (mean) 1 122.1 122.7 127.5 122.5 126.1 123.5 126.1 124.7 125.9 127.9 127.7 2 123.3 121.3 135.8 134.7 138.3 139.4 138.2 136.3 138.9 136.0 137.0 p-Value 0.11 0.21 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Percent difference between measured SBP levels and basal values 1 0.00 0.49 4.42 0.33 3.28 1.15 3.28 2.13 3.11 4.75 4.59 2 0.00 -1.62 10.1 9.21 12.1 13.0 12.1 10.5 12.6 10.2 11.1

DBP (mean) 1 78.9 80.1 81.3 79.5 81.7 79.9 82.1 83.3 81.5 79.9 80.5 2 79.5 77.5 84.7 84.1 87.7 90.0 88.8 87.3 87.7 90.4 85.9 p –Value 0.41 0.009 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Percent difference between measured DBP levels and basal values 1 0.00 1.52 3.04 0.76 3.55 1.27 4.06 5.58 3.30 1.27 2.03 2 0.00 -2.54 6.59 5.79 10.3 13.2 11.6 9.79 10.4 13.7 8.0

Attenuation of heart rate related hemodynamic re-sponse to tracheal intubation by a single 2 μg/kg bolus of fentanyl was observed at all measured time points. At induction both the groups were observed to have a 5% decrease in heart rate in comparison to basal lev-els. At intubation, however, the fentanyl group had a highly significant mean heart rate at 12% below the control group (P≤0.0001).

Further, significant attenuation was also observed at post intubation (P≤0.001), which was lower than the control value by 15%, 1 min after intubation by 12% (P≤0.001), 2 min after intubation by 18% (P≤0.0001), 3 min after intubation by 15% (P≤0.001),4 min after intubation by 15% (P≤0.0001), 5 min after intubation by 13% (P≤0.001), at 10 min post-intubation the fen-tanyl group was 12% lower than that of the control (P≤0.001) and at 15 min post-intubation the fentanyl group was 11% lower than that of the control (P<0.001).

Highly significant attenuation of systolic blood pres-sure was observed in the fentanyl group with a 10% average lower value than the control over all measured points. The difference between measured points at in-tubation was 8% decrease observed in the fentanyl group (P≤0.01), followed by a 10% difference at 1 min post-intubation (P≤0.001), 12% at 2 min (P≤0.001), 10% at 3 min (P≤0.001), 8% at 4 min (P≤0.01), 11% at 5 min (P≤0.001), 6% at 10 min (P≤0.01) and 7% at 15 min post-intubation (P≤0.001).

As with SBP, high attenuation of the DBP pressor re-sponse to intubation in the fentanyl group was ob-served at all measured times – on average 10% greater attenuation than the control group.

The attenuation was observed at 1 min post-intuba-tion with a 3% difference (P<0.04).This was preceded

by a 7% difference at 1 min (P=0.012), 12% at 2 min (P≤0.001), 7% at 3 min (P<0.01),4% at 4 min (P<0.04),7% at 5 min (P<0.01),12% at 10 min (P<0.001)and a 6% reduction at 15 min post-intuba-tion.

DISCUSSION

There is a substantial evidence that laryngoscopy and intubation is accompanied by a considerable increase in HR and BP4 and this hypertensive response has been shown to be due to a sympathomimetic dis-charge caused by stimulation of upper respiratory tract. These changes are usually of short duration and well tolerated by healthy patients but can cause many dangerous complications like left ventricular failure, acute myocardial infarction and cerebral haemorrhage especially in patients with cerebral and cardiovascular diseases.3 In principle, the response can be diminished or modified locally, centrally or peripherally and at-tempts have been made to accomplish this by using different approaches. 10

The use of beta adrenergic blocking drugs for the treatment of angina pectoris, HT and arrhythmias is now well established. It is a common practice in an-aesthesia to give increments of beta blockers9 to con-trol tachycardia intraoperatively in patients at risk for developing myocardial ischemia but there is a concern about the long duration of action of these drugs and other side effects like bronchospasm, hypotension etc.

The circulatory effect of laryngoscopy, both tachycar-dia and systemic hypertension are proportion to the duration of conventional endoscopy beginning at 15 and peaking at 45 seconds. The 30 second laryngos-



copy followed by intubation was chosen so that pro-tective measures could be adequately tested while not unduly endangering the patients in the control group.

At pre-induction, when fentanyl or the saline pla-cebo10 was administered, a significant difference be-tween fentanyl and the control group HR was not ob-served, but at intubation a 12% lower HR value11 was recorded for the fentanyl group. Over all measured points, the fentanyl group HR was 11% lower than the control.

Results of our study show that laryngoscopy and intu-bation resulted in significant increase in HR, SBP and DBP in control group which could be associated with critical increase in myocardial oxygen consumption. Despite these any ischemic ECG changes or any car-diac adverse events did not occur in any of our patient of control group because patients were healthy of physical status ASA I/II and myocardial perfusion was maintained. Fentanyl also has added advantage of analgesia during intra operative course. Fentanyl’s low economic cost and unique pharmacodynamic proper-ties make it still one of the best opioids at present to attenuate hemodynamic responses to endotracheal in-tubation with minimal side effects.

CONCLUSION

In conclusion, fentanyl attenuated the cardiovascular response to laryngoscopy & intubation, and was more effective in attenuating these responses. DBP was maintained in the fentanyl group. No patient mani-fested any ischemic ECG changes so fentanyl is safe in patients of ASA physical status I/II.

REFERENCE

1. Randell T. Hemodynamic responses to intubation: what more do we have to know? ActaAnaesthesiolScand 2004; 48: 393-5.

2. Kayhan Z, Aldemir D, Mutlu H. Which is responsible for the hemodynamic response due to laryngoscopy and endotra-cheal intubation? Catecholamines, vasopressin or angioten-sin? Eur J Anaesthesiol 2005; 22: 780-5.

3. Prys-Roberts C, Greene LT, Meloche R, Foëx P. Studies of anaesthesia in relation to hypertension. II. Hemodynamic consequences of induction and endotracheal intubation. Br J Anaesth 1971; 43: 531-47.

4. Kovac AL. Controlling the hemodynamic response to laryn-goscopy and endotracheal intubation. J ClinAnesth 1996; 8: 63-79.

5. Hung O. Understanding hemodynamic responses to tracheal intubation. Can J Anaesth 2001; 48: 723-6.

6. Ebert JP, Pearson JD, Gelman S, Harris C, Bradley EL. Cir-culatory responses to laryngoscopy: the comparative effects of placebo, fentanyl and esmolol. Can J Anaesth1989; 36: 301-6.

7. Reid LC, Brace DE. Irritation of the respiratory tract and its reflex effect upon the heart. SurgGynecolObstet 1940; 70: 157-62.

8. Malde AD, Sarode V. Attenuation of the hemodynamic re-sponse to endotracheal intubation: fentanyl versus ligno-caine. The Internet Journal of Anesthesiology 2007; 12.

9. Helfman SM, Gold MI, DeLisser EA, Herrington CA. Which drug prevents tachycardia and hypertension associ-ated with tracheal intubation: lidocaine, fentanyl, or esmolol? AnesthAnalg 1991; 72: 482-6.

10. Ebert JP, Pearson JD, Gelman S, Harris C, Bradley EL. Cir-culatory responses to laryngoscopy: the comparative effects of placebo, fentanyl.

11. Dahlgren N, Messeter K. Treatment of stress response to laryngoscopy and intubation with fentanyl. Anaesthesia 1981;36: 1022-6.



ORIGINAL ARTICLE

EVALUATION OF ACTIVITIES OF SERUM GAMMA GLUTAMYL TRANSFERASE AND ADENOSINE DEAMINASE IN PRE-ECLAMPSIA-A CASE CONTROL STUDY Rajeshwari R Patil1, Archana S Choudhari2 Author’s Affiliations: 1Tutor, 2Associate Professor, Dept. of Biochemistry, MRMedical College, Gulbarga. Karnataka Correspondence: Dr Archana S Choudhari Email: [email protected]

ABSTRACT

Introduction: Preeclampsia is a Pregnancy Specific Syndrome characterised by Hypertension with BP 140/90 mm Hg or more, Proteinuria and Oedema contributing significantly to Maternal and Foetal Morbidity and Mortality. Endothilial cell dysfunction within the Uteroplacental circulation leads to systemic release of Gamma Glutamyl Transferase(GGT) . The activity of Serum Adenosine Deaminase(ADA) is also increased due to pos-sible role of enhanced Cell Mediated Immunity during Preeclamsia. In the developing Countries with inade-quately cared Pregnancy, Preeclampsia on many occasions remains undetected till major complications super-vene. So this Study is undertaken at providing some of the Promising Enzyme Markers as GGT and ADA.

Methodology: Present study comprised Fifty Women with Pre-eclampsia as Cases and Fifty age matched nor-mal pregnant Women as Controls. The Parameters were estimated by Standard Biochemical Methods. Statistical Analysis of the Data was done by Student’s t Test and ANOVA.

Results: The activity of Serum GGT was significantly increased in Pre-eclampsia Patients compared to Normal

Pregnant Women with a p˂0.001, and there was a highly significant increase in Serum ADA with p<0.000

Conclusion: The Study concludes that Enzyme Markers like Serum GGT and ADA could be Sensitive, Accu-rate and Cost effective Biomarkers in aiding the Diagnosis and to assess the severity of Preeclampsia.

Keywords: Adenosine Deaminase, Enzyme Markers, Gamma Glutamyl Transferase, Preeclamsia INTRODUCTION

Preeclampsia is a Pregnancy specific Syndrome char-acterized by Hypertension with BP 140/90mm Hg or more,Proteinuria and Oedema contributing significi-cantly to Maternal & Foetal morbidity & mortality, the incidence of preeclampsia in hospital practice varies widely from 5-15%.1

The aetiology of Preeclampsia is unknown but thought to be related to hypoxia in placenta & endo-thelial dysfunction.2 Recent studies revealed that ex-cessive placental secretion of soluble forms like Tyro-sine kinase(SF1t-I) may contribute to Endotelial dys-function ,Hypertension and Proteinuria in Preeclamp-sia.3 Endothelial cell dysfunction & intense vasospasm play an important role in the pathogenesis of Preeclampsia.Endothelial cell dysfunction within the uteroplacental circulation leads to systemic release of gamma glutamyl transferase-GGT.2, 4

The activity of serum Adenosine deaminase (ADA)-A Purine metabolising enzyme is also increased due to possible role of enhanced cell mediated immunity dur-ing Preeclampsia.5 Preeclampsia if untreated may lead to Liver and Renal failure,Dissemenated Intravascular

Coagulation and Central Nervous System abnormali-ties including Seizures.6 In the developing countries with inadequately cared Pregnancy, Preeclampsia on many occasions remains undetected till major compli-cations supervene. So the present study is under taken at providing some of the promising enzyme markers as GGT and ADA which are cost effective accurate & identified by easy method of detection that are ap-proachable for general population.

METHODOLOGY

The present study comprised of 50 women with Preeclampsia in the age group of 20-40 years as Cases and 50 Normal Pregnant women as Controls. The study was conducted over a period of one year and it is an unmatched case control study.

Ethical clearance was obtained from the Institutional Ethical Committee. An informed consent was ob-tained from all the Participants for conducting the study and another separate consent was taken before collecting the blood samples.



Criteria for selecting Patients with Preeclampsia

Inclusion criteria: Patients diagnosed with Preeclamsia & Patients with an onset of Hypertension more than 140/90mm Hg during the second or third trimester of Pregnancy were included in the study.

Exclusion criteria: Patients with Multiple foetuses, Chronic Hypertension, Diabetes mellitus, Renal dis-eases, Tuberculosis, Hepatobiliary disease and Thy-roid disease were excluded

Sample collection: About 2 ml of VenousBlood was collected from Antecubital vein under all aseptic pre-caution & was allowed to clot. Serum was separated by centrifugation to estimate GGT and ADA. The es-timation of parameters was carried out immediately.

Serum GGT was estimated by Szacz & Rosalki method.7 using kit supplied by Erba diagnostics. Se-rum ADA by colorimetric method of Galanti & Giusti.8 using ADA –MTB microxpress Tulip Diag-nostics(p) Ltd, kit. The estimations were carried out on Semi Auto Analyser ERBA CHEM-7

The above mentioned parameters were recorded as Mean & Std deviation. Statistical analysis of all the ob-

tained parameters were done by student’s ´tˊtest & ANOVA. The observations were tabulated & conclu-sions were obtained by biochemical data.

RESULTS

In our study a basic parameters were tabulated as shown in Table 1.

Table 1: Basic Parameters in Pre-eclampsia Cases and Controls

Parameter Cases Controls

Age (In years) 25.54±4.24 24.96±4.63

Gestational age(In weeks) 32.56±4.85 30.86±4.52

SBP (In mmHg) 154.42±16.54 116.56±8.0

DBP (In mmHg) 96.80±13.99 82.6±2.68

SBP=Systolic blood pressure DBP=Diastolic blood pressure

Table 2: Comparison of serum levels of GGT and ADA between controls and Pre eclampsia cases and their p values

Parameter Cases Controls p-Value

GGT(IU/L) 28.82±2.65 10.23 ±4.31 <0.001

ADA(U/L) 41.07±5.29 16.78±2.22 <0.001

In our study a significant increase in mean Serum GGT was observed in Preeclampsia Patients when

compared to Controls (with a p˂0.001)as shown in the Table 2. It is also documented in our study that a highly significant increase in mean Serum ADA level

in Preeclampsia Patients when compared to controls with a p<0.000 as shown in the Table 2.

DISCUSSION

Hypertension is one of the common medical compli-cations of pregnancy & contributes significantly to maternal & perinatal morbidity & mortality.the identi-fication of this clinical entity and effective manage-ment play a significant role in the outcome of preg-nancy both for the mother and the baby[1]. Preeclampsia is considered as idiopathic multisystem disorder that is specific to human pregnancy. 9

Pre eclamsia is a syndrome of generalised endothelial dysfunction initiated by abnormal placentation and consequent placental under-perfusion, release of cyto-kines, peroxidants, vasoconstriction and platelet acti-vation.10

Several potential biochemical markers have been pro-posed to predict the severity of preeclampsia. En-zymes are one among them which are known as mark-ers of cellular damage.

GGT is a microsomal glycoprotein enzyme that cata-lyzes the transfer of gamma-glutamyl group from a peptide to an acceptor peptide or an L-Amino acid.11

Endothelial cell dysfunction within the uteroplacental circulation leads to systemic release of GGT.2 In our study serum GGT level was significantly increased in preeclampsia patients when compared to controls. Similar results were documented by Churchill D2, Hazari R4 ,Sarkar PD12, Babu R13 and Portelinha A et al. 14

ADA is the major enzyme of purine salvage pathway & catalyses the irreversible deamination & hydrolytic cleavage of adenosine & deoxyadenosine to inosine & doxyionosine respectively with liberation of ammo-nia.15,16 It is present in all human tissues with the high-est levels in the lymphoid system and is regarded as a cellular inflammatory indicator. ADA activity has been detected on the surface of hematopoetic cells and ADA binding to the surface of T Lymphocytes has been reported. 17,18

In our study a highly significant increase in serum ADA was observed in preeclampsia patients com-pared to controls which is due to possible role of en-hanced cell mediated immunity during preeclampsia. Similar results were documented by Yoneyama, 5,19 Oladipo O20 Kafkasli A.21

CONCLUSION

The study concludes that enzyme markers like serum ADA & GGT could be sensitive, accurate & cost ef-fective. Biomarkers in adding the diagnosis & assess the severity of preeclampsia.



REFERENCES

1. Konar H. Hypertensive Disorders in pregnancy.In : D C.Dutta Text book of obstetrics.7th edition.Kolkatta:New Central book Agency (p)Ltd;2013.p 219-240.

2. Churchill D, Kilby MD,etal.Gamma Glutamyl Transferase ac-tivity in gestational hypertention.BR.J obestes Gyne-col.1994;101:251-53.

3. Maynard SE, MinJ Y, Merchan J et al. Excess placental soluble fms- like tyrosine kinase(SF1t-1) may contribute to endothelial dysfunction, hypertension and proteinuria in pre eclamsia. J Clin Invest. 2003;111:649-658.

4. Hazari.NR, Hatolkar VS 7 Munde SM.Study of serum Hepatic Enzymes in Pteeclampsia.International Journal of Current Medical and Applied Sciences.2014;2(1);01-08.

5. Yoneyana Y,Sawa R and Suzaki Setal. Serum Adenosine De-aminase activity in women with Pre-eclampsia.Gynacol Ob-stet Invest.2002;54(3):164-7.

6. Indumati V, Rajeshwari V, Vijay V and Maligi A. M . a study of serum lactate dehydrogenase in eclamsia and serum magne-sium levels in patients with eclampsia undergoing magnesium sulphate therapy. Int J Med Health Sci. 2014 Oct; 3(4): 278-282.

7. Panteghini M and Bias R. Serum enzymes.In:Burtis CA,Bruns Dr,editors.Teitz fundamentals of clinical chemistry and mo-lecular diagnnostics7th ed.Elsevier Publications,2014,p318-336.

8. Giusti G.Adenosine Deaminase.In:Bergmeyer HV, editors. Methods of enzymetic analysis.Vol ll New York Academic press;1974.

9. Norwitz ER,Hsu CD,Repke JT.Acute complications of preeclampsia.Clin obstet Gynacol 2002;45:308-29.

10. Perloff D. Hypertension and pregnancy related hypertension. Cardiol clin. 1998 Feb; 16CD;79-101.

11. Wilkinson JH.Chemistry of enzymes of diagnostics interest 11.In:The principls and practice of Diagnostic Enzymol-ogy.London:Edward Arnold Publishers Ltd,1976.p.80-104.

12. Sarkar PD and Sogani S.Evaluation of Serum Lactate dehy-drogenase and Gamma Glutamyl Transferase in Pre-eclamptic

pregnancy and its comparision with normal pregnancy in third trimester.Int J Res Med Sci.2013 Nov;1(4):365-368.

13. Babu R, Venugopal B, Sabita K et al. Comparative study of liver and kidney biochemical parameters in normal and pre eclamtic gestation. Journal of current trends in clinical medi-cine and laboratory biochemistry. 2013 Oct-Dec; 1(3);26-30.

14. Portelinha A, Cerdeira AS, Belol et al. Altered Alanine Ami-notransferase and Gamma glutamyl transpeptidase in women with history of preeclampsia: association with waist hip ratio and body mass index. Eur J Gastroenterol Hepatol 2009 Feb; 21(2): 196-200.

15. Bansal S K, Singh R P, Narang R K, Joshi L D, Bansal A, Agarwal A K. Serum adenosine deaminase activity in Pulmo-nary Tuberculosis, malignancy and Non-tubercular respiratory disease. Indian J Chest Dis Allied Sci. 1991;33:189-93.

16. Choudhari A S, Desai P B, Indumati V and Kadi S M. Activi-ties of serum ADA, GGT and ALP in carcinoma Breast – A Case Control Study for Diagnosis and Prognostic Significance. . Indian Journal of Medical Sciences 2013 May-june: 67(5&6): 123-129.

17. Cristalli G, Costanzi S, Lambertucci C, Lapidi G, Vittori S, Volpini R et al: adenosine deaminase functional implication and different classes of inhibitors. Med Res Rev 2001; 21 : 105-128.

18. Gakis C. Adenosine deaminase (ADA) isoenzymes ADA1 and

ADA2 : diagnostic and biological role. Eur Respir J 1996;9:623-633.

19. Yoneyama Y, Sawa R, Suzuki S, DoiD, Yoneyana K, Otsubo Y, et al : Relationship between plasma malondialdehyde levels and adenosine deaminase activities in Pre-eclampsia. Clin Chin Acta 2002; 322;169-173.

20. Oladipo OO,A folabi BB and Okorodudu AO.Adenosine de-aminase activity in subjects with normal pregnancy, pregnancy induced hypertention and Pre-eclampsia. West Afr J Med.2009 May;28(3):161-4.

21. Kafkasli A,Karabulut AB,Atmaca R and Lavrini R.Clinical correlation between Adenosine Deaminase Activity and Pre-eclampsia Severity.The J of Int Med Research 2006,34:247-255.



ORIGINAL ARTICLE

ROLE OF FIBEROPTIC BRONCHOSCOPY IN NON-RESOLVING PNEUMONIA Rajesh Kumar Balakrishnan1, Gyanshankar P Mishra2, Shivhari V Ghorpade3 Author’s Affiliations: 1Senior Resident, Dept. Pulmonary Medicine, Jawaharlal Institute of Postgraduate Medical Educa-tion & Research, Puducherry; 2Assistant Professor, 3Professor and Head, Government Medical College, Nagpur Correspondence: Dr Gyanshankar P Mishra Email: [email protected]

ABSTRACT

Introduction: Non-resolving pneumonia is always a challenging clinical scenario where various diagnostic mo-dalities are greatly required to reach the diagnosis. We aimed to study the role of fiberoptic bronchoscopy in non-resolving pneumonia along with the various comorbidities associated with the disease condition.

Methodology: A cross sectional study in a tertiary care hospital was undertaken. A total of 60 patients diag-nosed with non-resolving consolidation were recruited for diagnostic fiberoptic bronchoscopy.

Results: The overall diagnostic yield of fiberoptic bronchoscopy in non-resolving pneumonia was 96.66%. The causes of non-resolving pneumonia were tuberculosis (40 (66.67 %), bacterial pneumonia (8 (13.33 %)), malig-nancy (6 (10%)), fungal pneumonia (3 (5 %)) and foreign body (1 (1.66 %) in order of decreasing proportions. 2 cases (3.33 %) were undiagnosed. 29 (48.33%) patients had a significant past history which also revealed associated co morbid conditions. Chronic obstructive pulmonary disease (COPD) (14 (23.33 %)) and diabetes (10 (16.66%)) were the leading comorbid conditions.

Conclusion: Fiberoptic bronchoscopy is a great utility tool in reaching the diagnosis in patients with non-resolving pneumonias.

Keywords: Bronchoscopy, pneumonia, consolidation, Fiberoptic, Tuberculosis, COPD, Diabetes

INTRODUCTION

The term non resolving or slowly resolving pneumo-nia commonly refers to the persistence of radio-graphic abnormalities beyond the expected time limit.

Such patients may be at an increased risk of delayed diagnosis which may adversely affect their outcomes. Evaluation of patients with non-resolving pneumonia is extremely difficult and requires an aggressive ap-proach to prevent the delay in diagnosis and treat-ment. It accounts for approximately 10% to 15% of nosocomial pneumonias and is estimated to be re-sponsible for approximately 15% of inpatient pulmo-nary consultation and 8% of bronchoscopies. Delay in diagnosis and treatment may lead to rise of mortal-ity by 3% to 5% in both community-acquired pneu-monia and nosocomial pneumonia.1 Mortality in non-responding pneumonia increases three-fold in com-munity-acquired and five-fold in nosocomial pneu-monia compared with global mortality in hospitalized patients.2 In such a scenario, there is a need of a diag-nostic test of increased utility in reaching the diagno-sis at an earlier stage. Such an optimum diagnostic test should help the treating physician to identify the un-derlying etiology so as to be able to plan a specific

etiology directed management, a prerequisite for im-proved treatment outcomes in today’s era of evidence based medicine. Among the various diagnostic mo-dalities available to the treating physician, fiberoptic bronchoscopy, as a diagnostic tool has immense po-tential to deliver this important role in diagnosis of non-resolving pneumonia. Efficacy of fiberoptic bronchoscopy in the etiological diagnosis of non-re-solving or slowly resolving pneumonia has been around 70% to 86% in some studies. Detailed micro-biological, cytological and histopathological tests of the yielded specimens by this procedure can be done for etiological diagnosis of underlying cause.1 In this study, we aimed to establish the role of fiberoptic bronchoscopy in evaluating the etiological diagnosis of non-resolving pneumonia or slowly resolving pneumonia and also to find out co-morbid conditions if any associated with non-resolving pneumonia.

METHODOLOGY

Study design: This study was a cross-sectional study, performed in the department of Pulmonary Medicine at a tertiary care teaching institution of central India



over a period of two years (November 2012 to Octo-ber 2014). Study Population: Sixty consecutive cases of non-resolving or slowly resolving pneumonia of both genders, attending the department of Pulmo-nary Medicine during the study period, were selected by adhering to the inclusion and exclusion criteria. In-clusion criteria: Non-resolving or slowly resolving pneumonia was defined in this study by the presence of persistence of clinical symptoms and signs (cough, sputum production, with or without fever more than 100°F), failure of resolution of the radiographic fea-tures by fifty percent in two weeks or completely in four weeks on serial chest radiographs (indicated in at least two consecutive chest radiographs) in spite of antibiotic therapy for a minimum period of ten days, and sputum for acid fast bacilli (AFB) smear negative for two consecutive days.1 Exclusion criteria: Known patients of lung cancer or sputum smear-positive pul-monary tuberculosis, bleeding diathesis, patients hav-ing very poor general condition, very severe breath-lessness, recent history of myocardial infarction, pos-itive test result for human immunodeficiency virus (HIV) infection, and unwilling patients were excluded from our study. Study Protocol: The study was initi-ated after approval from the institutional ethics com-mittee. After application of inclusion and exclusion criteria, with prior informed consent, the patients were included in the study. Detailed demographic and clinical parameters were recorded in all the patients. All patients were subjected to the following investiga-tions:

1. Screening investigations prior to bronchoscopy: Complete haemogram, random blood sugar, chest ra-diograph - PA and lateral views, sputum smear exam-ination for AFB - two samples (one spot sample & one early morning sample) carried out by Ziehl–Neel-sen (ZN) staining technique, induced sputum smear examination for AFB (if previous test negative), elec-trocardiogram (ECG), tests for HIV and HBsAg. An-cillary investigations included computed tomography scan (CT Scan) of the thorax and Mantoux test as and when required as per individual assessment of each case.

2. Study Investigation - Bronchoscopy: Next, a fiber-optic bronchoscopy was planned. During bronchos-copy, the macroscopic appearance of the bronchial tree was noted. In most patients, various combina-tions of bronchial washings, endobronchial biopsy, bronchial brushing and trans-bronchial needle aspira-tion (TBNA) were carried out according to the bron-choscopic findings. When no lesion was seen, bron-chial washings were collected in all patients and bron-chial brushing in some patients from the appropriate segments as determined by chest x-ray and CT-scan thorax images. Post bronchoscopy sputum was col-lected and sent for investigations in all patients. Bron-chial washings were sent for cell type, AFB smear and

culture for mycobacterium tuberculosis. The meth-ods used for culture of mycobacterium tuberculosis were solid culture -Löwenstein–Jensen (LJ) medium and/ or mycobacterial growth indicator tube (MGIT-960). A growth on either of the two culture media or AFB positive smear or biopsy suggestive of tubercu-losis was considered favorable for a definitive diagno-sis of tuberculosis. Bronchial washings were also in-vestigated for gram stain and culture, fungal stain and culture, and malignant cells in all patients. Bronchial brushings and biopsy when done, were sent for AFB smear and cytopathology, and histopathology, re-spectively. Post-bronchoscopic sputum for analysis of AFB smear and malignant cells were also sent.

Analysis of results: After completion of the study, the clinical data as per pro forma was analyzed for all the 60 patients; observation and results were docu-mented. Descriptive statistics like mean, standard er-ror of mean (SEM) were calculated and proportion method were used to express the results. Data were analyzed by Epi Info software.

RESULTS

During the period of two years, sixty consecutive pa-tients of both sexes, having chest radiograph sugges-tive of non-resolving pneumonia or slowly resolving pneumonia as per the study criteria, were enrolled in this study. Overall, the mean age of the patients was 41.2 ± 1.51 years (mean ± SEM). Among the 60 pa-tients, 45 (75%) were male and 15 (25%) female. Mean duration of illness was 1.6 ± 0.09 months (mean ± SEM). 44 (73.33%) patients had history of smoking, alcoholism or tobacco chewing. Of these, 34 patients (56.66%) were addicted to more than one of these habits. 30 patients (50%) had smoking habits, 19 patients (31.66%) were alcoholic and 33 patients (55%) had tobacco chewing habits. The addiction his-tory of the patients is depicted in table 1.

29 (48.33%) patients had a significant past history which also revealed the associated co morbid condi-tions. Of these 29 patients, 8 patients had more than one co-morbid condition. 14 patients (23.33 %) had chronic obstructive pulmonary disease (COPD), 10 patients (16.66%) had diabetes mellitus, 5 patients (8.33%) had pulmonary tuberculosis in the past hav-ing received treatment for the same. 4 patients (6.66%) had systemic hypertension and 4 patients (6.66%) with bronchial asthma. COPD being the most common comorbidity noted in 14 patients (23.33%) of which, 8 patients were diagnosed cur-rently with active pulmonary tuberculosis, 3 patients with malignancy, 2 patients with bacterial pneumonia and one patient with fungal pneumonia. In 10 dia-betic patients, there were 3 patients each of fungal pneumonia, pulmonary tuberculosis, malignancy and 1 case of bacterial pneumonia. All 5 patients with past



history of pulmonary tuberculosis were found to have active pulmonary tuberculosis in current study.

Table 1: Distribution of study group by Addic-tion history (N=60)

Addiction history No. (%)

Smoking 30 (50.0) Alcoholism 19 (31.7) Tobacco chewing 33 (55.0)

Table 2: Gross fiberoptic bronchoscopic findings (N=60)

Findings No. (%)

Growth 4 (6.7) Erosion / Ulcer 28 (46.7) Congestion / Hyperaemia 44 (73.3) Stenosis 4 (6.7) Secretions 46 (76.7) Bleeding 6 (10.0)

Table 3: Diagnostic outcome of fiberoptic bron-choscopy in cases of non-resolving pneumonia (N=60)

Outcome No. (%)

Pulmonary Tuberculosis 40 (66.7) Bacterial pneumonia 8 (13.3)

Klebsiella pneumonia 3 (5.0) Pseudomonas aeruginosa 2 (3.3) Streptococcus pneumonia 2 (3.3) E.coli 1 (1.7)

Malignancy 6 (10) Adenocarcinoma 3 (5.0) Squamous cell carcinoma 2 (3.3) Small cell carcinoma 1 (1.7)

Fungal Pneumonia 3 (5.0) Candida albicans 2 (3.3) Aspergillus fumigatus 1 (1.7)

Foreign body 1 (1.7) Undiagnosed 2 (3.3)

Chest radiograph: Analysis of chest radiograph for the site of the lesion among the 60 patients studied revealed that 11 patients (18.33%) had bilateral le-sions, 49 patients (81.66%) had unilateral lesions. Of these 49 patients, 31 patients (51.66%) had right sided lesions and the remaining 18 patients (30%) had left sided lesions. Further analysis revealed that 40 pa-tients (66.66%) had infiltrates in one lobe or one seg-ment, whereas 20 patients (33.33%) had multilobar infiltrates. CT scan Thorax: In the study, out of 60 patients, 24 patients had their CT scan thorax done prior to fiberoptic bronchoscopy. Of these 24 pa-tients, the most common radiological lesion on CT scan thorax were consolidation, seen in 21 patients (87.5%) and lymphadenopathy (≥10 mm) in 21 pa-tients (87.5%), followed by tree-in-bud appearance in

9 patients (37.5%), nodule in 8 patients (33.3%) and cavity in 6 patients (25%).

Bronchoscopy: The gross fiberoptic bronchoscopic findings are enumerated in table no.2. The overall di-agnostic yield of fiberoptic bronchoscopy in non-re-solving pneumonia was 96.66 %. The details are de-picted in table no. 3. Specific procedures: i) Bronchial washings: 1) AFB staining: In this study bronchial washings were taken in all 60 patients. 40 patients out of 60 (66.67%) patients with non-resolving pneumo-nia were diagnosed as pulmonary tuberculosis. 22 pa-tients were positive for AFB smear staining in bron-chial washings. 2) AFB culture: All the pulmonary tu-berculosis suspected patients’ bronchial washings were sent for culture for mycobacterium tuberculosis. 36 patients’ specimens were found to be culture pos-itive. 3) Cytology: Bronchial washings were routinely sent for cytological evaluation. Malignant cells were seen in 2 specimens out of which one was squamous cell carcinoma and another was adenocarcinoma. 4) Gram stain, culture and sensitivity: Out of 60 pa-tients, 8 patients were diagnosed with bacterial pneu-monia. Bronchial washings bacterial culture yielded 3 cases of Klebsiella pneumonia, 2 cases of Pseudomo-nas pneumonia, 2 cases of streptococcus pneumonia and 1 case of E-coli pneumonia. 5) Fungal stain and culture: Out of 60 patients, 3 patients were diagnosed as fungal pneumonia. ii) Bronchial brushing: Bron-chial brush cytology proved malignancy in 3 patients. 2 patients had adenocarcinoma and 1 had squamous cell carcinoma. iii) Endobronchial biopsy: Endobron-chial biopsy was done in 12 patients. Out of these, malignancy was diagnosed in 6 patients (squamous cell carcinoma in 3 patients, adenocarcinoma in 2 pa-tients and small cell carcinoma in 1 patient). Endo-bronchial biopsy of 4 patients showed features sug-gestive of tuberculosis. Nonspecific findings were seen in 3 endobronchial biopsy specimens. iv) TBNA: TBNA was done in 5 patients. Among them 2 patients’ TBNA was suggestive of tuberculosis, 1 patient had malignant deposits and remaining 2 pa-tients’ TBNA were non-specific. v) Post bronchos-copy sputum: All pulmonary tuberculosis suspected patients had their post bronchoscopy sputum sent for AFB staining and suspected malignant patients’ sam-ples were sent for additional cytological evaluation. 5 patients’ post bronchoscopy sputum was positive for AFB staining. 1 patient’s post bronchoscopy sputum was positive for malignant cells (adenocarcinoma). Complications: Complications during or after bron-choscopic procedure were very few. Minor hemor-rhage following forceps mucosal biopsy was seen in only 1 patient (1.66%). Hypoxia during the broncho-scopic procedure was seen in 1 patient (1.66%). How-ever, serious complications like respiratory failure, cardiac arrhythmia & cardiac arrest did not occur in our study group.



DISCUSSION

Amberson was the first person to describe the term “unresolved organizing or protracted pneumonia” in 1943.3 There is lack of uniformity regarding the defi-nition for non-resolving pneumonia, however in many studies, the entity of “slow resolution” has been defined as failure of radiographic resolution by 50% in two weeks or failure of complete resolution by one month despite adequate antibiotic therapy.4 A non-resolving pneumonia heralds a clinical scenario where the diagnostic dilemma is a cause of clinical concern. The lack of a definitive etiological diagnosis prevents a more targeted approach in the management. Among the various diagnostic tools available for such a scenario, the role of diagnostic bronchoscopy can-not be undermined.

In our study 23.33% patients were above the age of 50 years. Fein has shown in his study that only 30% of patients above 50 years of age show complete ra-diological resolution by 4 weeks.5 Non-resolving or slowly resolving pneumonia is common in elderly pa-tients due to age related impairment of several com-ponents of host defenses.

COPD (23.33%) and diabetes (10%) were the com-mon comorbidities in our study. Jaiprakash et al. in their study also found that COPD (35.7%) and diabe-tes (45.7%) were the major comorbidities in patients of non-resolving consolidation.6 The presence of these comorbidities should alert the treating physician of a possibility of these patients progressing to non-resolving consolidation at a later time period in the course of the disease and hence initial aggressive management of pneumonia is warranted in these pa-tients.

The overall diagnostic yield of fiberoptic bronchos-copy in our study was 96.66%. Previous studies by Silver et al. and Choudhary et al. demonstrated a di-agnostic yield of 86% and 85.7% in similar scenario.1,7 Thus our study showed a higher diagnostic yield of fiberoptic bronchoscopy compared to previous stud-ies.

Pulmonary Tuberculosis was the most common cause of non-resolving pneumonia in our study (66.67%). This was followed by bacterial pneumonia, malignancy, fungal pneumonia and foreign body re-spectively in decreasing proportion as the etiology in our study. Thus all non-resolving pneumonia patients should be evaluated for active pulmonary tuberculo-sis. This finding reiterates the role of fiberoptic bron-choscopy in diagnosis of sputum smear negative pul-monary tuberculosis. Jacomelli et al. in their previous study have also demonstrated the good utility of bronchoscopy for the diagnosis of pulmonary tuber-culosis in patients with negative sputum smear mi-croscopy results.8 Also all patients with past history

of pulmonary tuberculosis in this study revealed pul-monary tuberculosis as the etiology of non-resolving consolidation. Thus in patients with past history of pulmonary tuberculosis, there should always be a high index of suspicion of relapse. Any delay in the diag-nosis of tuberculosis in such patients may be a risk factor for drug resistant form of the disease.9 Correct diagnosis and proper treatment is always imperative in such a scenario as any error in either of the two are known detrimental factors in the prognosis of tuber-culosis, especially in India.9,10

Though two third of the patients (66.67%) were diag-nosed to be suffering from pulmonary tuberculosis, remaining one third of the patients were diagnosed with other etiologies like malignancy and bacterial pneumonia. Thus even though tuberculosis was the most common etiology of non-resolving consolida-tion in this study it is recommended to search for an evidence based diagnosis of the etiology as initiation of empirical anti-tuberculosis treatment could lead to delay in diagnosis of other possible etiologies like ma-lignancy or even foreign body which could adversely affect the disease outcome.11,12

Bacterial pneumonia was the etiology of non-resolv-ing pneumonia in 8 patients (13.33 %) in the current study. The possible causes of bacterial etiology of non-resolving pneumonia may be inadequate or inap-propriate initial antibiotic therapy or antibiotic re-sistant pathogens.13

Three patients in the current study were diagnosed to be cases of fungal pneumonia. These patients were immunocompetent and did not have any investigative evidence to the contrary. Also previously even rare fungal infection of the lungs has been reported in im-munocompetent individual.14 Thus the differential di-agnosis of fungal pneumonia should be considered in cases of non-resolving consolidation even in appar-ently immunocompetent patients. In this study 73.33% of the patients had addiction to smoking, al-coholism or tobacco chewing. This factor needs to be considered in evaluating a case of non-resolving con-solidation. Fiberoptic bronchoscopy is useful in eval-uating infective etiology and central mass lesion. It is less useful for peripheral mass lesion wherein a CT guided FNAC can be more reliable. In our study, complications during or after bronchoscopic proce-dure were very few thus fiberoptic bronchoscopy can be considered to be a relatively safe procedure with minor complications.

To summarize, non-resolving pneumonia is a great clinical challenge along with all the possible uncer-tainties it brings with its diagnostic possibilities. Fi-beroptic bronchoscopy is a great utility tool in reach-ing the diagnosis among such patients.



REFERENCES

1. Chaudhuri A, Mukherjee S, Nandi S, Bhuniya S, Tapadar S, Saha M. A study on non-resolving pneumonia with special reference to role of fiberoptic bronchoscopy. Lung India: of-ficial organ of Indian Chest Society. 2013;30(1):27-32.

2. Menendez R, Perpina M, Torres A. Evaluation of non-resolv-ing and progressive pneumonia. Sem in Respir Infect 2003;

18:103‑11.

3. Amberson JB. Significance of unresolved organizing or pro-

tracted pneumonia. J Mich State Med Soc. 1943; 42:599‑603.

4. Rome L, Murali G, Lippmann M. Non-resolving pneumonia and mimics of pneumonia. Med Clin North Am 2001;

85:1511‑30.

5. Fein AM. Pneumonia in the elderly: Overview of diagnostic

and therapeutic approaches. Clin Infect Dis 1999; 28:726‑9.

6. B Jaiprakash. V Varkey, K Anithakumari. Etiology and out-come of non-resolving Pneumonia. Journal of Asso of Phy-sicians of India,2012;60:20-23

7. Feinsilver SH, Fein AM, Niederman MS, Schult DE, Faegen-burg DH. Utility of fiberoptic bronchoscopy in non-resolving

pneumonia. Chest 1990; 98:1322‑6.

8. Jacomelli M, Silva PR, Rodrigues AJ, Demarzo SE, Seicento M, Figueiredo VR. Bronchoscopy for the diagnosis of pul-monary tuberculosis in patients with negative sputum smear

microscopy results. Jornalbrasileiro de pneumologia: publica-caooficial da SociedadeBrasileira de Pneumologia e Tisilogia. 2012;38(2):167-73.

9. Mishra G, Ghorpade SV, Mulani J. XDR-TB: An outcome of programmatic management of TB in India. Indian journal of medical ethics. 2014;11(1):47-52.

10. Mishra G, Mulani J. Tuberculosis Prescription Practices In Private And Public Sector in India. NJIRM. (2013), [cited Oc-tober 28, 2016]; 4(2): 71-78.

11. Jain A, Madan N, Arava S, Pandey D, Madan K. Delayed di-agnosis of endobronchial mucoepidermoid carcinoma in a 29-year-old male. Lung India: official organ of Indian Chest Society. 2016;33(3):323-5.

12. Mishra G, Mulani J. A Non–Resolving Consolidation which was Caused by a Bronchial Foreign Body in an Adult: A Case Report. Journal of Clinical and Diagnostic Research: JCDR. 2013;7(8):1750-2.

13. Finch Simon, Chalmers JD. Brief Clinical Review: Non-re-sponding Pneumonia. EMJ Respir. 2014; 2:104-111.

14. Meshram SH, Mishra GP. Pulmonary scedosporiosis–A rare entity. Asian Pacific Journal of Tropical Disease. 2011;1(4):330-2.



ORIGINAL ARTICLE

A COMPARATIVE STUDY OF INTRAVENOUS METHYL PREDNISOLONE VERSUS DEXAMETHASONE IN MANAGEMENT OF PATIENTS WITH POSTERIOR SCLERITIS Shashi Prabha Prasad1, Abha Gahlot1, Nimrita Nagdev2, Preeyam Biswas2, Bhargav Kotadia2, Kanisha Jethwa2 Author’s Affiliations: 1Professor, 2Junior Resident, Dept. of Ophthalmology, D.Y. Patil Medical College, Pune Correspondence: Dr Shashi Prabha Prasad Email- [email protected]

ABSTRACT

Introduction: Posterior scleritis is a relatively uncommon condition and often misdiagnosed due to varied manifestations. The main stay of treatment is systemic steroids and immunosuppressive therapy. The present study was done to compare the effect of intravenous methyl prednisolone and the conventional intravenous dexamethasone in management of patients diagnosed with posterior scleritis at a tertiary eye care center.

Methodology: It was a retrospective comparative study of 6 patients of posterior scleritis at a tertiary eye care center which were treated primarily with intravenous methylprednisolone or dexamethasone. Group A and B comprised of 3 patients each. Group A patients were started on intravenous Methylprednisolone therapy wherein a dose of 1gm in 500ml of 5% Dextrose was infused over 2 hours under cardiac monitoring for 3 days. Group B patients were administered 08 mg intravenous Dexamethasone twice daily for first 3 days. Subse-quently on 4th day patients of both groups were switched over to 1.5 mg/ kg body weight of oral Prednisolone therapy in tapering dose.

Results: control of pain and inflammation was achieved faster in group A patients treated with intravenous methylprednisolone as compared with group B patients receiving intravenous dexamethasone. Though the final visual and clinical outcomes were nearly the same.

Conclusion: Patients of posterior scleritis treated with intravenous Methylprednisolone had a quicker and a more effective response when instituted early in the disease in comparison to Intravenous dexamethasone.

Keywords: Posterior Scleritis, Pain, Inflammation, Methyl Prednisolone, Dexamethasone, Ultrasonography, Computed Tomography.

INTRODUCTION

Posterior Scleritis is defined as inflammation of sclera, which may start primarily posteriorly or may be an ex-tension of anterior scleritis. The clinical presentation is varied and the diagnosis is easily missed, particularly in cases with no pain or no anterior segment involve-ment.1, 2 Clinical features include decreased vision, pain, proptosis or restricted ocular movements. The ocular features of posterior scleritis include exudative retinal detachment, choroidal detachment, subretinal fibrosis, subretinal mass, retinal folds, choroidal folds, macular and optic disc edema.1 Several inflammatory and non-inflammatory ocular diseases such as poste-rior uveitis, Vogt-Koyanagi-Harada syndrome, pseudotumour of the orbit, and central serous chori-oretinopathy can closely mimic this condition.3,4,5,6 It is a rare disease and the mean age at onset is 49 years.4,5 Posterior scleritis can also be a clinical manifestation

of presumed ocular TB.7 Patients more than 50 years of age with posterior scleritis have increased risk of associated systemic disease and more likely to be as-sociated with visual loss, hence these patients require systemic immunosuppressive therapy for manage-ment of disease.,8,9 The autoimmune nature of scleritis also is supported by the frequent association with sys-temic autoimmune disorders and by the favorable re-sponse to immunosuppressive therapy. 8 Posterior scleritis can present in various ways, mimicking orbital tumors, orbital inflammation, optic neuritis and vas-culitis. 6,7,8 Early diagnosis is important because prompt treatment often leads to complete resolution with excellent visual recovery.8,9 Ultrasonography has been found to be very useful in the diagnosis of pos-terior scleritis.10,11,12 Computed Tomography (CT) scan13,14,15,16 and fundus fluorescein angiography (FFA) 17 also be used as ancillary tests. The main stay



of treatment of posterior scleritis is systemic steroids.

Intravenous methylprednisolone pulse therapy is used in the cases of severe eye inflammatory diseases.18,19,20

Pathophysiology: An autoimmune dysregulation in a genetically predisposed host is presumed to cause scleritis.7,8 Inciting factors may include infectious or-ganisms, endogenous substances or trauma. The in-flammatory process may be caused by immune com-plex–related vascular damage (type III hypersensitiv-ity) and subsequent chronic granulomatous response (type IV hypersensitivity). The following interact as part of the activated immune network, which can lead to scleral destruction: immune complex vessel deposi-tion in episcleral and sclera perforating capillary and postcapillary venules (inflammatory microangiopathy) and cell-mediated immune responses. The autoim-mune nature of scleritis also is supported by the fre-quent association with systemic autoimmune disor-ders and by the favorable response to immunosup-pressive therapy. 7,8 Most common association with scleritis is Rheumatoid Arthritis , Wegener’s disease, Inflammatory bowel disease, Systemic lupus Erythe-matosus , Polyarthritis nodosa. Patients undergoing pterygium surgery with adjuvant therapy with Mito-mycin- C or Beta irradiation have increased risk for infectious scleritis. Posterior scleritis can also be a clin-ical manifestation of presumed ocular TB.7

The aim of the current study was to assess and com-pare the efficacy of the two drugs methylprednisolone and dexamethasone in relieving the pain and inflam-mation.

METHODOLOGY

Six cases with diagnosis of posterior scleritis were se-lected at Armed Forces hospitals in Pune (a referral and tertiary eye care center) between March 2010 and Jun 2014. This study was done on six cases only as it is a rare and uncommon condition.

Group A and B comprised of 3 patients each. Group A patients were started on intravenous Methylpredni-solone therapy wherein a dose of 1gm in 500ml of 5% Dextrose was infused over 2 hours under cardiac monitoring for 3 days. Group B patients were admin-istered 08 mg intravenous Dexamethasone twice daily for first 3 days. Subsequently on 4th day patients of both groups were switched over to 1.5 mg/ kg body weight of oral Prednisolone therapy in tapering dose.

Patients were studied to evaluate the response with in-travenous methyl prednisolone and dexamethasone in treating the posterior scleritis. Ethical committee per-mission was taken prior to the study and written in-formed consent was taken from each patient.

Diagnostic Criteria: The diagnostic criteria for diag-nosing posterior scleritis included at least four of the

following: exudative retinal detachment, Uveal effu-sion with choroidal folds posterior to equator, Sub ret-inal mass posterior to equator, Unilateral disc edema, Diplopia and painful ocular movement and local ten-derness, Mild ptosis /proptosis, T - Sign and increased scleral thickness on ocular ultrasound or CT scan

The exclusion criteria were as follows: Previous epi-sode of posterior scleritis, uncontrolled diabetes melli-tus and bilateral cases of posterior scleritis.

Grouping of patients: Group-A patients were treated with intravenous methyl-prednisolone. Group-B pa-tients were treated with intravenous dexamethasone.

Soon after diagnosis of posterior scleritis was made, group-A patients were started on 1 gm IV methyl-prednisolone in 500 ml of 5% Dextrose over 2 hrs was given daily for 3 days under cardiac monitoring. Group-B patients were administered 08 mg intrave-nous dexamethasone twice daily for first 03 days. Sub-sequently on 4th day the patients of both groups were switched over to 1.5 mg /kg body weight of oral pred-nisolone therapy. The oral prednisolone therapy was continued for at least 03 weeks or at least a week after resolution of all clinical signs and symptoms and then tapered off. The response to the two regimens was evaluated and compared at day 1, 3, 7, 14 and 30. At each visit, the patients were examined on slit-lamp, IOP, indirect ophthalmoscopy and ocular ultrasound was done.

The clinical parameters evaluated for comparison were pain, visual acuity, inflammation of anterior and posterior segment and the time taken for symptomatic improvement.

Figure 1: Exudative Retinal Detachment


NJMR│Volume 6│Issue 4│Oct – Dec 2016 3

Figure 2: Exudative Retinal Detachment

Figure 3: T sign (suggestive of Posterior Scleri-tis)

RESULTS

Group A: Control of pain was seen as early as 24 hrs. Inflammatory symptoms started settling by 48-72 hrs. By day 7, all 03 patients had marked control of inflam-matory symptoms. Distant uncorrected visual acuity at the end of day 10 was ranging between 3/60 - 6/60 in these 03 patients. Group-B: Control of and pain took about 48-72 hrs. Inflammatory symptoms started settling down after 72 hours. Patients were completely asymptomatic by day 10. At the end of day 10, the vis-ual acuity was between 4/60 and 6/60 in the 03 pa-tients.

Table 1: Comparison of symptoms and visual acu-ity in patients

Variable Group A Group B

Relief of Pain 24 hours 48-72 hours Relief of Inflammation 48-72 hours >72 hours Visual acuity 3/60 -6/60 4/60 – 6/60

This shows that intravenous methyl prednisolone had a quicker and more effective response as compared to intravenous dexamethasone when instituted early in the disease.

DISCUSSION

The present study was conducted on six patients to compare effect of intravenous methyl prednisolone and dexamethasone in management of posterior scle-ritis at a tertiary eye care center. Six patients were di-vided in two groups and effect of intravenous methyl prednisolone and dexamethasone were studied. Con-trol of pain and inflammation was better in patients treated with methyl prednisolone. Good response to intravenous methylprednisolone is reported in refrac-tory posterior scleritis and this also is known to reduce the recurrence.17,18,21

Patients with posterior scleritis need to be on long term steroids or immunosuppressive drugs. Oral ster-oids take a longer duration for control of inflamma-tion and intravenous methylprednisolone is known to control the inflammation faster and reduce the recur-rence. 19 Early introduction of methylprednisolone may reverse or mitigate the inflammatory process and there improve visual prognosis.19 Response to intra-venous methylprednisolone was dramatic and was fol-lowed by complete resolution of active disease within a month.19 Comparison with other studies could not be done as no study was done earlier on comparison of intravenous methylprednisolone and dexame-thasone in cases of posterior scleritis as per literature search. The earlier studies were done on varied presentation of posterior scleritis, diagnostic dilemma and treating patients with oral steroids or intravenous methylprednisolone or immunosuppressive agents singly or in combination.

CONCLUSION

Intravenous methyl prednisolone pulse therapy showed a quicker and more definitive response in the initial 03 days of instituting therapy for posterior scle-ritis. A relatively slower response to therapy was seen in cases treated with intravenous dexamethasone though the final visual and clinical outcomes were nearly the same. The definitive advantages of intrave-nous methyl-prednisolone vis-à-vis intravenous dexa-methasone in sight threatening posterior scleritis are: faster recovery and aggressive control of inflamma-tion and less sequelae of inflammatory response due to severe scleritis. Thus intravenous methyl-predniso-lone is preferred in posterior scleritis if cardiac moni-toring facilities are available.

REFERENCES

1. Ozdek SC, Gürelik G, Hasanreisoğlu B. An atypical posterior scleritis case: A diagnostic challenge. Retina 2001;21:371-3.

2. Benson WE, Shields JA, Tasman W, Crandall AS. Posterior scleritis: a cause of diagnostic confusion. Arch Ophthalmol. 1979; 97:1482–1486. [PUBMED]



3. Benson WE Posterior scleritis. Surv Ophthalmol 1988;32:297-316.

4. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Oph-thalmol. 1976; 60:163–191. doi: 10.1136/bjo.60.3.163.

5. McCluskey PJ, Watson PG, Lightman S, Haybittle J, Restori M, Branley M. Posterior scleritis: Clinical features, systemic as-sociations, and outcome in a large series of patients. Ophthal-mology. 1999; 106:2380–6.

6. Biswas J, Mittal S, Ganesh SK, Shetty NS, Gopal L. Posterior scleritis: Clinical profile and imaging characteristics. Indian J Ophthalmol. 1998; 46:195–202.

7. Gupta A, Gupta V, Pandav SS, Gupta A. Posterior scleritis associated with systemic tuberculosis. Indian J Ophthalmol 2003;51:347-9.

8. Cleary PE, Watson PG, McGill JI, Hamilton AM. Visual loss due to posterior segment disease in scleritis. Trans Ophthal-mol Soc UK. 1975; 95:297–299.

9. Meyer-Paul AR, Watson PG, Franks W, Dubord P. “Pulsed” immunosuppressive therapy in the treatment of immunologi-cally induced corneal and scleral disease. Eye 1987:1-487-95.

10. Munk P, Nicolle D, Downey D, Vellet AD, McKeoun M. Pos-terior scleritis: ultrasound and clinical findings. Can J Ophthal-mol 1993; 28:177.

11. Cappaert WE, Purnell EW, Frank KE. Use of B-sector scan, ultrasound in the diagnosis of benign choroidal folds. Am J Ophthalmol 1977; 84:375-79. [PUBMED]

12. Rochels R, Reis G. Echography in posterior scleritis. Klin Monatsbl Augenheilkd 1980;177:611-13.[PUBMED]

13. Chaques VJ, Lam S, Tessler HH, Mafee ME Computed to-mography and magnetic resonance imaging in the diagnosis of posterior scleritis. Ann Ophthalmol 1993; 25:89-94.

14. Trokel SL. Computed tomographic scanning of orbital inflam-mations. Int Ophthalmol Clin 1982;22:81-98..[PUBMED]

15. Trokel SL, Hilal SK. Submillimeter resolution of CT scanning of orbital diseases. Ophthalmology 1980; 87:412-17. [PUBMED]

16. Leo JS, Halpern J, Sackler JP. Computed tomography in the evaluation of orbital infections. Computerized Tomography 1980; 4:133-38. [PUBMED]

17. Norton EWD. A characteristic fluorescein angiographic pat-tern in choroidal folds. Proc R Soc Med 1969; 62:119-28.

18. Wakefield D, McCluskey P, Penny R. Intravenous pulse methylprednisolone therapy in severe inflammatory eye dis-ease. Arch Ophthalmol 1986; 104:847-51.

19. Bappal A, Puthran N, Hegde V. Benefits of early treatment with intravenous methylprednisolone in recurrent posterior scleritis. Arch Med Health Sci 2014; 2:214-6.

20. McCluskey P, Wakefield D. Intravenous pulse methyl predni-solone in scleritis. Arch Ophthalmol 1987; 105:793-797.



ORIGINAL ARTICLE

COMPARISON OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY WITH MACINTOSH AND MCCOY BLADES IN PATIENTS UNDERGOING GENERAL ANAESTHESIA Dinesh Thakur1, B K Mehta2 Author’s Affiliations: 1Associate Professor, Dept. of Anaesthesia, GMERS, Medical College Sola, Ahmedabad, 2DIG (M)/ Consultant Orthopaedic, Composite Hospital, CRPF, Gandhinagar, Gujarat Correspondence: Dr Dinesh Thakur Email: [email protected]

ABSTRACT

Introduction: Air medical transportation has greatly evolved undertaken by the Indian forces in Kashmir. Many more patients are transported daily in need of advanced medical attention to higher centers like Srinagar M.H & AIIMS & M.H Delhi. The condition of some injured patients necessitates specially modified aircraft, and monitoring and interventions during transport by trained medical personnel.

Methodology: Hospital records of all air medical transportation undertaken to the composite hospital, CRPF, Bentalab, J&K during the period and were analyzed for demographics, primary etiology, and events during transport. The causes were grouped together under the organ system for ease of interpretation. Derived data are presented as mean ± standard deviation and percentage.

Results: 100 patients (100% male) of ages 30 to 45 yrs transported to the station hospital Srinagar and Delhi. The study was conducted after obtaining the proper permission from the Chief Medical Officer incharge (NFSG) of the Composite Hospital, CRPF. Cardiac and central nervous system ailments are the most common indication for air medical transportation like intubation, monitoring of vitals (pulse, BP, Sa, O2 etc.) followed by CPR required. The overall complication rate was 5.3% There was no transport related mortality. Thus having more merits than demerits.

Conclusion: Patients who are transported with a medical escort may need invasive and advanced monitoring and interventions. Cardiovascular diseases remain the most common reason for interhospital air medical transport. Complication rate during interhospital air transportation of critical patients is similar to ground trans-portation. Keywords: Air ambulance, air medical transportation, critical care, Cardio Pulmonary Resuscitation (CPR)

INTRODUCTION

Air medical transportation has greatly evolved under-taken by the Indian forces in Kashmir. Many more pa-tients are transported daily in need of advanced med-ical attention to higher centers like Srinagar M.H & AIIMS & M.H Delhi. These are interhospital transfers of critical patients using the available air infrastruc-ture.

Most individuals with mild to moderate medical or surgical conditions are able to travel safely in a normal cabin seat with some assistance from the airline in the form of wheelchair and oxygen in case of emergency 1 Some patients need either a stretcher in a commercial scheduled flight or a smaller dedicated chartered flight with all medical equipment and medical staff experi-enced to handle the situation. This may include con-tinuous oxygen supply, airway management, cardiac monitoring, and interventions.

On case basis, the cost of air medical transportation may seem expensive when compared to ground trans-portation and even in comparison to the actual cost of treatment. On the contrary, studies show it is cost ef-fective due to the decrease in time to treatment2 sur-vival benefits3 and quality of life years added4. Over the past decade, wide availability of air ambulance ser-vices has brought a reduction in mortality and mor-bidity in India5. Some of these patients are in serious medical condition and require urgent transportation and life-saving intervention by our dedicated air trans-portation team. We present our experience based on 2 years of activity with the domestic air transfer.

METHODOLOGY

This is a retrospective analysis of all air medical trans-portations undertaken by the hospital 1998 to 2000. Predetermined demographic and variable parameters were accessed from medical records of all air medical



transportation undertaken to the composite hospital, CRPF, Bentalab, J&K after due clearance from hospi-tal authorities and fed into an Excel sheet for analysis. The primary underlying cause identified was recorded as the underlying indication for transportation. The causes were grouped together under the organ system for ease of interpretation. Derived data are presented as mean ± standard deviation and percentage. Evacu-ation time was defined as time from actual possession of the patient at the transferee hospital to handing over to primary admitting team at the transferred hos-pital.

It is important to note that all transportations were carried out by our team and subsequently admitted to our hospital, after a request for the same was received from the next of kin or legal guardian. Fixed wing air-craft were used in all transportations.

Aircraft: The aircraft can accommodate 2 doctors, 1 nurse, 1 accompanying person and the patient on a stretcher (figure 1). These small unscheduled flights can be arranged on short notice, and can land and take off from small airstrips.

Figure 1: 6 Seater Medical Aircraft Commercial flights are the routine scheduled opera-tions of the airlines between airports. Most aircrafts can have seats customized to accommodate a stretcher on a prior request and approval by the air-lines.

Equipment: Standard equipment for all medical transport includes airway management devices (laryn-goscope, endotracheal tubes, tracheostomy tubes etc.), patient monitors, vascular access devices, and adequate number of oxygen cylinders.

Staffs: Medical staff included 1 to 2 doctors and a nurse depending on the criticality of the case. Thus selection of highly motivated staff is very important.

Procedure: All medical transports are under direct supervision of the Chairman, critical care and trauma of our institute. Request for transport of patients to the hospital is usually received by the hospital call cen-ter which is directed to the operations manager who acts as the coordinator between all concerned. He takes situation from the doctor where the patient is admitted, alerts the admitting specialty of our hospital, checks for availability of aircraft, applies for clearances from airport authorities and assembles the team of flight medical staff for preparations accordingly. The team is dispatched to the airport after affirmation from all concerned.

The accompanying staff is usually one doctor and one nurse. All equipment and patient responsibility have to be borne by the accompanying doctor. The transport team, the patient’s family and the operations manager remain in constant touch and appraise each other of the patient’s condition and his/her further requirement all the time till the patient is handed over to the admitting team.

RESULTS

Within 2 years of study period, 100 patients were air transported to the hospital, Srinagar & Delhi (MH & AIIMS). Patient demographics and mission details are presented in Table 1. Central nervous system disease including head injury and stroke in 100 patients was the most common indication [Table 2].

Table 1: Demographic profile of patients

Variable Value

Total Patients 100 Mean age of males 35 to 45 yrs Average Evacuation time 1-2 hrs

Table 2: Etiology (n=100)

Etiology No.

Central nervous disease with head injury 80 Trauma other than head injury 20

Five patients were intubated on board by the anesthe-tist/ critical care physician. The indication for tracheal intubation was cardiorespiratory arrest in 2 and inabil-ity to maintain oxygen saturation with noninvasive ventilation in 4 patients. Oneendotracheal tube-changeforcuff malfunction and 5 tube depth change were needed for optimalventilation. Four patients needed cardio pulmonary resuscitation (CPR) during transportation out of which 2 died.

Inotropic and vasopressor infusion was used. This in-cluded 50 (45.8%) patients on a single drug. Most commonly used single agent was noradrenaline infu-sion in 32 patients. 59 (54.2%) patients were on more

Cockpit Medical

Equipment

Cargo Door for Stretcher

Seat Seat Seat

Seat Stretcher



than 2 inotropes. The most common inotropic com-bination used at the receiving hospital was dopamine and noradrenaline in 25 patients.

DISCUSSION

Prehospital and transportation data analysis has been done earlier, and it gives an insight into the de-mographics and travel patterns of the particular coun-tries.6,7 There are a few commentaries on the unique-ness of air medical transport scenario in India.8

The main patient-related concerns when air transport-ing a critical patient are the low atmospheric pressure and gas expansion effects of altitude, patient and fam-ily anxiety; and movement related complications. Fixed wing propeller aircrafts fly at an altitude of 15,000-30,000 feet. Barometric pressure decreases from 760 mm Hg at sea level to 226 mm Hg at 30,000 feet. The aircraft cabin is pressurized to an equivalent pressures of 5000-8000 feet which corresponds to a PO2 (inspired) of 107 mm Hg.9 This PiO2 is easily tolerated by normal individuals but in critical patients with limited reserves, it causes hyperventilation and tachycardia with an increase in cardiac output. This may also alter the need of vasopressors and inotropes and can be particularly detrimental to patients with underlying respiratory or cardiac diseases.10

Ground transportation may seem cheaper than air transportation. Some emergencies are potentially life or limb threatening and require urgent care and speedy transport to an advanced care center. This has been made possible only by air medical transportation with proven benefits in survival.2-4 Bruhn et al. created an economical model to compare the cost of air ambu-lance services and ground ambulance services.

Almost all districts in India have access to either a ci-vilian or military airstrip which can be used for air am-bulance services on request to competent authori-ties.11 There is an inequitable distribution of tertiary care hospitals in India.12 Further, access to internet has made it easy to locate and communicate with specialty centers worldwide.

The condition of the air transported patients is the same as in any other critical area of the hospital and thus necessitates the same monitoring and interven-tions in a totally different environment.13 This requires specialized equipment and trained staff. At present, there is no air medical training facility for civilians in India.14 Norton pointed that there is a need for air medical transport curriculum for emergency medical residents.15 We feel there is a need of a structured ac-creditation policy and training program to bring ac-countability to the mushrooming air ambulance busi-ness in India. There is a need for trained medical staff,

equipment, and dedicated aircraft to fill in the gap cre-ated by the inequitable distribution of hospitals in In-dia.

CONCLUSION

Patients who are transported with a medical escort may need invasive and advanced monitoring and in-terventions as in any critical care area of the hospital. Cardiovascular diseases remain the most common reason for interhospital air medical transport. Compli-cation rate during interhospital air transportation of critical patients is similar to ground transportation.

REFERENCE

1. International Air Transport Association. [www.iata.org] Med-ical Manual; c2013. Available from: http://www.iata.org /whatwedo/safety/health/Documents/medical-manual-2013.pdf. [Last accessed on 2014 Feb 02].

2. Phillips M, Arthur AO, Chandwaney R, Hatfield J, Brown B, Pogue K, et al. Helicopter transport effectiveness of patients for primary percutaneous coronary intervention. Air Med J 2013;32:144-52.

3. 4. Gearhart PA, Wuerz R, Localio AR. Cost-effectiveness analysis of helicopter EMS for trauma patients. Ann Emerg Med 1997;30:500-6.

4. Silbergleit R, Scott PA, Lowell MJ, Silbergleit R. Cost-effec-tiveness of helicopter transport of stroke patients for throm-bolysis. Acad Emerg Med 2003;10:966-72.

5. Mehra A. Air ambulance services in India. J Postgrad Med 2000;46:314-7.

6. Judi C, Frank T. A 10-year analysis of 214 HEMS backcountry hoist rescues. Air Med J 2012;32:64-5.

7. Wegmann F, Kromann-Andersen B, Staehr Johansen T, Jessen K. Sixteen years with the Danish search and rescue hel-icopter service. Aviat Space Environ Med 1990;61:436-9.

8. Chawla NP, Chawla K. Against all odds: Air medical transport in India. Air Med J 1998;17:146-8.

9. Khera R, Jain S, Lodha R, Ramakrishnan S. Gender bias in child care and child health: Global patterns. Arch Dis Child 2014;99:369-74.

10. American Medical Association. Medical aspects of transporta-tion aboard commertial aircraft. J Am Med Assoc 1982; 247:1007-11.

11. Cong H. Air travel and oxygen therapy in cardiopulmonary disorders. Chest 1992;101:463-76.

12. Airports Authority of India [www.aai.aero]. New Delhi List of Airports. Available from: http://www.aai.aero/public_ no-tices/aaisite_test/policy.jsp#4.[Accessed on 2014 Feb 02].

13. Lackner CK, Stolpe E. New order of things: An international overview of air medical transport. Air Med J 1998;17:142-5. 20. Fromm RE Jr, Varon J. Critical care transport. Crit Care Clin 2000;16:695-705.

14. Aggarwal NN, Aggarwal S. Transfer of sick children by air. Indian Pediatr 2000;37:853-71.



ORIGINAL ARTICLE

COMPARING CLINICAL DIAGNOSIS AND LABORATORY DIAGNOSIS IN PAEDIATRIC PATIENTS OF ACUTE VIRAL HEPATITIS IN AHMEDABAD, GUJARAT Ekta A Dalal1, Gaurav Vishal2 Author’s Affiliations: 1Associate Professor Department of Pediatrics, GMERS Medical College Gandhinagar, Gujarat; 2Consultant Pediatrician, Gujarat Correspondence: Dr. Ekta A Dalal Email: [email protected]

ABSTRACT

Introduction: During the last 30 years, Paediatric hepatology has been transformed by advances in our under-standing and management of a wide spectrum of liver diseases. Globally however, viral hepatitis remains one of the most important causes of liver disease in children. Typical symptoms of acute hepatitis are fatigue, ano-rexia, nausea, and vomiting. Very high aminotransferase values (>1000 U/L) and hyperbilirubinemia are often observed. The objective of the study was to compare the clinical diagnosis and laboratory diagnosis. Methodology: The current study was conducted in Paediatric department of tertiary care hospital of Ahmed-abad, Gujarat, India. It was a record based cross sectional study. Complete data of basic socio demographic profile, symptoms, signs, all laboratory investigations, outcome of patients were obtained and analysed. Results: There were total 150 cases of symptoms of acute viral hepatitis fulfilling inclusion criteria in Paediatric department. It was observed that first rise in cases was seen in the month of June and another peak was seen in the month of September. After September, there was rapid fall in total number of cases. Yellow sclera (94.67%) and yellow colour urine (93.33%) were most common symptoms reported by patients, followed by fever (88.67%) & loss of appetite (73.33%). Icterus (94.67%) and Subcostal Tenderness (66.67%) were most common sign. Conclusion: Clinical diagnosis corresponds laboratory investigations and whenever laboratory facility is not accessible, further management should be started at the earliest as per clinical diagnosis of viral hepatitis in children to prevent mortality. Majority of the patients had bilirubin below 10 mg/dl 126 patients (84%), while 12 (8%), patients had bilirubin up to 15, 7 (4.67%) between 15-20 mg/dl. Mean Serum bilirubin was 7.28 mg/dl. Keywords: Hepatitis, SGPT, S. Bilirubin, Icterus INTRODUCTION

During the last 30 years, Paediatric hepatology has been transformed by advances in our understanding and management of a wide spectrum of liver diseases. Globally however, viral hepatitis remains one of the most important causes of liver disease in children. Ma-jor advances in this field include the implementation of hepatitis B virus (HBV) and hepatitis A virus (HAV) vaccination, definition of the immunologic phases of HBV infection, and the development of treatments for chronic HBV infection. Advances in virology, epidemiology, and therapeutics have led to considerable progress in understanding and managing hepatitis infection in childhood.1,2,3

In developing countries, where routine HAV vaccina-tion is not available, HAV infection is still common and is a leading cause of acute liver failure (ALF). This is in stark contrast to developed countries where the infection risk is now low. HBV infection remains a global public health problem. Although vaccination

has reduced the prevalence of chronic hepatitis B in-fection in many countries, it is still high in areas such as Western Africa and Asia. Human immunodefi-ciency virus (HIV) coinfection has added to the com-plexity of managing these children. Although less common than HAV and HBV infection, increasing numbers of children with HCV are presenting for treatment.4 Viral pathogens are the main cause of hep-atitis in Asian children. Of these viruses, HBV infec-tion remains a major health hazard in Asia because of its high prevalence and the severe complications of chronic infection. This problem persists in children even in the era of HBV vaccination.

HAV (South and South-East Asia) and HEV (Central and South-East Asia) are endemic in parts of Asia. HAV and HEV are transmitted through the fecal-oral route and transmission is significantly associated with poor hygiene.5,6 HAV and HEV infections are gener-ally mild and self-limiting diseases in immune-compe-tent children, although rarely ALF may occur. Typical symptoms of acute hepatitis are fatigue, anorexia, nau-sea, and vomiting. Very high aminotransferase values



(>1000 U/L) and hyperbilirubinemia are often ob-served. Severe cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic synthetic function.7 Acute liver injury caused by the hepatotropic viruses manifests in 3 main functional liver biochemical profiles. These serve as an important guide to supportive care and monitoring in the acute phase of the infection for all viruses. As a reflection of cytopathic injury to the hepatocytes, there is a rise in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Rapidly falling ami-notransferase levels can predict a poor outcome, par-ticularly if their decline occurs in conjunction with a rising bilirubin level and a prolonged prothrombin time; this combination of findings usually indicates that massive hepatic injury has occurred.

Cholestasis, defined by elevated serum conjugated bili-rubin levels, results from abnormal bile flow at the canalicular and cellular level due to hepatocyte damage and inflammatory mediators. Elevation of serum alka-line phosphatase (ALP), 5′-nucleotidase, γ-glutamyl transpeptidase (GGT), and urobilinogen all mark cho-lestasis. Improvement tends to parallel the acute hep-atitis phase. The most important marker of liver injury is altered synthetic function. Abnormal liver synthetic function is a marker of liver failure and is an indication for prompt referral to a transplant center. Serial as-sessment is necessary because liver dysfunction does not progress linearly. Synthetic dysfunction is re-flected by a combination of abnormal protein synthe-sis (prolonged prothrombin time, high international normalized ratio [INR], low serum albumin levels), metabolic disturbances (hypoglycemia, lactic acidosis, hyperammonemia), poor clearance of medications de-pendent on liver function, and altered sensorium with increased deep tendon reflexes. The objective of the study was to compare the clinical diagnosis and labor-atory diagnosis.

METHODOLOGY

The current study was conducted in Paediatric depart-ment of tertiary care hospital of Ahmedabad, Gujarat, India. It was a record based cross sectional study. Rec-ords of all patients admitted in paediatric ward during the study period of October 2011 to September 2013 with symptoms of acute viral hepatitis, not having chronic hepatitis, obstructive jaundice, portal hyper-tension, underlying liver disease, poisoning, toxin or drug induced hepatitis and patients with complete data were enrolled in the study.

Patients age less than one month or patients with in-complete data were excluded from the study. Records of Patients having incomplete data were excluded.

Permission of Institutional Ethical Committee and hospital administration were taken to obtain the data

and conduct the study. Confidentiality of data was maintained at all level.

Complete data of basic socio demographic profile, symptoms, signs, all laboratory investigations, out-come of patients were obtained.

Data analysis: Data was entered in Microsoft excel and analyse in excel itself.

RESULTS

There were total 150 cases of symptoms of acute viral hepatitis fulfilling inclusion criteria in Paediatric de-partment.

Figure 1: Trend of Hepatitis infection

Figure 1 shows trend of Hepatitis infection during whole year. It was observed that first rise in cases was seen in the month of June and another peak was seen in the month of September. After September, there was rapid fall in total number of cases.

Yellow sclera (94.67%) and yellow colour urine (93.33%) were most common symptoms reported by patients, followed by fever (88.67%) & loss of appetite (73.33%). Icterus (94.67%) and Subcostal Tenderness (66.67%) were most common sign.

Table 1 shows that Yellow sclera, yellow urine, Fever, Loss of Appetite and Nausea/Vomiting were com-mon symptoms. It was observed that out of 150 study participants, 142 (94.67%) of patients were having yel-low sclera, 140 (93.33%) were having yellow sclera and 133 (88.67%) were having fever. Table also shows that Icterus and subcostal tenderness were most common signs in study participants.

Table 1: Sign and Symptoms wise distribution of study participants (N=150)

Symptoms No. (%)

Loss of Appetite 110 (73.33)

24

8

0

4

34

22

26

38

9

3

00

5

10

15

20

25

30

35

40

No

. o

f C

ase



Nausea/Vomiting 90 (60.0) Abdominal Pain 78 (52.0) Abdominal Distension 42 (28.0) Yellow Sclera 142 (94.67) Yellow Urine 140 (93.33) Fever 133 (88.67) Seizures 12 (8.0)

Signs No. (%)

Icterus 142 (94.67) Subcostal Tenderness 100 (66.67) GI Haemorrage 46 (30.67) Splenomegaly 24 (16.0) Ascites 22 (14.67) Pruritus 22 (14.67)

Majority of the patients had bilirubin below 10 mg/dl 126 patients (84%), while 12 (8%), patients had biliru-bin up to 15, 7 (4.67%) between 15-20 mg/dl. Mean Serum bilirubin was 7.28 mg/dl. Considering SGPT, total 15 (10%) of patients were having SGPT of 0-500 IU/L. Total 22 (14.7%) and 48 (32%) patients were having SGPT of 1001 to 1500 IU/L and 1501 to 2000 IU/L.

Table 3 shows that maximum number of deaths occur due to Hepatitis A and children less than 5 years of age were major culprit.

Table 2: Important Laboratory investigations of study participants

Lab Investigations No. (%)

S. Bilirubin (mg/dl) 0-5 66 (44.0) 5.1-10 60 (40.0) 10.1-15 12 (8.0) 15.1-20 7 (4.7) 20.1-25 3 (2.0) >25 2 (1.3)

SGPT (IU/L) 0-500 15 (10.0) 501-1000 18 (12.0) 1001-1500 22 (14.7) 1501-2000 48 (32.0) 2001-2500 28 (18.7) 2501-3000 10 (6.7) 3001-3500 2 (1.3) 3501-4000 3 (2) >4000 4 (2.7)

Table 3: Incidence of fulminant hepatic failure in relation to age distribution and mortality

Age Group Hepatitis A (%) Hepatitis E (%) Hepatitis A & E (%)

Hepatitis B (%) Other (%) Total (%)

< 5 54 (85.71) 4 (6.35) 2 (3.17) 3 (4.76) 4 (6.35) 63 (100) 5-10 28 (58.33) 12 (25.0) 6 (12.50) 2 (4.17) 3 (6.25) 48 (100) 10 – 16 6 (20.00) 20 (66.67) 4 (13.33) 0 2 (6.67) 30 (100)

DISCUSSION

There were total 150 cases admitted in the hospital during the study period. Trend of Hepatitis infection during whole year shows two peaks first in June and another September. After September, there was rapid fall in total number of cases.

Based on data from 28 studies, irregular, cyclical pat-terns were observed for acute viral hepatitis, with most prominent peaks were shown in spring and sum-mer for hepatitis A; B; C and E in some of the coun-tries subjects. These findings have been explained by some authors as due to summer travel to an endemic area, swimming habits of the population in hot months, increase sexual contact, tattoo, poor hygiene and environmental sanitation, and food habits (feco-oral transmission of viral hepatitis).8,9

HAV and HEV are communicable by way of the fe-cal-oral. On the other hand, HBV, HCV are conta-gious by blood and blood products, also may be trans-mitted by sexual intercourse and household exposure to an infected contact, exposure to multiple partners and perinatal exposure, particularly for hepatitis C, but

the efficiency of transmission in these settings appears to be low.

Hepatitis A virus is an extremely stable virus and can survive for 12 weeks to 10 months in water.10,11 This stability accounts for the frequent occurrence of wa-terborne and shellfish-transmitted outbreaks.12,13 In this regard, the virus is relatively resistant to heat or chemical inactivation and this situation allow the dis-semination of HAV infection. Therefore, disruption of sanitation and water supplies was the most likely contributing factor for the seasonal occurrence of hepatitis A and E.

In our study it was observed that in all patients having two or more symptoms and signs suggestive of Hep-atitis, laboratory markers are raised considerably. Clin-ical management of Hepatitis is simple if started early. Early treatment also halts the progression of disease and prevents further complication. Thus, whenever laboratory facility is not accessible, further manage-ment should be started at the earliest as per clinical diagnosis of viral hepatitis in children to prevent com-plications and mortality.



REFERENCES

1. Jonas MM, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology 2010;52:2192–205.

2. Haber BA, Block JM, Jonas MM, et al. Hepatitis B Founda-tion. Recommendations for screening, monitoring, and refer-ral of pediatric chronic hepatitis B. Pediatrics 2009; 124:e1007–e1013.

3. Mack CL, Gonzalez-Peralta RP, Gupta N, et al. NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gas-troenterol Nutr 2012; 54:838–855.

4. Hepatitis in Children. http://jour-nals.lww.com/jpgn/Fulltext/2012/11000/Viral_Hepati-tis_in_Children.7.aspx. Last accessed on 10th October, 2016

5. Barameechai K, Sa-Nguanmoo P, Suwannakarn K, et al. Mo-lecular characterisation of the hepatitis A virus circulating in the 2001–2005 outbreaks in Thailand. Ann Trop Med Parasi-tol 2008; 102:247–257.

6. Zhu FC, Zhang J, Zhang XF, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomized, double-blind placebo-controlled, phase 3 trial. Lancet 2010; 376:732–734.

7. Hepatitis. http://emedicine.medscape.com/article/775507-overview. Last accessed on 10th October, 2016

8. Al-Naaimi AS, Turky AM, Khaleel HA, Jalil RW, Mekhlef OA, Kareem SA, et al. Predicting acute viral hepatitis serum markers (A and E) in patients with suspected acute viral hep-atitis attending primary health care centers in Baghdad: A one year cross-sectional study. Glob J Health Sci. 2012;4:172–83.

9. Villar LM, De Paula VS, Gaspar AM. Seasonal variation of hepatitis A virus infection in the city of Rio de Janeiro, Brazil. Rev Inst Med Trop Sao Paulo. 2002;44:289–92.

10. Biziagos E, Passagot J, Crance JM, Deloince R. Long-term survival of hepatitis A virus and poliovirus type 1 in mineral water. Appl Environ Microbiol. 1988;54:2705–10.

11. Sattar SA, Jason T, Bidawid S, Farber J. Foodborne spread of hepatitis A: Recent studies on virus survival, transfer and in-activation. Can J Infect Dis. 2000;11:159–63.

12. Velázquez O, Stetler HC, Avila C, Ornelas G, Alvarez C, Had-ler SC, et al. Epidemic transmission of enterically transmitted non-A, non-B hepatitis in Mexico, 1986-1987. JAMA. 1990;263:3281–5.

13. Leoni E, Bevini C, Degli Esposti S, Graziano A. An outbreak of intrafamiliar hepatitis A associated with clam consumption: Epidemic transmission to a school community. Eur J Epi-demiol. 1998;14:187–92.



ORIGINAL ARTICLE

STUDY OF ADVERSE DRUG REACTION IN ANAESTHESIA PRACTICE Rachana Gandhi1, Ila Patel2, Alka Shah1 Author’s Affiliations: 1Assistant Professor, 1Associate Professor, Dept. of Anaesthesia, GMERS Medical College Sola, Ahmedabad, Gujarat Correspondence: Dr. Rachana Gandhi Email: [email protected]

ABSTRACT

Introduction: Adverse drug reaction generally occurs on re-exposure to a specific antigen and requires the release of pro-inflammatory mediators, but it can also occur on first exposure, because there is cross-reactivity among many commercial products and drugs. Thus present study was aimed to study the incidence of adverse drug reactions, and to identify common drugs, that causes adverse drug reaction.

Methodology: Patients included in study were all age groups undergoing different types of surgery under an-aesthesia from June 2006 to October 2008 at civil hospital, Ahmedabad. Total 77 patients included in the study were examined preoperatively and history noted in proforma. Perioperatively any type of localized or general-ized reactions of any organ system involved also noted.

Results: Majority of the patients had reactions due to muscle relaxants (20.77%) followed by colloids (19.48%). Haemacele was most common 9.09%, among all colloids causing ADR. Among IV induction agent thiopental (6.49%) was most common followed by Propofol (5.19%). Bronchospasm was the most common reaction occurring about (37.66%) of the patients. Urticaria (23.37%), Rigors (12.98%), Hypotension (9.09%) and others like rash, itching, collapse, convulsion etc, occur in (16.78%).

Conclusion: Drugs involved in adverse drug reactions were Muscle relaxants, Colloids, I.V induction agents, Antibiotics, BT, Rantac, Emset and other drugs like local anesthetics, methyl methacrylate cement used in re-placement surgeries causes reaction. Muscle relaxants, IV induction agents, colloids are the most common an-esthetic drugs or substances that may lead to anaphylaxis.

Keywords: Adverse Drug Reaction, Haemacele, Bronchospasm, Urticaria, Convulsion

INTRODUCTION

Adverse drug reaction generally occurs on re-expo-sure to a specific antigen and requires the release of pro-inflammatory mediators, but it can also occur on first exposure, because there is cross-reactivity among many commercial products and drugs. Anaphylaxis is generally an unanticipated severe allergic reaction, of-ten explosive in onset that can occur perioperatively, especially during a surgical procedure when multiple drugs are administered during the conduction of an anesthetic.

A survey of drug reaction during anesthesia demon-strated that cardiovascular symptoms (73.6%), cutane-ous symptoms (69.6%) and bronchospasm (44.2%) were the most common clinical features. 1 Incidence of anaphylaxis and anaphylactoid reaction during an-esthesia has been calculated to range from 1 in 3,500 to 1 in 13,000 cases.

Muscle relaxants are associated with the most frequent incidence of anaphylaxis, and over the two decades, natural rubber latex has emerged as the second most

common cause of anaphylaxis. Incidence of cause of latex anaphylaxis is decreasing as a result of identifica-tion of at-risk patients and prevention measures. An-tibiotics and induction drugs account for the next group of drugs more likely to lead to anaphylactic re-actions. Muscle relaxants (69.1%) and latex (12.1%) were the most frequently involved drugs according to the most recent French epidemiological survey.

Pre and postoperative investigation must be per-formed to confirm the nature of the reaction, the re-sponsibility of the suspected drugs and to provide pre-cise recommendations for future anesthetic proce-dures. These include plasma histamine, tryptase and specific IgE concentration determination at the time of the reaction and at skin tests 6 weeks later. Treat-ment of anaphylaxis is aimed at interrupting contact with the responsible antigen, inhibiting mediator pro-duction and release, and modulating the effects of re-leased mediators. It must be initiated as quickly as pos-sible and relies on widely accepted principles.



Thus present study was aimed to study the incidence of adverse drug reactions, and to identify common drugs, that causes adverse drug reaction.

METHODOLOGY

This Study was conducted at B.J.Medical College, Civil Hospital, Ahmedabad, after taking Ethical Com-mittee clearance.

Selection of Patients: Patients included in study were all age groups undergoing different types of surgery under anaesthesia from June 2006 to October 2008 at civil hospital, Ahmedabad.

Inclusion Criteria: Patients fulfilling all of the below criteria were included in the study.

1) Patients with no previous anesthesia exposure. 2) Patients with no history of previous adverse drug

reactions. 3) ASA Risk category I AND II patients. 4) Adverse event appear after the suspected drug was

administrated. 5) Adverse reaction improves when the drug was dis-

continued or a specific antagonist was administered. 6) Patients willing to participate in the study and agree

to give informed written consent.

Exclusion Criteria: Patients fulfilling any of the be-low criteria were excluded from the study.

1) Patients with previous anesthesia exposure.

2) Patients with previous history of drug reactions.

3) ASA Risk category III and IV patients.

4) Patients not willing to participate in the study and not agree to give informed written consent.

Patients included in the study were examined preoper-atively and history noted in proforma. Perioperatively any type of localized or generalized reactions of any organ system involved also noted.

Reactions if any were observed were: Cutaneous Le-sions: Rash/ erythema, urticaria, itching, burning, pain at site, pigmentation; Respiratory system: Bron-chospasm, pulmonary oedema, respiratory depres-sion, hypoxia, cyanosis; Cardiovascular system: Hypo-tension, bradycardia, collapse, cardiac dysrhythmias; Gastro-intestinal system: Nausea, vomiting; Central nervous system: Delirium, disorientation, convulsion; Renal system: Decreased urine output (oliguria / anu-ria).

According to the type of drug reaction, treatment was given in the form of anti-histaminic, corticosteroid drugs and IV fluids. Treatment given was recorded in proforma. Recorded data was analyzed statistically and Mean as well as S.D, was analyzed with the help of computer software.

RESULTS

This study was conducted at B.J.Medical College, Civil Hospital, Ahmedabad. Total number of the patients operated was 57,605. Out of those 77 patients were observed having adverse drug reaction. Following ob-servation and results were recorded from patients hav-ing drug reactions.

Table 1: Distribution of drugs causing adverse drug reaction (N=77)

Name of drug No. (%)

Muscle relaxant 16 (20.77) Depolarizing (Scoline) 6 (7.79) Non depolarizing (Nor + Atra )

10 (12.98)

Colloids 15 (19.48) Haemacele 7 (9.09) Microspan 5 (6.49) Dextran-40 3 (3.89)

IV induction agent 11 (14.28) Thiopental 5 (6.49) Propofol 4 (5.19) Ketamine 2 (2.59)

Antibiotics 10 (12.98) Blood Transfusion 7 (9.09) Rantac 6 (7.79) Emset 3 (3.89) Others 9 (11.68)

Majority of the patients had reactions due to muscle relaxants (20.77%) followed by colloids (19.48%). Only three muscle relaxants were used named Scoline, Atracurium, and Norqurone. Other drugs have been not used. Haemacele was most common 9.09%, among all colloids causing ADR. Among IV induction agent thiopental (6.49%) was most common followed by propofol (5.19%) for causing ADR.

Table 2: Type of reaction (N=77)

Type of reaction No. (%)

Bronchospasm 29 (37.66) Urticaria 18 (23.37) Rigors 18 (12.98) Hypotension 7 (9.09) Others 13 (16.78)

Bronchospasm was the most common reaction occur-ring about (37.66%) of the patients. Urticaria (23.37%), Rigors (12.98%), Hypotension (9.09%) and others like rash, itching, collapse, convulsion etc, oc-cur in (16.78%).

DISCUSSION

An adverse drug reaction generally occurs on re-expo-sure to a specific antigen and requires the release of pro inflammatory mediators, but it can also occur on



first exposure because there is cross reactivity among many commercial products and drugs. By definition, Any noxious change which is suspected to be due to a drug occurs at doses normally used in man, requires treatment or decrease in dose or indicates caution in future use of same drug is called adverse drug reaction.

One study was conducted In France with repeated in-quiries by the perioperative anaphylactic reactions study group. Laxenaire MC.1 had done survey. The survey concerned 1,750 patients tested in 27 diagnos-tic centers, from January 1992 to June 1994. The reac-tions occurred at all ages, predominantly between 10 and 50 years, the sex-ratio (F/M) was 2.4. IgE depend-ent anaphylaxis--was diagnosed in 1,000 patients (57.8%) and due to 1,030 agents muscle relaxants (59.2%), latex (19%), hypnotics (5.9%), benzodiaze-pines (2.1%), Opioids (3.5%), plasma substitutes (5%), antibiotics (3.1%) and other drugs given during anaesthesia such as aprotinine and protamine (2.2%). Suxamethonium was responsible for 39.3% of muscle relaxant anaphylaxis, vecuronium for 36%, atracurium for 14.5%, pancuronium for 4.8%, gallamine for 3.1% and alcuronium for 2.3%.

Another study done by Paul Michel.7 Anaphylactic and anaphylactoid reactions were diagnosed in 518 cases (66%) and 271 cases (34%), respectively. The most common causes of anaphylaxis were neuromus-cular blocking agents (NMBAs) (n = 306, 58.2%), la-tex (n = 88, 16.7%), and antibiotics (n= 79, 15.1%). Rocuronium (n = 132, 43.1%) and succinylcholine (n = 69, 22.6%) were the most frequently incriminated NMBAs.

In our study reactions were also most common be-tween 10 to 50 years and female are more prone as compared to males. Mean age of the patients is 40.13 ± 13.31. in years. Sex difference include females (56%) more common then males (44%). Drugs involved in adverse drug reactions were Muscle relaxants (20.77%), Colloids (19.48%), I.V induction agents (14.28%), Antibiotics (12.98%) BT (9.09%), Rantac (7.79%), Emset (3.89%) and other drugs like local an-esthetics, methyl methacrylate cement used in replace-ment surgeries causes (11.68%) reactions. So our study correlates with above two studies.

Study done by Laxenaire MC.2 anaphylactic reactions to anesthetic and associated agents used during the perioperative period have been reported with increas-ing frequency in most developed countries. Most pub-lished reports on the incidence of anaphylaxis come from France, Australia, the UK and New Zealand. The estimated incidence of anaphylaxis ranges from 1:10,000 to 1:20,000. Muscle relaxants (69.1%) and la-tex (12.1%) were the most frequently involved drugs according to the most recent French epidemiological survey. The present study also showed that muscle re-laxants were most common among drugs causing ad-verse drug reactions.

One study done by Laxenaire MC.1 Study was carried out in 49 public and private hospitals spread through out France. A series of albumin and 95% of dextrans, 43 anaphylactoid reactions were recorded, giving an overall frequency of 0.219%, or one reaction for 456 patients. The frequency differed according to the sub-stitute considered: 0.345% for gelatins, 0.273% for dextrans, 0.099% for albumin and 0.058% for HES.

In our study reaction due to Colloids was 19.48%. Difference in result of colloid study may be due to that, in our institution we used more colloid agents in-stead of blood.

Regarding anaphylactic reactions due to antibiotics, one study done by Soupramanien Sivagnanam.6 the study was done on Vancomycin. Vancomycin can cause two types of hypersensitivity reactions, the red man syndrome and anaphylaxis.

Red man syndrome has often been associated with rapid infusion of the first dose of the drug and was initially attributed to impurities found in vancomycin preparations. Even after improvement in vancomycin purity, however, reports of the syndrome persist. Other antibiotics (e.g. ciprofloxacin, amphotericinB, rifampicin and teicoplanin) or other drugs that stimu-late histamine release can result in red man syndrome.

Other study done by T.Ayyappan Pillai et al.3 Case re-port on, drug reaction due to i.v cefotaxime in burn patient.

In our study antibiotics were responsible for 12.98% reactions. Most common antibiotics were cefotaxime and other include vancomycin because we had used vancomycin in only patients of open heart surgeries.

Regarding IV induction agents one study done by Nishiyama. T, Hanaoka. K.4 at France on propofol in-duced bronchoconstriction. According to their study about 1.2% of cases of perioperative anaphylactic shock were attributable to propofol. According to our study reaction due to propofol was 5.19%, which cor-relates with above study.

According to our study the most common drug caus-ing adverse drug reactions was muscle relaxants, fol-lowed by colloids. Other common being i.v induction agents, blood, benzodiazepines, opioids, and antibiot-ics. These results were comparable with above studies.

According to our study most common type of reac-tion was Bronchospasm in (37.66%). Other reactions include Urticaria (23.37%), Hypotension (9.09%), Ri-gors (12.98%) and other like rash, itching, etc. in (16.78%).

There were some variation in results because of those studies were carried out wide spread across multiple centers and thousands of patients, but our study was single institution based involvement.



CONCLUSION

Drugs involved in adverse drug reactions were Muscle relaxants, Colloids, I.V induction agents, Antibiotics, BT, Rantac, Emset and other drugs like local anesthet-ics, methyl methacrylate cement used in replacement surgeries causes reaction. Muscle relaxants, IV induc-tion agents, colloids are the most common anesthetic drugs or substances that may lead to anaphylaxis.

Most common type of reaction was bronchospasm. Other reactions include Urticaria, Hypotension, Ri-gors and other like rash, itching, etc.

Drug reactions can occur to any of patient coming for surgery with any of drug and sometimes these reac-tions are fatal so prevention is the most important component to decrease the incidence of anaphylaxis.

REFERENCE

1. Laxenaire MC, Feldman L. Anaphylactoid reactions to colloid plasma substitutes. Ann Fr Anesth Reanim. 1994; 13: 301-310.

2. Laxenaire MC. Substances responsible for peranesthetic ana-phylactic shock. A third French multicenter study. Ann Fr Anesth Reanim.1996; 18: 796-809.

3. T. Ayyappan Pillai, Ashwani Kumar Jalewab, Indu A Chadha. Antibiotic prophylaxis- Hobson’s choice in burns manage-ment. Journal of international society for burns injuries. 1998; 24: 760-762.

4. Nishiyama.T, Hanaoka.K. Propofol induced bronchocon-striction; two case reports. Aneasth Analg. 2001; 93: 645-646.

5. S. Moorthy. Anaphylactoid Reaction to Etomidate: Report of a Case. Journal of Clinical Anesthesia. 2003; 13: 582 – 584.

6. Soupramanien Sivagnanam and Dirk Deleu. Red man syn-drome. Crit Care. 2003; 7: 119–120.

7. Paul Michel, Laxenaire, Marie-Claire; Anaphylactoid reactions during anesthesia, anesthesiology. 2003; 99: 536-545.

8. Paul Michel, Laxenaire, Marie-Claire; Anaphylactoid reactions during anesthesia, anesthesiology. 2003; 99: 536-545.

9. Amir-Ali Sohrabpour, Mehdi Saberi-Firooz; Halothane hepa-titis in Iran: A review of 59 cases World J Gastroenterol 2008; 14: 5322-5326.

10. Daghfous R, el Aidli S, Sfaxi M, Daghfous M, Kastall S. Hal-othane-induced hepatitis. 8 case reports. Tunis Med 2003; 81: 874-878

11. Laxenaire MC, Moneret- Vaytrin, et al. Anaesthetic drugs re-sponsible for anaphylactic shock. Ann Fr Anesth Reanim. 1990; 9: 501-6.

12. Boston Collababorative Drug Surveillance Survey. Drug in-duced anaphylaxis. JAMA. 1973; 224: 613-15.

13. Fisher M, Munro L. Life threatening anaphylactoid reaction to muscle relaxants. Anesth Analg. 1983; 62: 559-64.

14. Beamish D, Brown DT. Adverse response to iv anesthetics. Br J Anesth.1981; 53: 55-7.



ORIGINAL ARTICLE

RENAL CELL CARCINOMA: MRI AND HISTOPATHOLOGICAL SUBTYPE CORRELATION Rahul H Sharma1, Hinal R Bhagat2, Yash N Jardosh1, Pradip K Anand1 Author’s Affiliations: 1Resident, 2Assistant Professor, Dept. of Radiodiagnosis & Imaging, New Civil Hospital, Surat, Gujarat Correspondence: Dr Rahul H Sharma Email: [email protected]

ABSTRACT

Introduction: Renal cell carcinoma (RCC) is the most common malignant tumor involving the kidney. Ap-proximately 40% of patients with RCC eventually die from progression of this disease, making it the most lethal urologic malignancy. Determining the subtypes of RCC is among major goal in preoperative radiological work up in further management. MRI has advantages of having inherent soft tissue contrast, detection of blood and lipid products and excellent sensitivity to detect small amounts of intravenous contrast. Methodology: In this article, study of histopathological and MRI imaging features of various subtypes of RCC is discussed emphasizing role of MRI in characterization and presurgical staging of renal masses. Results: MRI is particularly helpful in evaluating small lesions which cannot be studied by Ultrasonography (USG) or Computed tomography (CT). Percutaneous biopsy is a minimally invasive method to diagnose renal tumors with accuracy upto 70 to 90%. Apart from diagnosing lesions, MRI along with histopathological subtype is very crucial to decide severity and prognosis of RCC and to guide treatment protocol. Conclusion: RCC is divided into various subtypes according to histopathological examination like clear cell, papillary, collecting duct, chromophobe, multilocular cystic and unclassified variety. Accurate characterization of renal masses is essential to ensure appropriate case management and to assist in staging and prognosis. Keywords: Renal cell carcinoma ( RCC ), Magnetic resonance imaging ( MRI ), Clear cell carcinoma, Tumor to cortex enhancement index, Bosniak grading system

INTRODUCTION

Renal masses are being discovered with increasing fre-quency due to the large number of cross sectional studies being performed in clinical practice1. Deter-mining the histopathological subtype of renal cell car-cinoma better guides further management of tumor2. MRI study of renal mass helps not only determining histopathological subtype of RCC but also differenti-ates the renal cell carcinoma from metastasis in kid-neys which significantly changes further diagnostic al-gorithm for the patient and guides physician to go for other diagnostic tool for primary detection3. Compar-ison of pre and post contrast T1-weighted images is the key to the detection and characterization of renal mass4. Determining the subtypes of RCC is essential for predicting prognosis and managing therapeutic strategies6. In the preoperative radiological work-up, MRI is the best modality for providing important in-formation to diagnose RCC subtypes7. MRI is also helpful in detecting recurrence of RCC from new ma-lignancy in patient treated with partial nephrectomy or kidney salvageable therapeutic management with or without chemotherapy taken8.

METHODOLOGY

Patients presenting with complaints of hematuria, ab-dominal pain or abdominal lump went under screen-ing procedures and diagnosed as renal mass.

We reviewed MR imaging findings and pathological diagnoses in 50 patients encountered over period of 1 year in our institution. MR imaging examinations are performed with a phased arraqy body coil with the pa-tient supine. Each examination includes coronal half Fourier single-shot fast spin echo image( MAGNETOM Essenza 1.5 Tesla MRI Scanner from SIEMENS at AatmaJyoti MRI Centre, New Civil Hospital, Surat ) There are three indispensable com-ponents of renal MRI: breath hold imaging, three di-mensional (3D) gradient echo pulse sequence and fat detection techniques1. The detection of fat is critical in characterizing renal masses2,3. Macroscopic fat is as-sessed using frequency selective fat suppression tech-niques4 , intracytoplasmic vacuoles containing lipids, is assessed using chemical shift imaging, available only in gradient-echo imaging5.

Exclusion criteria: Patient with pacemaker implant, prosthetic cardiac valve implants, claustrophobia and allergy to contrast.



RESULTS

We studied MRI imaging features and histo-patholog-ical diagnosis in 50 patients with RCC. Maximum number of patients were from age group of 70 to 80 years. There were 32 males and 18 females among study groups.

Table 1: Age and Gender wise distribution of pa-tients

Age group (years)

Male Female Total

< 20 2 0 2 20 – 30 1 1 2 30 – 40 3 1 4 40 – 50 5 3 8 50 – 60 6 4 10 60 – 70 7 4 11 70 – 80 8 5 13

Clear cell subtype is most common subtype diagnosed in highest 30 patients. Papillary subtype was diagnosed in eight patients. Five patients had chromophobe va-riety whereas multilocular cystic variety was detected

in four patients. Two patients had unclassified variety. Collecting duct variant is rare and diagnosed only in single patient.

Table 2: Subtype of Renal cell carcinoma

No. (%)

Clear cell 30 (60) Papillary 8 (16) Chromophobe 5 (10) Multilocular cystic 4 (8) Unclassified 2 (4) Collecting duct 1 (2)

MRI is particularly helpful in evaluating small lesions which cannot be studied by Ultrasonography (USG) or Computed tomography (CT). Percutaneous biopsy is a minimally invasive method to diagnose renal tu-mors with accuracy upto 70 to 90%. Apart from diag-nosing lesions, MRI along with histopathological sub-type is very crucial to decide severity and prognosis of RCC and to guide treatment protocol.

Figure 1. Clear cell RCC (a) Axial in-phase T1-weighted MR image shows a right renal mass with a thick rim of tumor with signal intensity of the rim is similar to that of the renal cortex and central lowsignal- intensity area. (b) On an axial opposed-phase T1-weighted MR image, the mass appears homogeneous and is hy-pointense relative to the renal cortex.

Figure 2. Papillary RCC a, b. Axial T2-weighted STIR turbo spin echo (a) and axial postcontrast VIBE (b) images show a rhabdoid variant of papillary RCC. A huge hemorrhagic right renal mass with solid mural com-ponent is observed (a, b). There is heterogeneous signal intensity on T2-weighted image (a). On postcontrast images there is minimal heterogenous enhancement of the mural nodule (b, arrow).



e

Figure 3.Transitional Cell Carcinoma (a)Thin-section 3D T1-weighted view of the right kidney on a coronal subtraction image shows enhanced filling defects within the renal pelvis (arrows) (b) T2-weighted MR urogram shows filling defects in the renal pelvis (arrow) and lower ureter (small arrowheads). Note the dilatation of the ureter (large arrowhead) distal to the filling defects (“goblet sign”).

Figure 4. Collecting duct RCC Axial T1-weighted GRE (a), T2- weighted STIR turbo spin echo (b), and axial postcontrast 3D VIBE (c, d) images show a collecting duct RCC. A right mid-lower pole renal mass with ill-defined borders slightly protruding through the pelvicalyceal system. It is slightly hypointense on T1-weighted GRE (a) and hypointense on T2-weighted image (b) compared with the renal cortex. Heterogenous enhance-ment at the periphery of the lesion is prominent, and delayed enhancement is demonstrated on postcontrast images (c, d).

DISCUSSION

We studied MRI imaging features and histopatholog-ical diagnosis in 50 patients with RCC. Clear cell sub-type is most common subtype diagnosed in highest 30 patients. Papillary subtype was diagnosed in eight pa-tients. Five patients had chromophobe variety whereas multilocular cystic variety was detected in four patients. Two patients had unclassified variety. Collecting duct variant is rare and diagnosed only in

single patient. Male patients were 37 while 13 female patients had renal cell carcinoma. Incidence of carci-noma was increased with increasing age with median age 52 years.

Clear cell variant is responsible for 70% of all RCC with unfavorable prognosis6 with 30 patients detected. Multicentricity and bilaterality are rare (5%) in spo-radic cases.7 Necrosis, hemorrhage and cysts are the



main causes of varying appearances on MRI. Postcon-trast images demonstrate a lack of enhancement in ar-eas of necrosis and marked enhancement in the viable components of the tumor9. Considerable loss of signal intensity within the solid portions of clear cell RCCs on opposed phase images compared with in-phase im-ages is detected in up to 60% of clear cell RCC10. In contrast-enhanced MRI with heterogenous enhance-ment in the arterial phase continuing with or without washout, the degree of contrast enhancement may help distinguish clear cell RCC from non-clear cell subtypes. Papillary RCC tend to be solid, large, well-defined, and slow-growing tumors11. They frequently exhibit bilaterality (4%) and/or multifocality (22.5%). It exhibits hypointensity and provides an accurate dis-tinction from clear cell RCC, which typically exhibits heterogeneously increased signal intensity on T2-weighted images12. A fibrous capsule is typically pre-sent in papillary RCCs13. Papillary RCC shows hypo- or avascularity on angiography14. Chromophobe RCC is the third most common subtype and accounts for approximately 4%–11% of RCCs. They might appear hypointense on T2-weighted images compared with renal parenchyma15. Cystic changes can be observed within a solid tumor, and central necrosis might be ab-sent, even in very large chromophobe carcinomas.16 Collecting duct carcinoma is rare, accounting for less than 1% of cases, and an aggressive RCC subtype. This carcinoma has a very unfavorable prognosis.17 Almost all tumors exhibit focal cortical extension, and some even exhibit perirenal extension18. They have a tendency to display infiltrative patterns, preserving re-nal contour rather than an expansile growth. Unclas-sified variety is a diagnostic category for RCC that does not fit readily into any other category and is a diagnosis of exclusion. It accounts for 4%–5% of RCC subtypes. There are some features that may help identify a tumor as unclassified: sarcomatoid cells without recognizable epithelial elements, mucin pro-duction, mixtures of epithelial and stromal elements, and unrecognizable cell types. This category has the worst prognosis among RCC subtypes. Multilocular cystic RCC is characterized by septated, variable- sized cysts separated from the kidney by a fibrous capsule20.

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2. Yoshimitsu K, Honda H, Kuroiwa T, et al. Fat detection in granular-cell RCC using chemical shift gradient-echo imag-ing: another renal tumor that contains fat. Abdom Imaging 2013; 25:100–102.

3. Mao J, Yan H, Brey WW, et al. Fat tissue and fat suppres-sion. Magn Reson Imaging 2012; 11:385–393.

4. Outwater EK, Blasbalg R, Siegelman ES, Vala M. Detection of lipid in abdominal tissues with opposed-phase gradient-

echo images at 1.5 T: techniques and diagnostic importance. Radiographics 1998; 18:1465–1480.

5. Sukosd F, Kuroda N, Beothe T, Kaur AP, Kovacs G. Dele-tion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma. Cancer Res 2013; 63:455–457.

6. Polascik TJ, Bostwick DG, Cairns P. Molecular genetics and histopathologic features of adult distal nephron tumors. Urology 2012; 60:941–946

7. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of RCC. Am J Surg Pathol 2013; 27:612–624.

8. Amin MB, Amin MB, Tamboli P, et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol 2012; 26:281–291.

9. Outwater EK, Bhatia M, Siegelman ES, Burke MA, Mitchell DG. Lipid in renal clear cell carcinoma: detection on op-posed- phase gradient-echo MR images. Radiology 2014; 205:103–107.

10. Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 2011; 155:517–526.

11. Yoshimitsu K, Irie H, Tajima T, et al. MR imaging of renal cell carcinoma: Its role in determining cell type. Radiat Med 2014; 6:371–376.

12. Eble JN, Sauter G, Epstein JI, Sesterhenn IA, et al. Pathol-ogy and genetics of tumours of the urinary system and male genital organs. In: Kleihues P, Sobin LH, eds. World Health Organization Classification of Tumours. 1st ed. Lyon: IARC Press, 2012; 10–43.

13. Sun MR, Ngo L, Genega EM, et al. Renal cell carcinoma: dy-namic contrast-enhanced MR imaging for differentiation of tumor subtypes—correlation with pathologic findings. Radi-ology 2009; 250:793–802.

14. Pedrosa I, Sun MR, Spencer M. MR imaging of renal masses: correlation with findings at surgery and pathologic analysis. Radiographics 2008; 28:985–1003.

15. Rosenkratz AB, Hindman N, Fitzgerald E, Niver BE, Mela-med J, Babb JS. MRI features of renal oncocytoma and chro-mophobe RCC. AJR Am J Roentgenol 2010; 195:421–427.

16. Srigley JR, Eble JN. Collecting duct carcinoma of the kidney. Semin Diagn Pathol 2011; 15:54–67.

17. Pickhardt PJ, Siegel CL, McLarney John K. Collecting duct carcinoma of the kidney: are imaging findings suggestive of the diagnosis? AJR Am J Roentgenol 2015; 176:627–633.

18. Pickhardt PJ, Lonergan GJ, Davis CJ, Kashitani N, Wagner BJ. Infiltrative renal lesions: radiologic-pathologic correla-tion. Radiographics 2011; 20:215–243.

19. Gurel S, Narra V, Gurel K, Chen ZM, Brown J. The role of magnetic resonance imaging in the radiological work-up of subtypes of renal cell carcinoma. Paper presented at 2005 Annual Meeting of the Radiological Society of North Amer-ica, Chicago, Illinois, USA; November 27, 2014.

20. Prasad SR, Humphrey PA, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imag-ing spectrum with pathologic correlation. Radiographics 2015; 26:1795–1810.



ORIGINAL ARTICLE

A STUDY OF THE ASSOCIATION BETWEEN PATTERNS OF EYE DROP PRESCRIPTION AND MEDICATION USAGE IN GLAUCOMA SUBJECTS Punit Singh1, Raghunandan Kothari2, Ruta Shah3, Shrey Rayajiwala3, Aakash V Patel3, Roshni Patel3 Author’s Affiliations: 1Assistant Professor, 2Professor & Head, 3Resident, Dept. of Ophthalmology, SBKS MIRC, Vado-dara, Gujarat Correspondence: Dr. Punit Singh Email: [email protected]

ABSTRACT

Introduction: To investigate the association between patterns of eye drop prescription and medication usage in patients with glaucoma. Methodology: Sixty two patient who were diagnosed glaucoma and were on any topical anti glaucoma medi-cation were included in the study and the pattern of eye drop instillation was studied with the help of a ques-tionnaire at Dhiraj General Hospital, Piparia, Vadodara, Gujarat. The questionnaire determined how patients routinely used medications, including the method of eye drop administration, number of eye drops per instilla-tion, accuracy of eye drop placement, weekly frequency of eye drop application, and their awareness of local side effects. Results: Of 60 patient 34 patients (56.67%) instilled medication by their own, 36 patients (60%) instilled drop accurately at first attempt, 51 patients (85%) instilled drop in sitting position, 22 patients (33.67%) patients instilled one drop at a time. 47 patients (78.33%) kept a gap of less than 2 minutes, 9 patients (15%) instilled another drop between two to four minutes and 4 patients kept interval of more than four minutes between different drug instillation. Only 3 patients (5%) were familiar with the local side effects of the drug. Conclusion: From our study we conclude that there is a huge scope in the area of patient education regarding glaucoma. The findings in our study suggest a need to better educate our patients by providing them detailed information about its administration and its importance. This would help to improve patient compliance and increase the efficiency of anti-glaucoma treatment. Keywords: Glaucoma, Prescription, Ophthalmology, Eye Drops

INTRODUCTION

Glaucoma is chronic, progressive, multifactorial optic neuropathy caused by a group of ocular conditions which lead to damage of optic nerve with loss of visual field. The most common risk factor known is raised intraocular pressure.1

Glaucoma is not curable, and vision lost cannot be re-gained. With medication and/or surgery, it is possible to halt further loss of vision. Since open-angle glau-coma is a chronic condition, it must be monitored for life. Proper administration of medicines is as im-portant as the proper choice of medicines for a suc-cessful treatment, since, whatever the effectiveness of the medicine is, the benefit from the treatment de-pends on the correct administration.2

For some years authors have suspected that a substan-tial proportion of patients with chronic glaucoma fail to comply with medical advice. Noncompliance is par-ticularly hazardous in glaucoma because of the contin-uing possibility of blindness. And yet the nature of the

disorder and its therapy might well foster noncompli-ance. The patient's collaboration in treatment is obvi-ously mandatory if his intraocular pressure is to be kept under control and visual loss prevented.3,4

The purpose of the study was to determine how com-monly patient with glaucoma do not comply with the doctors’ prescription.

METHODOLOGY

Our study is a non comparative, observational, cross sectional and questionnaire based study. We obtained due permission from the ethics committee of the institute and started our study thereafter. We have examined a total of 60 patients after obtaining an informed written consent. Primary data like name, age, sex, socioeconomic status and residential address were recorded. Patients were examined by whole of our team. For examination we used Snellen’s chart to check visual acuity. We examined refraction with auto-refractometer, trial set with cycloplegic refraction.



Anterior segment examination was done with slit lamp biomicroscope and posterior segment with ophthalmoscopes (direct and indirect). For screening of glaucoma, we measured intra-ocular pressure with NCT (non-contact tonometer) and with Goldmann applanation tonometry, followed by gonioscopy using Zeiss 4 mirror indentation gonioscope and ultrasound pachymetry. Visual field analysis was performed using Humphrey’s automated perimeter.

RESULTS

Of 60 patients included in the study 35 (58.3%) were male and 25 (41.67%) were female.

Table 1: Sex wise distribution of patients

Sex No. (%)

Male 35 (58.3) Female 25 (41.7)

Table 2: Practices of eye drop instillations by pa-tients

Variable Inaccu-rate

Accu-rate

p-Value

Self instillation 19 15 0.004 Family mem-

ber 5 21

Total 24 36

Table 3: Number of drops instilled

Variable One drop Two drops p-Value

Self 5 29 0.00005 Family Member 17 9

Table 4: Interval between eye drop instillation

Interval No. (%)

< 2 mins 47 (78.3) 2- 4 mins 9 (15.0) > 4 min 4 (6.7)

34 patients (56.67%) instilled medication by their own and family members of patient instilled drops in 26 patients (33.33%). 36 patients (60%) instilled drop ac-curately inside the eye at first attempt and 24 patients (40%) failed to do so. However accuracy in those pa-tients in whom family member instilled drops was quite high (80.76%) compared to that of self instilling (44.11%).(p=0.004)

51 patients (85%) instilled drop in sitting position while 9 patients (15%) instilled drop in supine posi-tion.

The number of patients instilling one drop at a time were only 22 (33.67%) and those using two drops were 38 (66.33%). Family member instilling the drop had higher percentage (65.38%) of instilling one drop compared to those who were self instilling (14.7%). (p = 0.00005)

47 patients (78.33%) kept a gap of less than 2 minutes interval between two eye drops. 9 patients (15%) in-stilled another drop between two to four minutes after instilling one. Only 4 patients kept interval of more than four minutes between different drug instillation.

Only 3 patients (5%) were familiar with the local side effects of the drug.

DISCUSSION

The success of the Glaucoma treatment is highly de-pendent on the patient compliance and the process of eye drop instillation.5, 6, 7, 8 By this study our purpose was to investigate the association between patterns of eye drop prescription and medication usage in patients with glaucoma with the help of a questionnaire. Of 60 glaucoma patients included in the study we found that 34 (56.67%) instilled medication by themselves. Self medication has many problems associated with it. One such problem is a proper drug placement. As enquired through the questionnaire it was found that of these 34 patients, only 15 patients instilled the medication at first attempt and rest 19 patients had to instill another drop of a costly medication. Even those 15 patients who claim to instill the drop at the first attempt cannot be completely thought to be unbiased as this is a ques-tionnaire based study. Of the remaining 26 patient, where family member instilled the medication it was found that 21 of them were sure of instilling the med-ication properly at first attempt and also remaining 5 patient required another drop only at times.

In one of the study, significant differences were found between the group of patients who instilled their eyedrop into the inner canthal region and those who instilled their eye drop into the inferior conjunctival cul-de-sac, in visual field defect severity and IOP measurements. The visual field defect severity and IOP were lower in the inferior conjunctival cul-de-sac group compared to the inner canthal region group.5, 6,

9, 10

Therefore, patients should be adequately instructed about the proper techniques for eye drops instillation and motivated to take help of a family member instead of self instilling the drop as self instilling cannot be as accurate compared to another person instilling the drop.

Another disadvantage of self instilling the medication is the wastage of costly Glaucoma medications as self instillation is more prone to improper placement of the drug often than not requiring another drop to be



used. As glaucoma treatment is a lifelong process, it is a heavy financial burden to the family. Wastage of the drug would definitely add to this burden which possi-bly, is one of the important factors responsible for ter-mination of treatment leading to blindness.11, 12, 13

One of the important factors in eye drop instillation is touching of the nozzle to the eye or lids leading to bottle contamination, infection and inadvertent trauma. In a study of 70 POAG patients on self-ad-ministration of anti glaucoma medication, fifty-three patients (75.7%) touched the tip of the bottle to the globe or periocular tissue. Only 6 patients (8.57%) were able to correctly instill the eye drops (squeeze out 1 drop and instill it into the conjunctival sac without bottle tip contact).14Bottle contamination adds to the wastage and also can lead to more dangerous situa-tions like corneal ulceration.15

It wound not be erroneous to assume that the com-pliance of patient self administering the drop would be less than the patient taking help of the family mem-bers as two people would be responsible for the task. Respecting the view that the members of family are emotionally attached it would not be incorrect to be-lieve that timing of the drug instillation would be maintained correctly if such a person is made respon-sible as compared to self. This gap would be more ev-ident where the patient is illiterate and has a family member who can understand the depth of Glaucoma disease severity. A hidden advantage of making family members responsible for the task is incorporating awareness regarding glaucoma and its medication into them. It is a well accepted fact that family history of glaucoma is a risk factor for the same. So imparting knowledge to the families having a glaucoma patient by involving them in the task of eye drop instillation to the patient would definitely be fruitful.

Another aspect of eye drop instillation is hygiene. Though simple but an important step in proper eye drop instillation is washing hands. Unwashed hands may touch the eye while instilling the drop and impart infection to the eye. Also the unwashed hand may touch the nozzle and the bottle may get contaminated. In our study only 6 patients/relatives (10%) washed their hands before eye drop instillation. As many of our patients belong to the rural area it is a clear cut reflection of lack of awareness about the hygiene in rural population. Hence it is very necessary to educate the patients to maintain their hygiene by introducing them to the side effects otherwise.16,17,18,19

38 patients (63.3%) instilled two drops at a time. The normal volume of a conjunctival cul de sac is 7 micro litre which increases to 30 micro litre after instillation of a drop temporarily. Most commercially available eye drops have drop size equal to 30-75 micro litre which means even a single drop exceeds the capacity of conjunctival cul de sac, so that excess drains into the lacrimal sac and onto the skin. If eye drops spill

during administration, the risks of blepharitis and eye-lid pigmentation increase.Hence there is no added benefit of instilling more than one drop. Rather it adds to the side effect and the economic burden. This leads to early emptying of the medication and hence drug delivery is missed until the new drops are purchased. Thus questioning the patient about the period of last-ing the bottle would help the ophthalmologist getting an idea of improper drug instillation. Those patients can be educated regarding the same.

Time period between two glaucoma medications is an important factor regulating drug efficacy.20 47 patients (78.3%) kept a gap of less than two minutes between instilling two different medications. It is advisable to keep a gap of four to five minutes between two drops.6,21,22 This will keep the first drop from being washed out by the second before it has had sufficient time to work. Only 4 patients (6.6%) kept a gap greater than four minutes. Since most of the anti-glaucoma medications lead to dryness, all the patients were pre-scribed a lubricating drop along with the glaucoma medication, Hence all the patients even those who were on a single anti glaucoma medication were con-sidered for this question.

Last question in the questionnaire in this study was to enquire about the knowledge regarding the side ef-fects of the glaucoma medications. Only 3 patients (5%) were aware about it. Glaucoma medications have multiple local side effects but IOP lowering benefits of the medications are not outweighed by these local side effect.Conjunctival allergies, conjunctival injec-tion, corneal epithelium disorders, blepharitis, ocular pemphigoid are few local side effects of anti glaucoma medications.10, 15, 23, 24, 25 Patients often discontinue the medication when they suffer from local side effects of medication. Educating patients on the various adverse reactions associated with anti-glaucoma eye drops willmake patients recognize that a minor adverse event does not necessarily mean they should discon-tinue medication use and hence the patient compli-ance will improve.

The limitation of the study was that it was a question-naire based cross sectional study so we could not eval-uate the impact of instillation pattern on IOP. We need more long term studies to evaluate the rate of glaucoma progression associated with different instil-lation patterns. Since most of the patients are from ru-ral area, the results of the study cannot be applied to general population.

CONCLUSION

From our study we conclude that there is a huge scope in the area of patient education regarding glaucoma. The findings in our study suggest a need to better ed-ucate our patients by providing them detailed infor-mation about its administration and its importance.



This would help to improve patient compliance and increase the efficiency of anti-glaucoma treatment.

REFERENCE

1. Ramanjit sihota&radhikatandon. Parson’s diseases of the eye, 21 ed. 188-192 New Delhi: Elsevier; 2013

2. Glaucoma research foundation; 2015 May 5 [cited 2016 Aug 30]. Available from: http://www.glaucoma.org/glaucoma/ glaucoma-facts-and-stats.php.

3. Bloch S, Rosenthal AR, Friedman L, Caldarolla P. Patient compliance in glaucoma. Available from: http://www.ncbi. nlm.nih.gov/pmc/arti-cles/PMC1043033/pdf/brjopthal00236-0038.pdf. (Last ac-cessed on 30/8/2016)

4. Review on the Eyedrop Self-Instillation Techniques and Fac-tors Affecting These Techniques in Glaucoma Patients. Avail-able at: http://www.ncbi.nlm.nih.gov/pmc/articles /PMC4826945/. (Last accessed on 30/8/2016)

5. Evaluating eye drop instillation technique in glaucoma pa-tients. http://www.ncbi.nlm.nih.gov/pubmed/21336146. (Last accessed on 30/8/2016)

6. Glaucoma. Available from: http://www.iapb.org/vision-2020/what-is-avoidable-blindness/glaucoma. (Last accessed on 30/8/2016)

7. Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol. 1996;80:389–393.

8. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthal-mol. 2000;130:429–440.

9. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120: 1268–1279.

10. Anderson DR. Collaborative normal tension glaucomastudy. CurrOpinOphthalmol. 2003;14:86–90.

11. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hy-pertension Treatment Study: a randomized trial determines

that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–713; discussion 829-830.

12. Kooner KS, AlBdoor M, Cho BJ, et al. Risk factors for progression to blindness in high tension primary open angle glaucoma: comparison of blind and nonblind subjects

13. Norell SE, Granstrom P-A. Self-medication with pilocarpine amongoutpatientsinaglaucomaclinic.Br Ophthalmol1980;64:137-41.

14. Kass MA, Meltzer DW, Gordon M, Cooper D, Goldberg J. Compliance with topical pilocarpine treatment. Am J I Oph-thalmol 1986;101:515-23.

15. Kass MA, Hodapp E, Gordon M, Kolker AE, Goldberg I.Patient administration of eyedrops: observation, Part II.AnnOphthalmol1982;14:889-93.

16. SmithSJ, DranceSM. Dificulties patients have at home after cataract surgery. CanJ7Ophthalmol1984;19:6-9.

17. DonnellyD. Instiling eye drops: difficulties experienced by patients following cataract surgery. AdvNurs1987;12:235-43.

18. Lederer CM, Harold RE. Drop sizeof commercial glaucoma medications. AmJ7Ophthalmol1986;101:691-4.

19. Bloch S, Rosenthal AR, Friedman L, Caldarolla P. Patient complianceinglaucoma.BrJOphthalmol197;61:531-4.

20. LetochaCE. Methods for self-administration of eye drops. AnnOphthalmol1985;17:768-9.

21. Freeman MI. A method for delivery of ocular medication. MasonClinBull 1975;29:114-5.

22. Anonymous. New dispensing aid for instiling eye drops, ointment available. OphthalmolTimes1985;10:35.

23. LawS. Developmentand utilization of the eye drop per adaptation device: An example of interdisciplinary cooperation. HomeHealthcareNurse1987;5:50-1.

24. Sheldon GM. Self-administration of eyedrops. Ophthalmic Surg1987;18:393-4.

25. ZimmermanTJ, ZaltaAH. Facilitating patient compliance in glaucoma therapy. SurvOphthalmol1983;28:252-7.



ORIGINAL ARTICLE

ROLE OF RANDOM URINARY PROTEIN TO CREATININE RATIO IN MILD PREECLAMPSIA Manoj C Lokhande, Avinash N Jadhao Author’s Affiliations: Assistant Professor, Dept. of Biochemistry, Topiwala National Medical College and BYL Nair Hospital, Mumbai, India Correspondence: Dr. Manoj C Lokhande Email: [email protected]

ABSTRACT

Introduction: Preeclampsia is one of the important members of deadly triad, along with hemorrhage and in-fection which contributes for the maternal morbidity and mortality rates. Proteinuria is an important diagnostic component of preeclampsia. Aim: To compared the results of s random urine protein-creatinine (P/C) ratio with 24-hour urine protein excretion in women with mild preeclampsia. Methodology: 100 pregnant women with mild preeclampsia as cases and age matched 100 normal healthy pregnant women as controls were studied for proteinuria. Urine P/C ratio was determined in a random sample, and the amount of protein excretion was measured in 24-hour urine collected on the subsequent day and com-pared between cases and age matched controls of age group 18-35 years using unpaired two-tailed Student ‘t’ test. The correlation between the spot P/C ratio and 24-hour urine protein excretion was assessed. The receiver operating characteristic curve analysis was used to determine the best discriminator values of the spot urine P/C ratios for preeclampsia (proteinuria ≥ 300 mg/24 h). All statistical analyses were performed using GRAPH PAD PRISM version 5.00 software. Results: There was a strong correlation between the spot P/C ratio and 24-hour urine protein excretion (r = 0.94; P < .0001). ROC curve reveals area 0.95. The optimal spot P/C ratio cutoff point was 0.3 for 300 mg/24 h of protein excretion (preeclampsia), with a sensitivity, specificity, positive predictive value, and negative pre-dictive value of 94%, 94%, 94.4%, and 96.8%, respectively. Conclusion: We found that there is a significant correlation between the spot urine P/C ratio and 24-hour urine protein excretion in women with preeclampsia. Urine P/C ratio could be used for diagnosis as well as screening of mild preeclampsia. Keywords: Preeclampsia, Proteinuria, Protein to creatinine (P/C) ratio

INTRODUCTION

Hypertensive disorders accounts for 5-10% of all pregnancies, and considering their complications, they are among the major causes of maternal morbidity and mortality. 1, 2 Preeclampsia, the most prevalent hyper-tensive disorders of pregnancy, is defined as a systolic blood pressure level of 140 mm Hg or higher or a di-astolic blood pressure level of 90 mm Hg or higher that occurs after 20 weeks of gestation with pro-teinuria (≥300 mg/24 hrs). Preeclampsia can be mild or severe. In severe preeclampsia, patients have renal failure with high serum creatinine, more edema, BP>160/110 mmhg and 3+ or more protein on dip-stick, where diagnosis is very clear, patients are imme-diately started on treatment. Practically no time per-mits for 24 hrs urine collection and first priority is treatment.

In mild preeclampsia BP is >140/90 mmhg but <160/110 mmhg, normal creatinine and proteinuria

> 0.3 gm/24 hrs. So that in mild preeclampsia for di-agnosis 24 hrs urine is must along with BP > 140/90 mmhg. But the difficulties in 24 hrs urinary protein estimation are very well known. This test is unreliable in one third cases. 3 It is time consuming and also pro-longs the patient’s hospital stays. Detection of pro-teinuria in a single random urine sample can be an al-ternative to the timed urine collections in pre-eclamp-sia. 4 So that random urinary proteins to creatinine ra-tio measurement provide a good and fast estimation total 24 hrs proteinuria in hospitalized pregnant woman and can replace the time-consuming 24 hrs urine colletions.5, 6 To overcome these difficulties sin-gle random urinary protein to creatinine ratio is good alternative. So we planned to study this ratio in mild preeclampsia and to determine whether it can replace 24 hrs urinary protein estimation. Thus early diagnosis and treatment of preeclampsia is possible and its pro-gression to severe stage and complication can be pre-vented.



METHODOLOGY

The present study has been carried out in Indira Gan-dhi Government Medical College & Mayo Hospital, Nagpur. Total study carries out from November 2011 - April 2015. The study protocol was approved by the Institutional Ethical Committee. Informed written consent was obtained from all the study subjects en-rolled in the study. Study sample was included total of 200 individuals; 100 diagnosed mild preeclamptic pa-tients (Cases) admitted in ANC ward in this institute and 100 age matched healthy and apparently normal pregnant women (controls) were also selected for study.

The cases and controls were in the age group of 18-35 years.

Exclusion criteria for cases and controls: a known kidney disease, heavy exercise (more than 1 hour of vigorous exercise on the day of urine collection), bac-teriuria, Urinary tract infections, bed rest longer than 24 hours, and gestational diabetes mellitus.

24 hrs urine protein and random urinary protein to creatinine ratio: 4, 7 Random urine sample for deter-mining urinary protein and creatinine excretion col-lected in a sterile plain bulb during the daytime before the start of the 24-h urine collections. Patients were instructed to separate the labia while collecting the urine sample. The collected samples were analyzed immediately for urine protein and urine creatinine. Urine protein estimation was done with the kit based on Pyrogallol Red Method (End Point). Urine creati-nine estimation was done with the kit based on Initial Rate Modified Jaffe’s Method. The estimation was

done on TRANSASIA ERBA CHEM-5 Plus Semi-Automatic Analyzer. The Urine Protein/Creatinine Ratio was calculated as urinary protein concentration mg/ mg of creatinine.

For a 24-hour urine collection, all of the urine that pass over a 24-hour time period must be collected. Af-ter collecting random sample, next day in the morning patient instructed to urinate into the toilet after get up in the morning. Afterwards, collect all urine in a spe-cial container for the next 24 hours. On day 2 patient had told to urinate into the container when get up in the morning. Then immediately sample was analyzed with the kit based on Pyrogallol Red Method (End Point) on TRANSASIA ERBA CHEM-5 Plus Semi-Automatic Analyzer.

Statistical Analysis: Unpaired two-tailed Student‘t’ test was used to assess the significance of the differ-ences in values of the parameters in cases and controls and values were reported as the mean ± SD . Pear-son’s correlation coefficients were used to analyze lin-ear correlations between variables. Differences were considered statistically significant at a probability value p < 0.05. All statistical analyses were performed using GRAPH PAD PRISM version 5.00 software.8

RESULTS

In cases the mean age of distribution was 22.86 ± 2.63 years and gestational age was 34.85 ± 1.03 weeks while in controls the mean age of distribution was 22.95 ± 2.27 years and gestational age was 34.85 ± 1.03. (Table 1)

Table 1: Comparison of mean age and mean gestational age in cases and controls

Parameters Cases (n=100) Controls (n=100) p-value

Mean age ± SD 22.86 ± 2.625 22.95 ± 2.271 0.79 Mean Gestational age ± SD 34.85 ± 1.030 34.85 ± 1.028 0.97 Systolic blood pressure (mm Hg) 145.5 ± 2.303 105.7 ± 7.536 <0.0001 Diastolic blood pressure (mm Hg) 96.32 ± 2.767 72.08 ± 4.421 <0.0001 24 hrs urine proteins (mg/24 hrs) 772.6 ± 195.2 145.3 ± 26.79 <0.0001 Urine protein to creatinine ratio (mg/mg) 0.68 ± 0.24 0.22 ± 0.07 <0.0001

On comparing mean age and gestational age of cases and controls by unpaired t test, p value was 0.79 and 0.97 respectively which was statistically non signifi-cant. Hence both the groups were comparable.

Systolic blood pressure (SBP) of cases i.e. 145.5 ± 2.30 mm of Hg was higher than that of controls i.e. 105.7 ± 7.54 mm of Hg (Table 1). Statistically, the difference between mean SBP of cases & controls was highly sig-nificant (P < 0.0001). Cases had diastolic blood pres-sure (DBP) of 96.32 ± 2.77 mm of Hg which is higher as compared to that of controls which was 72.08 ± 4.42 mm of Hg. (Table 1) The mean DBP of cases &

controls has shown a statistically highly significant dif-ference. (P < 0.001)

Cases had 24 hrs urine protein level of 772.6 ± 195.2 mg/dl which was significantly higher than levels in controls i.e. 145.3 ± 26.79 mg/L (Table 1). The dif-ference between mean 24 hrs urine proteins levels of cases & controls was highly significant (P < 0.001). Urine protein/creatinine ratio of cases which was 0.68 ± 0.24 mg/mg of creatinine was significantly higher than the ratio in controls i.e. 0.22 ± 0.07 mg/mg of creatinine (Table 1). Statistical comparison of the



mean urine protein/creatinine ratio of cases & con-trols had shown highly significant difference (P < 0.0001).

Table 2: Correlation of 24 hrs urine protein and random urinary protein to creatinine ratio in cases

Parameter Pearson’s Cor-relation Coeffi-cient (r)

P value

24 hrs urine protein Vs Urine protein to creati-nine ratio

0.94 <0.0001

Figure 1: Correlation of 24 hrs urinary proteins with urinary protein to creatinine ratio

Correlation study of 24 hrs urine protein with random urinary protein to creatinine ratio in cases indicates that 24 hrs urine proteins was positively correlated with the random urinary protein to creatinine ratio. Pearson’s correlation coefficient for this correlation was r = 0.94 and the correlation is statistically highly significant (P < 0.0001). (Table 2 , Fig 1)

The ROC curve for the random urinary protein to cre-atinine ratio is shown in figure 2. The area under the ROC curve is 0.95 (95% confidence interval: 0.9220 to 0.9852; standard error = 0.016, p value is < 0.0001 i.e. highly significant).The cutoff value of > 0.3 yields a sensitivity of 94% and a specificity of 94%. With the use of this cutoff, there was 6 false–negative and 6 false –positive test results. (Table 3, Fig 2)

Figure 2: Random urinary protein/creatinine ra-tio for the detection of significant proteinuria with the cutoff value 0.3 using ROC analysis

Table 3: Result of the random urinary protein/creatinine ratio for the detection of significant pro-teinuria with the cutoff value 0.3 using ROC analysis

P/C ratio> 0.3 P/C ratio< 0.3 Area Std. Error 95% confidence interval P value

Cases 94 6 0.95 0.01611 0.9220 - 0.9852 < 0.0001 Controls 6 94

DISCUSSION

Preeclampsia is a syndrome of hypertension in preg-nancy, with or without edema and proteinuria. In a number of patients, the clinical appearance is mild, presenting only with small increase in blood pressure or protein in the urine but in other patients severe ma-ternal and fetal complications, such as the HELLP syndrome, eclampsia, preterm delivery, abruptio pla-centa, intra-uterine fetal death or fetal growth re-striction may take place. High blood pressure in preg-nant women could cause large placental infarcts and decreased placental growth. It also results in fetal mal-nutrition, decreased placental perfusion and reduced fetal growth. 9

One of the ways to diagnose preeclampsia, apart from the blood pressure criteria, is to look for the presence of significant proteinuria. The gold standard for deter-

mining protein excretion is the 24 hour urine collec-tion. 24 hours urine collection for estimation of pro-teins is considered the traditional comparator for quantification of proteinuria in pregnancy. But it has limitations: the urine collection is cumbersome, time consuming, inconvenient, expensive and unreliable in one third cases and potentially misleading if done in-accurately; and collection may not be possible during delivery. Previous studies have demonstrated inade-quate collected urine volumes in up to 37% of sam-ples. Waiting for the results of 24-hour urine collec-tion can often delay diagnosis of preeclampsia and may result in prolonged hospital stay for investiga-tions and also increase the cost. 10-12

The major problem with the 24 hour protein collec-tion is that it is often impractical in the outpatient set-ting with problems of incomplete collection. Accu-rately substitution of a spot urine P/C ratio for a 24-

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hour urine collection would have significant implica-tions including facilitation of prompt clinical decision making. This would also impact healthcare costs and improve patients’ satisfaction with care, too. During the day urinary protein and creatinine excretion rates are fairly constant provided the glomerular filtration rate is constant. Thus a random urinary protein to cre-atinine ratio in a single voided urine sample can indi-cate the cumulative excretion during the day since the ratio of two stable rates would cancel out the time fac-tor. 13 Current Australian guidelines advocate use of the spot urine protein-to-creatinine ratio as an alterna-tive to 24 hour urine collection. 14

Our data also suggested that 24 hrs urine proteins are positively correlated with the random urinary protein to creatinine ratio (Table 2 and Fig 1). Pearson’s cor-relation coefficient for this correlation is r = 0.94 and the correlation is statistically highly significant (P < 0.0001). This finding is consistent with other studies. 15, 16, 17 However, using the spot P/C ratio of 0.3 as a correlate to the critical value of 300 mg of protein over 24 hours would result in the failure to identify signifi-cant proteinuria in approximately 6% of affected pa-tients.

A good correlation between the spot urine P/C ratio and 24-hour protein excretion has been demonstrated in patients with diabetic nephropathy, lupus nephritis, chronic kidney disease, and transplanted kidneys.3, 18 The National Kidney Foundation guidelines have sug-gested that spot urine samples should be used to de-tect and monitor proteinuria in children and adults.19 These are characterized by excellent accuracy.

Our data suggested that the random urine P/C ratio is a highly accurate test for discriminating between in-significant and significant proteinuria, as demon-strated by an area under the ROC curve of 0.95. (Ta-ble 3 and Fig.2) The main concern in clinical use of this test is the false-negative test results, because 6% of patients with preeclampsia may be missed. To ob-tain the optimal cutoff, we selected the one that while increasing specificity maintains a sensitivity of higher than 90% in order to reduce the possibility of missing the diagnosis of preeclampsia. In our study at 0.3 cut-off both sensitivity and specificity were 94%. A sys-tematic review by Leaños-Miranda A et al (2007) 4 also stated that the protein: creatinine ratio ≥ 0.3 as an in-dicator of protein excretion >300 mg/24 h. The sen-sitivity and specificity were 98.2% and 98.8%, respec-tively. William’s textbook of obstetric has mentioned that urinary protein to creatinine ratio ≥ 0.3 use for diagnosis of proteinuria. Research in the future should be focused on the evaluation of clinical outcomes and the cost-effectiveness of the use of a random urinary P/C ratio for prediction of significant proteinuria. In addition, studying the test in an outpatient basis should be further considered in order to apply it in ambulatory management of preeclamptic patient.

Alternatives for the diagnosis of proteinuria in preg-nancy include urinary dipsticks. The dipstick is inex-pensive, easy to use, and provides a rapid result but has been shown to have low sensitivity and specificity for urinary protein excretion over 24 hours. 20-25 Dip-sticks poorly quantify 24 hrs proteins. Various studies proved that P: C ratio is more accurate and had better correlation with 24 hrs urine proteins than dipsticks. 16, 24, 26, 27

The need for a simple reliable screening test to quan-titate proteinuria is very important need. So we rec-ommend random urinary protein to creatinine ratio for diagnosis as well as screening purpose, especially in mild preeclamptic patient where for diagnosis pro-teinuria is must. So that rapid diagnosis and screening of mild preeclamptic patients along with blood pres-sure is possible and with prompt treatment further progression to severe stage can be prevented. The use of random urinary protein to creatinine ratio as a screening test proved in other studies also. 28-33

CONCLUSION

Based on the findings of the present study, we con-clude that a random urine P/C ratio predicts the amount of 24-hour urine protein excretion with a highly accuracy. This test could be a reasonable alter-native to the 24-hour urine collection for detection of significant proteinuria in hospitalized pregnant women with suspected preeclampsia. This test can re-ally solve the problem of diagnosis of proteinuria in mild preeclamptic patients. Because of its advantage over dipsticks it can even routinely use to screen pro-teinuria in pregnant women.

The random urinary protein-to-creatinine ratio is a rapid, reliable and cost effective test, so this test was suggested for the purpose of screening, assessment or follow-up of proteinuria in the preeclampsia. So we recommend that future study should perform in out-patient basis and to evaluate clinical outcome when using this test for follow-up of proteinuria in preeclamptic patients.

REFERENCE

1. Berg CJ, Chang J, Callaghan WM, et al. Pregnancy-related mortality in the United States 1991-1997. Obstet Gynaecol 2003; 101(2): 289-96.

2. Berg CJ, Harper MA, Arkinson SM, et al. Preventability of Pregnancy- related deaths. Obstet Gynaecol 2005; 106(6):1228-34.

3. Christopher-Stine L, Petri M, Astor BC, et al. Urine protein-to creatinine ratio is a reliable measure of proteinuria in lupus nephritis. J Rheumatol 2004; 31(8):1557–9.

4. Leaños-Miranda A, Márquez-Acosta J, Romero-Arauz F, et al. Protein: Creatinine ratio in random urine samples is a re-



liable marker of increased 24-Hour protein excretion in hos-pitalized women with hypertensive disorders of Preg-nancy.Clinical Chemistry 2007; 53 (9):1623–1628.

5. Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309 (25): 1543–6.

6. Schwab SJ, Christensen RL, Dougherty K, et al. Quantitation of proteinuria by the use of protein-to-creatinine ratio in sin-gle urine samples. Arch Intern Med 1987; 147(5):943–4.

7. Urine Protein: The test / Urine Protein Test : UPCR ; 24 Hours Urine https://labtestsonline.org/understanding/ an-alytes/urine-protein/tab/test/8 Prism 5 for Windows. Graph Pad software [Computer Program] Version 5.00. March 12, 2007. Inc.; 1992-2007.

8. Mohanty S, Nayak N, Nanda NN, et al. Serum lipids and Malondialdehyde levels in primiparous patients with preg-nancy induced hypertension. Ind J of Clin Biochem 2006; 21(1): 189-192.

9. Shaw AB, Risdon P, Lewis-Jackson JD. Protein creatinine in-dex and Albustix in assessment of proteinuria. BMJ 1983; 287(6397):929– 32.

10. Ruggenenti P, Gaspari F, Perna A, et al. Cross-sectional lon-gitudinal study of spot morning urine protein: creatinine ra-tio, 24-hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes. BMJ 1998; 316 (7130):504–9.

11. Price CP, Newall RG, Boyd JC. Use of protein: creatinine ratio measurements on random urine samples for prediction of significant proteinuria: a systematic review. Clin Chem. 2005; 51(9):1577-86.

12. Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983; 309 (25): 1543–6.

13. Cade TJ, Gilbert SA, Polyakov A, et al. The accuracy of spot urinary protein- to-creatinine ratio in confirming proteinuria in pre-eclampsia. Aust N Z J Obstet Gynaecol 2012; 52(2):179-82.

14. Yamasmit W, Wongkitisophon K, Charoenvidhya et al. Cor-relation between random urinary protein-to-creatinine ratio and quantitation of 24-hour proteinuria in preeclampsia. J Med Assoc Thai 2003; 86(1): 69-73.

15. Eigbefoh JO, Abebe J, Odike MAC, et al. Protein/ Creati-nine ratio in random urine specimens for quantitation of pro-teinuria in pre-eclampsia. The Internet Journal of Gynecol-ogy and Obstetrics 2007; 8(1): ISSN: 1528-8439.

16. Boler L, Zbella EA, Gleicher N. Quantitation of proteinuria in pregnancy by the use of single voided urine samples. Ob-stet Gynecol 1987; 70 (1):99–100.

17. Torng S, Rigatto C, Rush DN, et al. The urine protein to creatinine ratio (P/C) as a predictor of 24-hour urine protein excretion in renal transplant patients. Transplantation. 2001; 72 (8):1453-6.

18. NKF KDOQI GUIDELINES. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classi-fication, and Stratification Part 5- Evaluation of laboratory

measurements for clinical assessment of kidney diseases. Guideline 5- Assessment of proteinuria. (10):1159-64.

19. Kuo VS, Koumantakis G, Gallery ED. Proteinuria and its assessment in normal and hypertensive pregnancy. Am J Ob-stet Gynecol. 1992 Sep; 167(3):723-8.

20. Carroll MF, Temte JL. Proteinuria in adults: a diagnostic ap-proach. Am Fam Physician. 2000; 15; 62(6):1333-40.

21. Meyer NL, Mercer BM, Friedman SA, et al. Urinary dipstick protein: a poor predictor of absent or severe proteinuria. Am J Obstet Gynecol. 1994; 170:137-41.

22. Gangaram R, Ojwang PJ, Moodley J, et al. The accuracy of urine dipsticks as a screening test for proteinuria in hyperten-sive disorders of pregnancy hypertension in pregnancy. In-forma Healthcare 2005; 24(2):117-123.

23. Ebeigbe PN. Inadequacy of Dipstick Proteinuria in Hyper-tensive Pregnancy: evidence for a change to alternatives. The Nigerian postgraduate medical journal 2009; 16(1):46-9.

24. Phelan LK, Brown MA, Davis GK, et al. A prospective study of the impact of automated dipstick urinalysis on the diagno-sis of preeclampsia. Hypertension in Pregnancy : Official Journal of the International Society for the Study of Hyper-tension in Pregnancy 2004; 23(2):135-42.

25. Ebeigbe PN, Fayemi PO, Okpere EE. Quantitation of pro-teinuria in women with pregnancy induced hypertension: is it time to abandon use of dipstick strips for the spot urine protein to creatinine ratio? Trop J Obstet Gynaecol, 2004; 21(2):136, 137, 140, and 141.

26. Marnoch CA, Lason L, Weitzen S, et al. A practical approach to using spot urine protein/creatinine ratios for assessing proteinuria in pregnancy. Obstet Med 2008; 1 (1): 18-23.

27. Jaschevatzky OE, Rosenberg RP, Shalit A, et al. Protein/cre-atinine ratio in random urine specimens for quantification of proteinuria in pre-eclampsia. Obstet Gynecol 1990; 75(4): 604-606.

28. Young RA, Buchanan RJ, Kinch RA. Use of the protein/cre-atinine ratio of a single voided urine specimen in the evalua-tion of suspected pregnancy-induced hypertension. J Fam Pract 1997; 42(4):385-9.

29. Rodriguez-Thompson D, Lieberman ES. Use of a random urinary protein/creatinine ratio for the diagnosis of signifi-cant proteinuria during pregnancy. Am J Obstet Gynecol 2001; 185(4): 808-11.

30. Taherian AA, Dehbashi S, Baghban M. The relationship be-tween random urinary protein-to-creatinine ratio and 24-hours urine protein in diagnosis of proteinuria in mild preeclampsia. Journal of Research in Medical Sciences 2006; 11(1): 6-12.

31. Eslamian L, Behnam F, Tehrani ZF, et al. Random urine pro-tein creatinine ratio as a preadmission test in hypertensive pregnancies with urinary protein creatinine ratio. Acta Med Iran 2011; 49(2):81-4.

32. Dwyer BK, Gorman M, Carroll IR, et al. Urinalysis vs urine protein–creatinine ratio to predict significant proteinuria in pregnancy. J Perinatol. 2008; 28(7): 461–7.



ORIGINAL ARTICLE

TOPICAL PROPARACAINE 0.5% ANAESTHESIA: PAIN MANAGEMENT AND INTRAOPERATIVE CORNEAL EPITHELIAL EDEMA Shashi Prabha Prasad1, Gira Raninga2, Minal Doulatramani2, Saurabh Ashtamkar2, Asim Naik2 Author’s Affiliations: 1Professor, 2Resident, Dept. of Ophthalmology, D.Y. Patil Medical College, Pune Correspondence: Dr Shashi Prabha Prasad Email: [email protected]

ABSTRACT

Introduction: Cataract surgery performed under topical anesthesia provides sufficient patient comfort with lower incidence of complications. The main purpose and objective of this study is to evaluate the analgesic efficacy and intraoperative corneal edema of 0.5% propacaine hydrochloride as topical anesthesia during phacoemulsification surgery.

Methodology: Intraoperative pain intensity was assessed using a 5-category verbal rating scale during each of three surgical stages. Pain scores from each surgical stage and total pain scores were compared for the factors of patient age, gender, cataract laterality, and type.

Results: In comparison of cataract type subgroups, the mean total pain scores and mean stage 2 pain scores in both white mature cataract (WMC) and corticonuclear plus posterior subcapsular cataract (CN + PSC) groups were significantly higher than in the PSC-only (PSC) group.

Conclusion: Phacoemulsification with topical anesthesia is not a completely painless procedure. Pain intensity and corneal edema vary with cataract type, stage of surgery and number of instillations.

Keyword: Cataract, Propacaine Hydrochloride, Corneal Epithelial Edema

INTRODUCTION

For routine cataract surgery, topical anesthesia is pre-ferred because it provides sufficient patient comfort with lower incidence of complications compared to other types of anesthesia.1,2

The three most common methods of applying topical anesthesia are by eye drops, by eye drops with intra-cameral lidocaine injection, and in gel form.3,4 Topical anesthesia by eye drops is a noninvasive method, but in some cases it may provide insufficient analgesia and require an additional intracameral lidocaine injection.5

Side effects are minimal but are seen occasionally which are stinging, irritation, burning, conjunctival redness, lacrimation. Rare side effects are severe, immediate type hypersensitivity reaction – acute,intense and diffuse epithelial keratitis.

This study aimed to determine the efficacy of topical anesthesia by 0.5% propacaine hydrochloride in con-trolling pain and providing intraoperative comfort for patients undergoing phacoemulsification.

METHODOLOGY

This prospective study included 63 eyes from 63 pa-tients who presented at the Dr D Y Patil Hospital, Pimpri, Pune between April 1st, 2016, and November 1st, 2016. These patients had no medical history of ocular surgeries or pathologies such as glaucoma, trau-matic cataract, Retinal pathology or high myopia.

The pain scoring system was based on the Keele ver-bal pain chart.6 (Table 1). Each patient was informed about the pain scoring system before surgery and was asked to use the scoring system to describe their pain levels during surgery.

Patients were grouped according to age, gender, later-ality, and cataract type. The pain score for each surgi-cal stage and total pain score were compared between groups. There were three age groups: 40–59, 60–75, and 76–97 years old. The three categories of cataract were white mature cataract (WMC), posterior subcap-sular cataract (PSC), and corticonuclear plus posterior subcapsular cataract (CN + PSC).



Table 1: Pain intensity scoring system

None 0 Mild Momentary mild sensations of burning or

piercing 1

Mod-erate

Intermittent moderate sensations of burning, piercing, or fullness/tightness in the eye lasting a few seconds

2

Severe Continuous sensations of piercing or swelling/stretching in the eye severe enough to require additional intervention

3

Un-beara-ble

Continuous sensations of piercing or swelling/stretching of the eye severe enough to make the patient want to stop the procedure

The American Optometric Association’s grading sys-tem for cataracts7 was used to identify cataract types PSC and CN + PSC. Patients in these groups had stage 2 or 3 cataracts of their respective type according to the AOA’s grading system. Criteria for inclusion in the WMC group were total opacity and whiteness of the lens and inability to distinguish epinucleus from nucleus preoperatively or intraoperatively. Severely emulsified epinuclear component or hypermature or morgagnian cataract was not detected preoperatively or intraoperatively in any patients in this group. Also, these patients had no lens to iris contact and their pu-pil movements were normal in preoperative examina-tions.

None of the patients received sedation prior to sur-gery, and each patient underwent the same three-stage procedure performed by a single surgeon (Table 2). Patients spontaneously reported their intraoperative pain levels; these pain scores and the corresponding surgical stages were recorded by surgeons observing the procedure by live video. If patients reported more than one pain score during any surgical stage, the high-est value was used as the pain score for that stage. The total pain score is the sum of the pain scores from the three surgical stages.

Table 2: Surgical stages

Stage 1 Topical anesthesia (0.5% propacaine) ap-plication, side port incision, air/dye in-jection, viscoelastic injection, preincision and clear corneal tunnel incision, and capsulorhexis

Stage 2 Hydrodissection, phacoemulsification by divide-and-conquer method, and corneal rinsing by coaxial irrigation/aspiration

Stage 3 Filling with viscoelastic, one-piece hy-drophilic acrylic IOL in-the-bag implan-tation through insertion tube, viscoelas-tic removal by irrigation/aspiration, and stromal hydration

All surgeries were performed by one surgeon. No su-perior rectus suture was taken. A universal eye specu-lum was used in all cases. Patients were instructed to fixate on the microscope light during surgery. A side port incision was created on the appropriate side to stabilize the globe. A 3.2 mm clear corneal temporal incision was performed through, which viscoelastic (2% Hydroxypropyl methyl cellulose, Appavisc, Ap-pasamy Ocular Devices, Puducherry, India) was in-jected. A 5.5 mm wide capsulorhexis was created us-ing utrata forceps. Complete cortical cleaving hydro-dissection was performed by injecting a balanced salt solution between the lens capsule and the cortex with a 26 1/2 -gauge cannula. The nucleus was divided us-ing a direct chop technique. Parameters were vacuum 350 cc, flow rate 33 cc, and power 40-70 based on the grade of the nucleus in a pulse mode. Cortical cleanup was performed with the irrigation/aspiration probe. A single piece hydrophobic or hydrophilic intraocular lens based on the patient choice was implanted in the bag. The viscoelastic material was removed from the capsular bag and from the anterior chamber. Stromal hydration of the side port and main incision was per-formed. No sutures were required in any case.

The duration of the surgery was recorded by the ac-companying surgeon. Time of surgery (duration) was recorded from the creation of the side port incision to the completion of stromal hydration. No patients re-ceived intracameral miotics intraoperatively or sub-conjunctival injection at the completion of the sur-gery.

Immediately after the operation, the eye was closed and the patient was moved to the inpatient clinic. In the clinic, patients were interviewed using the ques-tionnaire below. They were asked to rate the success of their procedure and explain why they answered as they did.

The pain score data were analyzed statistically using SPSS 17.0 software. The variables were compared us-ing Kruskal-Wallis, Mann-Whitney, and chi-square tests. The study was approved by the Institutional Ethics committee and Scientific committee at Dr. D Y Patil Hospital Pimpri, Pune.

Group ‘A’ (20 patients instilled proparacaine twice)

Group ‘B’(20 patients instilled proparacaine thrice, 10min, 06min, and 03minutes before surgery)

Group ‘C’ (40 patients instilled proparacaine four times, 15min,10min, 06min and 03 minutes before surgery.

Corneal epithelial edema was evaluated by grading haziness of cornea under operating microscope.



RESULTS

The 63 patients had an average age of 69.27 ± 12.91 years (range: 40–97 years). The age distribution of the patients was as follows: 17 patients between 40 and 59 years; 25 patients between 60 and 75 years; 21 patients between 76 and 97 years. There were 32 men (50.7%) and 31 women (49.2%). The cataract type distribution was as follows: WMC; PSC; CN + PSC. The laterality distribution was 28 right eyes (44.4%) and 35 left eyes (55.5%). The procedures were performed without any complications.

During surgery, 56 patients (88.9%) received only top-ical anesthetic drops, whereas 7 patients (11.1%) de-scribed severe or unbearable pain and received addi-tional intracameral lidocaine injections (Table 3). Of the patients who received lidocaine injection, three had WMCs, one had PSC, and three had CN + PSCs. The pain scores of these patients were not included in the within-group statistics and were analyzed sepa-rately. For all patients who received intracameral lido-caine injection, their pain was completely relieved within the first 10 seconds, and they experienced no further intraoperative pain.

When the pain scores from all surgical stages of all 63 patients were analyzed, 6 patients (10.5%) experienced no pain throughout the entire procedure (PSC, CN + PSC). The analysis revealed that all patients in the WMC group experienced pain in one or more stages of the surgery.

In patients who received only topical anesthesia, the average total pain score was 3.05 ± 1.24 (0–5); the av-erage for stage 1 was 0.75 ± 0.43 (0-1), for stage 2 was 1.27 ± 0.67 (0–2), and for stage 3 was 1.04 ± 0.5 (0–2). Kruskal-Wallis nonparametric test was used to an-alyze the relation between cataract type and both mean total pain score and mean pain score per stage (statistics, Tables 4, 5(a), and 5(b)). The mean total pain scores and mean stage 2 pain scores of WMC and CN + PSC groups were significantly higher compared to those in the PSC group when analyzed by Kruskal-Wallis and Mann-Whitney nonparametric tests.

The mean total pain scores and mean pain scores from each surgical stage showed no significant differences between age groups when analyzed by Kruskal-Wallis nonparametric test.

Table 3: Cataract type, Surgical stage and Pain scores in patients requiring supplemental lido-caine injection

Cataract type Surgical stage Pain score No.

PSC 2* 4 1 CN + PSC 2* 3-4 3 WMC 2* 3 3

*- During nucleus fragmentation and rotation

Table 4: Pain score for patient who received only topical anesthesia (n=56)

Stage Mean Std. deviation

Total pain score 3.05 1.242 Stage 1 0.75 0.437 Stage 2 1.27 0.674 Stage 3 1.04 0.503

Table 5: The relation between cataract type and both mean total pain score and mean pain score per stage

Cataract type N Mean rank

Total pain score PSC 19 20.16 WMC 18 32.92 CN + PSC 19 32.66

Stage 1 PSC 19 26.66 WMC 18 29.28 CN + PSC 19 29.61



Table 6: The relation between age groups and both mean total pain score and mean pain score per stage

Cataract type N Mean rank

Total pain score 40–59 17 23.62 60–75 20 29.70 76–97 19 31.61

Stage 1 40–59 17 30.56 60–75 20 28.50 76–97 19 26.66

Stage 2 40–59 17 21.32 60–75 20 31.18 76–97 19 32.11

Stage 3 40–59 17 24.79 60–75 20 30.00 76–97 19 30.24

Table 7: The relation between gender groups and both mean total pain score and mean pain score per stage

Variable Male Female p-Value

Total 3.14 2.96 0.956 Stage 1 0.77 0.72 0.643 Stage 2 1.25 1.27 0.817

Stage 3 1.11 0.96 0.248



The relation between laterality groups and both mean total pain score and mean pain score per stage.

Table 8: The relation between side of Eye and both mean total pain score and mean pain score per stage

Variable Right Eye Left Eye p-Value

Total 2.92 3.17 0.194 Stage 1 0.70 0.79 0.440 Stage 2 1.29 1.24 0.084 Stage 3 0.92 1.13 0.175

Among all cataract types, there were a total of six pa-tients (9.5%) who felt no pain during the procedure, three in each of the PSC and CN + PSC groups; all of the patients in the WMC group experienced some level of pain.

Of the 63 patients who completed the postoperative questionnaire, 48 patients (76.1%) believed that their procedure had been successful, 5 patients (7.9%) be-lieved that it had been unsuccessful, and 10 patients (15.8%) had no opinion. Of the 48 patients who con-sidered their procedure successful, 33 patients (75%) gave different explanations for their opinion, but 15 patients (23.8%) gave similar answers. These 15 pa-tients belonged to the WMC group, and it became ap-parent that their perception of surgical success was based on the fact that they experienced an immediate visual improvement when the white mature cataract was removed. All five patients who believed that their procedure was unsuccessful had received a lidocaine injection; the reason that they felt their surgery had been unsuccessful was based on the pain that they ex-perienced during the procedure (three in the CN + PSC group and one in each of the PSC and WMC groups).

Table 9: Instillation of Proparacaine prior to surgery (in minutes)

GROUP A (06min, 03min)

GROUP B (10min, 06min, 03min)

GROUP C (15min, 10min, 6min, 03min)

Corneal haze (after 15min)

2/21 2/21 5/21

Epithelial edema (after 15min)

1/21 2/21 4/21

DISCUSSION

Clear corneal phacoemulsification surgery has been the subject of many studies.8-11 The advantages of top-ical anesthesia are early recovery of sight and lack of injection-related complications seen with peribulbar or retrobulbar anesthesia.12-14

In this prospective randomized study, we evaluated the effects of cataract type, age, gender, and laterality on the efficacy of topical 0.5% propacaine hydrochlo-ride anesthesia in providing patient comfort during phacoemulsification.

Soliman et al. reported that 73.3% of patients that re-ceived topical 0.4% benoxinate and 10% of patients that received topical 0.5% bupivacaine during phacoemulsification surgery had severe to unbearable pain which led to addition of subtenon lidocaine in-jection.4 In our study, seven patients (14.2%) experi-enced severe to unbearable pain which necessitated intracameral lidocaine injection. In all cases, the severe to unbearable pain occurred in stage 2 of the proce-dure.

Analysis of the data from 56 patients who received only topical anesthetic drops revealed that the mean total pain scores and mean stage 2 pain scores in both WMC and CN + PSC groups were significantly higher than in the PSC group (). This was thought to be re-ferred pain caused by mechanical effects of nucleus rotation or intracapsular manipulation on surrounding tissue, especially the corpus ciliare region, which were necessary due to the high density of the cataracts.

In a study by Malecaze et al. the efficacy of intra-cameral mepivacaine as a supplement to topical anes-thesia during phacoemulsification was investigated. They reported that, within 10 seconds after the intra-cameral injection, the pain scores of 84% of the pa-tients decreased by at least one level on the Keele ver-bal score. From this group of patients, 90.4% contin-ued to have decreased pain sensation for the remain-der of the procedure, while 9.6% required additional intracameral mepivacaine injection due to increasing pain.15 In our study, intracameral lidocaine injection resulted in complete pain relief within 10 seconds, and the patients reported no further pain during the re-mainder of the procedure.

In a study by Kaluzny et al., the analgesic efficacy of oral acetaminophen as a supplement to topical anes-thetic drops (0.5% tetracaine) during phacoemulsifi-cation was investigated. They reported that the mean verbal pain score of 80 patients in the oral placebo group was 1.11 ± 0.73.16 In our study, the mean pain score of 56 patients who only received topical anes-thesia was 3.05 ± 1.24 (0–5). The reason for this large difference is that the highest reported score from each of the three stages was added to calculate the total pain score for each patient in our study. If the highest pain score throughout the entire procedure is taken as the pain score of that patient, as in the study by Kaluzny et al., the mean pain score in our study decreases to 1.01 ± 0.41.

The analysis of the questionnaire showed that 15 pa-tients considered their procedure successful because



their visual clarity improved during surgery upon cat-aract removal. It is noteworthy to mention that all of these patients were from the WMC group. WMC blocks more light compared to other types of cataract; therefore, phacofragmentation of the cataract during surgery significantly changes the patients’ perception of the brightness of the microscope lamp. This change may have led the patients to conclude that their sur-gery was successful. Another point of note is that the five patients that required additional lidocaine injec-tion all considered their procedure unsuccessful due to feeling severe or unbearable pain during their sur-gery.

In conclusion, phacoemulsification with topical anes-thetic eye drops is not a completely painless proce-dure. The majority of patients feel mild or moderate pain, and patients with dense cataracts are more likely to experience severe to unbearable levels of pain. Our data suggest that intense pain leads patients to believe that their procedure was unsuccessful, whereas imme-diate visual improvements during surgery lead to a be-lief that the procedure was successful. Only 2-3 instil-lations about 3-5 minutes prior to surgery are suffi-cient for the effect to occur. Therefore, patients need to be informed preoperatively that their visual clarity or pain sensations do not reflect the success of the procedure.

REFERENCE

1. D. A. Lebuisson, P. Lim, J. C. Mary, and M. C. Jolivet, “Anes-thesie topique pour l'operation de la cataracte de l'adulte,” Journal Français D'Ophtalmologie 1996; 19(3):181–189.

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4. M. M. Soliman, T. A. Macky, and M. K. Samir, “Comparative clinical trial of topical anesthetic agents in cataract surgery: li-docaine 2% gel, bupivacaine 0.5% drops, and benoxinate 0.4%

drops,” Journal of Cataract and Refractive Surgery, vol. 30, no. 8, pp. 1716–1720, 2004.

5. A. S. Crandall, N. A. Zabriskie, B. C. K. Patel et al., “A com-parison of patient comfort during cataract surgery with topical anesthesia versus topical anesthesia and intracameral lido-caine,” Ophthalmology, vol. 106, no. 1, pp. 60–66, 1999.

6. K. D. Keele, “The pain chart,” The Lancet, vol. 252, no. 6514, pp. 6–8, 1948.

7. American Optometry Consensus Panel, Care of the Adult Pa-tient with Cataract, American Optometry Association, St. Louis, Mo, USA, 1996.

8. H. Maclean, T. Burton, and A. Murray, “Patient comfort dur-ing cataract surgery with modified topical and peribulbar an-esthesia,” Journal of Cataract and Refractive Surgery, vol. 23, no. 2, pp. 277–283, 1997.

9. P. S. Koch, “Efficacy of lidocaine 2% jelly as a topical agent in cataract surgery,” Journal of Cataract and Refractive Sur-gery, vol. 25, no. 5, pp. 632–634, 1999.

10. I. S. Barequet, E. S. Soriano, W. R. Green, and T. P. O'Brien, “Provision of anesthesia with single application of lidocaine 2% gel,” Journal of Cataract and Refractive Surgery, vol. 25, no. 5, pp. 626–631, 1999.

11. R. Aksu, C. Biçer, A. Özkırış, et al., “Comparison of 0.5% levobupivacaine and 0.5% bupivacaine for retrobulbar anes-thesia in cataract surgery,” Turkiye Klinikleri Journal of Med-ical Sciences, vol. 31, no. 4, pp. 867–872, 2011.

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ORIGINAL ARTICLE

A STUDY OF ADJUVANT CONCURRENT CHEMO-RADIOTHERAPY WITH CAPECITABINE IN ADENOCARINOMA STOMACH Vishesh Gumdal1, Manika Batra2, Prakash Chitalkar3, Rakesh Taran4, Prashant Kumbhaj1, Deepak Singla1 Author’s Affiliations: 1Senior Resident; 3Professor and Head; 4Professor, Department of Medical Oncology, 2Resident, Department of Radiotherapy, SAIMS, Indore, Madhya Pradesh

Correspondence: Dr Vishesh Gumdal Email: [email protected]

ABSTRACT

Introduction: Adenocarcinoma stomach is one of the leading causes of cancer related mortality in the world. Surgery is an established modality in the management of stomach cancer. Although it is well known that some form of adjuvant therapy is indicated, both chemotherapy and concurrent chemoradiotherapy give equivalent results. Methodology: Our study is a prospective observational study of the stomach cancer patients receiving adjuvant concurrent chemoradiotherapy with capecitabine. A total of 41 patients with stomach cancer undergoing gastric resection with a curative intent were evaluated. Results: With a Median follow up of 13 months, the estimated disease free survival was 21.2 months. Of the 41 patients, only 4 developed metastasis and none of the patients recurred locally. The regimen was well toler-ated. Conclusion: Concurrent chemoradiotherapy with capecitabine is well tolerated in our population with minimal side effects and good local control rate. Intensification of chemotherapy might reduce the incidence of metas-tasis. Keywords: Stomach cancer, Chemoradiotherapy, Capecitabine

INTRODUCTION

Gastric cancer is one of the oldest malignancies known to mankind with references in ancient Egyp-tian literature dating back to 3000 BC. . It was one of the most common malignancies causing death till 1980’s. The worldwide incidence of gastric cancer has declined rapidly over the recent few decades. Part of the decline may be due to the recognition of certain risk factors such as H. pylori and other dietary and en-vironmental risks. Despite the decline, the absolute number of new cases per year is increasing, mainly due to aging in the world population. There are mainly two types of gastric cancer: Intestinal type, which has mor-phologic similarity to adenocarcinomas arising in the intestinal tract. and Diffuse type, which is character-ized by the absence of intercellular adhesions is caused by a germline mutation in the cell adhesion protein E-cadherin and is more aggressive.

Etiology of gastric cancer is still unknown clearly. Mi-gration studies strongly suggest that environmental factors have an important role in the etiology of gas-tric cancer and that exposure to risk factors occurs early in life. H. pylori has been associated with devel-opment of gastric cancer as shown by several cross

sectional studies. Eradication of H. pylori has been as-sociated with lesser incidences of Gastric cancers1. H. pylori infection has been associated with an approxi-mate 6-fold increase in the risk with adenocarcinomas distal to the cardia, including both the intestinal and diffuse types2. Risk of gastric cancer increases with a high intake of salt and various traditional salt-pre-served foods such as salted fish, cured meat, and salted vegetables3. N-Nitroso compounds have also been associated with higher risk of gastric cancer. Hu-mans are exposed to them by tobacco smoke and by diet. N-nitroso compounds are generated after con-sumption of nitrates, which are natural components of foods like vegetables and potatoes and are used as a food additive in some cheeses and cured meats. Smoking, alcohol, obesity, poor socioeconomic status, Epstein Barr virus have also been associated with in-creased incidence of gastric cancer. Complete surgical eradication of a gastric tumor with resection of adja-cent lymph nodes represents the best chance for long-term survival4. The five-year survival rate for patients with completely resected stage I gastric cancer is ap-proximately 70 to 75 percent, while it drops to 35 per-cent or less for stage II disease and beyond5. These sobering results have spawned efforts to improve the



treatment results for this group of patients using adju-vant or neoadjuvant therapies. The positive impact of such therapies on survival in patients with resected gastric cancer has become clearer over time, although there is no consensus as to the best approach. In many parts of the world, chemotherapy alone is the pre-ferred treatment strategy4. Interest in adjuvant radia-tion therapy (RT) stems from the observation that over 80 percent of patients who die from gastric can-cer experience a local recurrence at some point.6 A large American Intergroup trial (INT0116) demon-strating a significant survival benefit for chemoradio-therapy after complete resection resulted in the adop-tion of this strategy in the United States (US).7

This study is a single institution study aiming to esti-mate the disease free survival and toxicity profile of gastric cancer patients who undergo adjuvant con-comitant chemoradiotherapy after gastric resection with a curative intent.

METHODOLOGY

All the patients with non metastatic gastric carcinoma who have undergone gastrectomy with a curative in-tent and who have presented to Sri Aurobindo Insti-tute of Medical Sciences from 2013 to 2015 and who are willing to be a part of this observational study are included in this study. These patients are explained about the prognosis of the disease, complications and cost related factors regarding this therapy. Informed consent form was obtained from all the patients and Institutional Ethics committee clearance was also ob-tained prior to data collection. Demographic parame-ters, surgical and histological details were collected as per the proforma of the patient. Location of the tu-mor was defined as Fundus, Body and Pylorus accord-ing to the location of the epicenter of the tumor. Pos-itive Margins were defined by the presence of tumor cells on the inked margin. Close margins were defined by the presence of tumor cells within 5mm of the sur-gical margin. Presence of H.pylori was based on iden-tification of the organism by light microscopy. AJCC 7th edition, 2010 was used to stage the patients.

Treatment consisted of one cycle of Capecitabine at 1250mg/m2 twice daily for fourteen days followed by one week later RT (45Gy in 1.8Gy fractions) given with concurrent Capecitabine (825mg/m2 on all days during the RT course). Two more cycles of Capecita-bine at 1250mg/m2 twice daily for 14days of a Q3weekly cycle. Prior to all the chemotherapy cycles, blood counts, renal parameters and electrolytes were done and chemotherapy was administered only if they were within acceptable limits (Hb >10gm%, TLC >3500/mm3, ANC > 1500/mm3, Platelets >1.5lakhs/mm3 and Urea < 40mg/dl, Creatinine <1.2 mg/dl, Na >130mg/dl, K+ >3.6 mg/dl and <5mg/dl, Calcium >9mg/dl and <10.3 mg/dl).

Chemotherapy was given with adequate anti emetic measures including dexamethasone, Pheniramine, ranitidine, Ondanseteron, Metaclo-peramide. The toxicities associated with this chemotherapy such as diarrhoea, anaemia, neutropenia, thrombocytopenia were monitored. Blood counts were monitored weekly during radiotherapy and also monitored during chemotherapy cycles and then grading is done. Maxi-mum grade of toxicity experienced during the treat-ment was documented. Corrective measures including delaying treatment were done if any toxicity grade be-comes Grade 3 or above and treatment was restarted if the grade falls down to grade 1 or 0.

All the toxicities were graded using Common Termi-nology Criteria for Adverse Events (CTCAE) version 4.0. Thermoplastic mould was used for immobiliza-tion with patient in supine position and hands over-head. After a fast of 3 to 4 hours, radiotherapy plan-ning CT scan images were taken at 5mm thickness from mid thorax to the bottom of L4 vertebra. Intra-venous contrast was used to help contour the lymph nodal groups. Target volumes were contoured as per the institutional protocol.

3D Conformal Radiotherapy was used to treat all the patients. Treatment was delivered on ELEKTA Pre-cise Linear Accelerator with 180cGy per fraction, one fraction per day, 5 days per week. The Clinical target volume was treated till 45Gy/25#/5weeks. All pa-tients were treated using 6MV/15MV photons with antero-posterior parallel opposed and opposed lat-erals, mono isocentric technique. The 4500 cGy of ra-diation was delivered in 25 fractions, five days per week, to the tumor bed, to the regional nodes, and 2 cm beyond the proximal and distal margins of resec-tion. The tumor bed was defined by preoperative computed tomographic (CT) imaging, and in some in-stances, surgical clips. We used the definitions of the Japanese Research Society for Gastric Cancer for the delineation of the regional-lymph-node areas. Perigas-tric, celiac, local paraaortic, splenic, hepatoduodenal or hepatic-portal, and pancreaticoduodenal lymph nodes were included in the radiation fields. Exclusion of the splenic nodes was allowed in patients with an-tral lesions if it was necessary to spare the left kidney. Radiation was delivered with at least 6-MV photons. The dose constraints to organs at risk were defined as per the instituitional protocol.

Follow up of the patients were done every month. Follow up visit consisted of a physical exam and fur-ther investigations like endoscopy or CT scan as clin-ically indicated.

RESULTS

A total of 41 patients who were diagnosed to have non metastatic gastric adenocarcinoma were enrolled in this study after gastrectomy with a curative intent. Out



of these 41 patients, 2 of the patients discontinued the treatment in the middle of chemoradiotherapy in view of personal reasons. All the patients were taken for toxicity grading and DFS calculations.

Of the 41 patients, 30 were males and 11 were females. Median age of the entire cohort was 58 years with a range of 26 to 73 years. A+ and O+ were the most common blood groups comprising 16 patients each. Lower third was the most common site of origin with around 50% of the patients falling under this group. All degrees of differentiation were seen but diffusely infiltrating type when seen was more common among females. 23 patients under went total gastrectomy and 18 underwent subtotal gastrectomy. Except for 2 pa-tients who underwent D0 nodal dissection, remaining underwent D1 nodal dissection. Surgery was associ-ated with negative margins in 29 patients whereas 12 patients had positive margins. Lymph vascular inva-sion was seen in 17 patients whereas perineural inva-sion was seen in 8 patients. H. pylori organism was identified on light microscopy in only 6 patients. 17 patients had T3 disease and the remaining had T4 dis-ease. When nodal staging was done, 11 patients had N3 disease, 10 patients had N2 disease, 12 patients had N1 disease and 8 patients had N0 disease. AJCC Stage III was seen in 25 patients and Stage II was seen in 16 patients.

Table 1: Age group and sex distribution

Age group in Years Males Females

20 - 29 1 2 30 - 39 2 2 40 - 49 2 0 50 - 59 13 3 60 - 69 8 4 70 - 79 4 0

Table 2: Association between the type of histol-ogy and the identification of H. pylori

Type of gastric cancer

H. pylori identified

H. pylori not identified

Diffusely infiltrating type 0 10 Intestinal type 6 25

Maximal incidence of Anemia was 8 patients develop-ing Grade 2 (10 gm % to 8 gm %) toxicity during week 5 of chemoradiotherapy. Maximal incidence of Neu-tropenia was 9 patients developing Grade 1 (ANC up to 1,500/mm3) toxicity during week 5 of chemoradi-otherapy. Maximal incidence of thrombocytopenia was 4 patients developing Grade 2 (50,000 to 75,000/mm3) toxicity during week 5 of chemoradio-therapy. Maximal incidence of diarrhea was 6 patients developing Grade 3 (>7 episodes of loose stools per day, requiring IV fluids) toxicity during week 5 of chemoradiotherapy.

Of the 41 patients, only 4 developed recurred with systemic metastasis and none of the patients recurred locally. 3 of them developed only liver metastasis and one of them developing liver, lung, brain and bone metastasis. All of these patients had an initial stage of IIIc.

With a Median follow up of 13 months following the diagnosis, the estimated disease free survival was 21.2 months (95% CI: 10.73 to 31.67) with a standard error of 5.34 as depicted in Figure 1. No significant differ-ences were found when factors such as sex, location of the primary, histology were compared.

Figure 1: Depiction of Kaplan Meir survival curve for estimation of disease free survival.

DISCUSSION

This observational study included eligible gastric can-cer patients enrolled during the study period men-tioned above. The results are discussed as below

When compared to the INT 0116 trial7, where around 53% patients developed grade 3 or higher hematolog-ical toxicity and 33% patients had grade 3 or higher diarrhoea, only 14% developed grade 3 or higher diar-rhea in this study with negligible hematological tox-icity. Although the reasons are not clear as to why there is such a difference in toxicity, lesser incidence of DPD deficiency in our populace8 might be one of the several contributing factors. Epidemiological stud-ies are required to investigate other possible causes.

When compared to the patients in the INT 0116 trial7 where around 8.2% and in the ARTIST trial9 where around 4.8% had local recurrences, local recurrences were not seen in this study. This might be in part be-cause of the possible delays the patients might have had in the latter because of the higher toxicity. An-



other possible reason could be that upper GI endos-copy was advised only when the patient had symp-toms suggestive of local recurrence.

Around 10% of the patients developed systemic re-currences. Though this number is low, it is very likely underestimated, in view of short follow up. Systemic recurrences continue to be high in carcinoma stom-ach, and are the principle reason for poor outcomes in general following therapy.

INT 0116 trial7 reported a median disease free survival of 30 months as against and estimated median disease free survival of 21.2 months in this study. The most important limitation of the study is poor follow up. Most of our patients were lost to follow up, either be-fore they recurred, or shortly following the diagnosis of recurrence because of which overall survival could not be estimated. Moreover, symptom based evalua-tion for recurrences could have potentially underesti-mated the number of recurrences. The numbers of patients included into the study are also small prevent-ing us from obtaining statistically significant correla-tions.

CONCLUSION

Adjuvant concurrent chemoradiotherapy can be of-fered to patients after gastrectomy in our country as the regimen is well tolerated. It appears that further chemotherapy can be advised to patients after this reg-imen as the majority of recurrences are systemic, alt-hough a phase III trial with a large number of subjects is required to validate the same.

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