Dr. Sunil Roy T

Dr. Anup R Warrier

Dr. Arun Wilson

Dr. Thamizharasan V

Sulfia Jabbar P

Anithadevi T S

Dr. Anil Kumar R

Infective endocarditis, 
Native valve, 
Prosthetic valve, 
Viridians Streptococci, 
Staphylococci


Infective Endocarditis (IE) is a serious condition with varied clinical presentations posing significant morbidity and mortality. This study aimed to describe the epidemiological, clinical, and microbiological profiles of IE. 

This retrospective cohort study was conducted at a quaternary care center in Kochi, India, for a period of six years. The study included 104 patients, and the pediatric population was excluded. Data were collected from electronic medical records and statistically analyzed.  

There were 104 patients with IE, of whom 71 were culture—positive. The mortality rate in this study was 16.3%. Native valves were affected in 80.8% of the cases. Gram—positive organisms were isolated in 52(73.24%), gram—negative in 12(16.9%), and fungi in 5 (7.04%) cases. Culture growth yielded two different organisms in two patients (2.82%). Streptococci were the most common organism isolated 21(29.57%), of which viridians streptococci accounted for 20.12%, followed by Staphylococci 20(28.16%), and Enterococci 11(10.6%). The study showed a significant association between complications like heart and renal failure, sepsis, septic and cardioembolic shock, embolism, and MODS with death.

Over a period of six years, a study was conducted to determine the epidemiological, clinical, and microbiological profiles of infective endocarditis. The findings showed streptococci, followed by staphylococci as the primary causative agent of IE, with the native valve being the most commonly affected.

Infective endocarditis (IE) is a pathological condition characterized by a significant propensity for morbidity and mortality. The incidence varies between 1.7 to 6.2 cases in the Western population per 100000 patient—years (male—to—female ratio of 2:1) to 14.5 cases per 100000 patient—years in India.(1) The average age of individuals with IE was found to be greater than 65 years of age at present. Predisposing factors in this age group include prosthetic valves, indwelling cardiac devices, valvular diseases, hemodialysis, and diabetes mellitus (DM).(2) Rheumatic heart disease accounts for less than 5% of all IE cases, whereas recreational intravenous drug use is an emerging risk factor, contributing to approximately 10% of all cases of IE.

The causative agents of IE include gram—positive cocci belonging to the Staphylococcus, Streptococcus, and Enterococcus species. In 80% to 90% of the cases, Staphylococcus aureus is the most frequently isolated pathogen that develops antibiotic resistance and methicillin—resistant strains.(4) Coagulase—negative staphylococci colonize indwelling catheters and devices, and are the most common isolates in early prosthetic valve endocarditis. Streptococcal infective endocarditis is common in low—income countries, and enterococci account for 10% of all cases. Other organisms causing IE include fastidious bacteria, zoonotic bacteria, and fungi. The clinical presentation ranges from general malaise to shock, depending on the virulence of the pathogen and host immune response. IE should be considered in cases of sepsis of unknown origin or fever with risk factors. The significance of echocardiography in patients presenting with Staphylococcus aureus bacteremia has been highlighted in the literature, given its association with IE in 20—30% of cases.(5,6) This study aimed to review the epidemiological, clinical, and microbiological profile of IE with outcomes in a quaternary care center.  

This retrospective cohort study was conducted at a quaternary care center in Kochi, Kerala, India. Patients with a definite diagnosis of IE according to the modified Duke Criteria between December 2015 and December 2021 were included in this study. Patients aged <18 years were excluded from the study. The study was reviewed and approved by the Institutional Ethics Committee. Data were collected from electronic medical records.

This retrospective cohort study was conducted at a quaternary care center in Kochi, Kerala, India. Patients with a definite diagnosis of IE according to the modified Duke Criteria between December 2015 and December 2021 were included in this study. Patients aged < 18 years were excluded from the study. The study was reviewed and approved by the Institutional Ethics Committee. Data were collected from electronic medical records.

Epidemiological, clinical, microbiological, echocardiographic, and laboratory data were collected. Epidemiological details included patient age, sex, length of hospital stay, coronary artery disease, atrial fibrillation, history of any surgeries (including valve replacement surgeries and cardiac surgeries), CKD on dialysis, diabetes mellitus, hypertension, and dyslipidemia. Clinical details included the presence of fever, angina, syncope, or dyspnea and the development of any complications such as heart failure, renal failure, cardioembolic stroke, septic shock, sepsis, embolism, and multiorgan dysfunction syndrome (MODS). Echocardiographic data collected included the presence of vegetation on any of the valves, the presence of a regurgitant or stenotic lesion on any of the valves, the presence of an intracardiac abscess, pseudoaneurysm, paravalvular leak, and pericardial/pleural effusion. The microbiological and laboratory data collected included the name of the infective organism grown in the blood culture/detected by PCR. The number of deaths in patients admitted with IE and the causes of death were examined. Data on the blood culture results and microorganism isolation were also collected. Microbiology laboratories use standardized methods to identify microorganisms and antimicrobial susceptibility. Additional tests, including fungal cultures, serology for Coxiella burnetti using enzyme immunoassay serology and Brucella melitensis, Brucella abortus and Bartonella hensale serologies byenzyme—linked immunoassay (7) were done for blood—culture negative endocarditis. 

Three sets of blood cultures were submitted to the microbiology laboratory within 24 hours of admission and were immediately loaded into the BACT/ALERT 3D system. Gram staining was carried out on bottles with positive results, and subsequent sub—culturing was performed by placing the Blood and Chrome agar plates in an incubator for 24 h at 37 °C. The Vitek 2 and Vitek 2 AST were used to identify Gram—negative and Gram—positive organisms respectively and Vitek 2 AST cards were used to test the antimicrobial susceptibility. 

Descriptive statistics were used to present all outcomes; normally distributed data were presented as means and standard deviations, and binary and categorical variables were presented as counts and percentages. The chi—square test or Fisher's exact test was used to find the association of categorical variables, and the Mann—Whitney U test was used to compare quantitative parameters, as the data did not follow normality. The confidence interval was 95%; thus, the significance level was 5%. All data were entered into Microsoft Excel and analyzed using SPSS Version 28.00.

A total of 114 patients were admitted with the diagnosis of infective endocarditis, of which 107 fulfilled the modified Duke’s criteria. A total of 104 patients aged >18 years were included in the analysis, and three patients aged <18 years were excluded from the study. The mortality rate was 16.34% (17/104). Seventy—three (70.2%) patients were male and 31 (29.8%) were female. The mean age of the study population ranged from 18 to 85 years, with an average of 57 years. The deceased patients had a mean age of 65 years and belonged to the older age group than the patients who were successfully discharged with a mean age of 57 years (p=0.034). The mean length of the hospital stay was 10 days. Atrial fibrillation was present in 23.5% of the patients and was significantly associated with mortality (p=0.023). Fever was the most common clinical presentation in 57.7%. Syncope was observed in 5.8% and dyspnea in 44.2% of patients, and both showed a significant association in the mortality group. No significant association with mortality was observed with either comorbidities or echocardiography findings in the study population. The most common comorbidity was hypertension (45.2%), followed by diabetes mellitus (41.3%), history of surgery (36.5%), and CAD (28.8%). The details of the baseline characteristics are presented in Table 1.

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The culture reports were positive in 71 patients (68.26%) and negative in 33 patients (31.73%). Gram—positive organisms were isolated in 52 cases (73.24%), gram—negative in 12 cases (16.9%) and fungi were isolated in 5 cases (7.04%) cases. Culture growth yielded two different organisms in two patients (2.82%) (Table 2).

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Streptococci were reported in 21 cases (29.57%), of which 15 were viridians streptococci (21.12%) and 6 were non—viridians streptococci (8.45%). Staphylococci were isolated in 20 patients (28.16%), of which 2 were MRSA, 8 were MSSA, 7 were coagulase—negative staphylococci, and 3 were Staphylococcus haemolyticus. Moreover, Staphylococci with other organisms were found in two cultures (2.82%). MSSA with Candida was observed in 1 patient, and MRSA with Burkholderia cepacia in 1 patient. Enterococci were isolated from 11 patients (10.6%). Gram—negative organisms were isolated in 12 cases (11.5%). Fungi were reported in 5 patients (7.04%), of which Candida spp. were grown in 4 cultures and Aspergillus niger in 1 patient. The distribution of organisms isolated from the cultures is presented in Table 3.

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Native valve IE was reported in 84 cases (80.76%) of the study population. Gram—positive organism was the causative agent for native valve IE in 52.38% (44/84), Gram—negative organisms in 5.6% (5/84), and fungi in 5.8% (3/84). Viridian Streptococci was found to be approximately 29.54% (15/44) of the gram—positive organisms responsible for native valve IE. 

Prosthetic valve IE was reported in 17 cases (16.34%). Gram—positive organisms as the causative organism for prosthetic valve IE were isolated in 52.94% (9/17), Gram—negative in 23.52% (4/17), and fungi in 5.88% (1/17). Viridian Streptococci were isolated in 22.22% (2/9) and CONS in 33.33% (3/9) of cases with gram—positive organisms. However, no significant association was found between the type of organism affecting each valve and mortality rate (Table 4). 

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This study showed a significant association between complications and mortality in IE. Patients with heart failure, renal failure, sepsis, septic shock, and multiorgan dysfunction syndrome (MODS) have higher mortality rates than those without these complications. Renal failure had a more profound impact, with a mortality rate of 64.71%. Sepsis, septic shock, heart failure, and MODS were also associated with elevated mortality rates of 52.94%, 52.94%, 47.06%, and 41.18% respectively (p<0.05) (Table 5).

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After analyzing the data over a period of six years, the study showed a mortality rate of 16.3%. The mortality rate was 28% in the study conducted by Lakhdhar et al. and 9% by Mathew et al. (8,9). In the present study, 73 patients (70.2%) were male. The mean age of the study population was 57 (47—66) years. The results obtained were in accordance with the study by Barry et al., in which 67% of their patients were males.(7) IE was reported more frequently in the elderly population in this study.

The clinical presentation of IE varied with studies; however, some common characteristics were observed among different studies which included fever, anemia, hematuria, splenomegaly, etc.(10) The clinical manifestation in this study was fever in 80.77%, angina in 57.69%, syncope in 45.19%, and dyspnea in 44.23%. Studies had reported association between dyspnea and infective endocarditis.(11,12)  Infective endocarditis may affect the valve causing valve dysfunction affecting the normal blood flow and may also cause complications such as heart failure which may cause dyspnea. Native valves were the most affected in this study (80.8%) and prosthetic valve IE was reported only in 16.3%. Device—related IE was found only in 2.9% of cases. A study by Zhu et al, reported that IE primarily affected the left native valve in 65.3%, the left prosthetic valve in 6.6%, and the right valve in 24%.(10) A study by Mano et al. reported that the site of infection was most frequent in the aortic valve. In our study, mitral valve vegetation was most commonly found (39.4%). Mitral valve regurgitation was reported in 45.2% of the study population. Mitral valve regurgitation as a risk factor for IE was reported in several studies.  Danchin et al. reported that the frequency of mitral valve prolapse was three times in patients with IE compared to the control group.(13) Another study reported that hypertrophic cardiomyopathy, can lead to mitral valve regurgitation increasing the risk of infective endocarditis.

Treatment for IE can be associated with potential complications. The major complications developed in patients with IE were cardiogenic shock, septic shock, acute heart failure, systemic thromboembolism, heart block, in—hospital dialysis, and disseminated intravasucular coagulation (DIC).(15) A study conducted by Mir et al. found that septic shock, cardiogenic shock, thromboembolism, and DIC were the complications most strongly linked to mortality.(15) In our study, we identified a significant correlation between heart failure, renal failure, sepsis, septic shock, cardio embolic shock, embolism, and MODS with mortality.  

We had 71 patients (68.26%) with positive blood cultures. Blood cultures were negative for 31.73%. Asopa et al. reported that 10% of their patients had no growth in the blood culture.(16) Literature showed that Staphylococcus aureus was the most common organism isolated, followed by Streptococci and Enterococci accounting for 80—90% of all cases of endocarditis.(17) Al—Tawfiq et al. documented Staphylococcus spp as the most prevalent microorganisms, with Staphylococcus aureus in almost 40%, MRSA in 4%, and CONS in 7.4% of the cases.(18) According to a study conducted by Mano et al. streptococci were found to be the most prevalent isolates (n=29), followed by staphylococci (n=23).(12) However, in our study, the most common organism isolated was Streptococci (29.57%), followed by Staphylococci (28.16%) and Enterococci (10.6%), together accounting for 68.33% of all cases of endocarditis. 

Our study showed that Gram—positive organisms were responsible for 52.38% (44/84) of cases of native valve IE and 52.94% (9/17) of cases of prosthetic valve IE, with viridans Streptococci accounting for 29.54% and 22.22% respectively. However, considering the Staphylococci infection, there were 2 cases of MRSA, 8 cases of MSSA, 7 cases of CONS, and 3 cases of Staphylococcus haemolyticus. Habib et al. reported CONS as the main causative organism for prosthetic valve IE.(19) Our study showed CONS as a causative organism in 33.33% of the patients with prosthetic valve IE. Most studies reported Staphylococci as the most common organism causing IE. Barry et al reported that Staphylococci infection, especially MSSA as the most common cause of prosthetic valve IE and also reported that 31.5% of the native valve IE was caused by viridans group streptococci.(7) Studies had reported the mortality rate to be high, especially with S. aureus infection in prosthetic valve with one year mortality rate of 50%.(20,21) However, in our study the mortality rate in prosthetic valve endocarditis was 17% with MSSA, CONS, and Aspergillus niger as causative agent in 1 patient each.

Similarly, the incidence of viridan groups Streptococci infection was reported in one case involving prosthetic valve IE. Moreover, the study also identified Aspergillus niger as the causative agent for IE in one case resulting in the death of the patient. Fungal infection was reported only in native valves in our study. In two cases, the culture yielded the growth of other microorganisms together with gram—positive organisms.

The study was retrospective in nature and was a single—center study limiting the generalization of the findings with other healthcare settings. The sample size was small and a larger sample size could have given a better picture. This research contributes valuable insights into the profile and outcomes of IE in a quaternary care center setting. The findings emphasize the importance of attention to IE, especially in the elderly population. Multi—center studies with larger cohorts could further improve our understanding of this potentially life—threatening condition. 

The study showed that the native valves were mostly affected. The most common causative organism in IE was Streptococci, especially viridians group streptococci, followed by Staphylococci and Enterococci. Culture—negative IE was found in 32.69% of the population. The overall mortality as per the study was 16.3%. The study showed a significant association between complications like heart and renal failure, sepsis, septic and cardioembolic shock, embolism, and MODS with death.

Gupta A, Gupta A, Kaul U, Varma A. Infective endocarditis in an Indian setup: Are we entering the ‘modern’ era? Indian J Crit Care Med Peer—Rev Off Publ Indian Soc Crit Care Med. 2013;17(3):140–7. 

Correa de Sa DD, Tleyjeh IM, Anavekar NS, Schultz JC, Thomas JM, Lahr BD, et al. Epidemiological trends of infective endocarditis: a population—based study in Olmsted County, Minnesota. Mayo Clin Proc. 2010 May;85(5):422–6. 

Murdoch DR, Corey GR, Hoen B, Miró JM, Fowler VG, Bayer AS, et al. Clinical Presentation, Etiology and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration on Endocarditis—Prospective Cohort Study. Arch Intern Med. 2009 Mar 9;169(5):463–73. 

Cahill TJ, Prendergast BD. Infective endocarditis. Lancet Lond Engl. 2016 Feb 27;387(10021):882–93. 

Fowler VG, Li J, Corey GR, Boley J, Marr KA, Gopal AK, et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardiol. 1997 Oct;30(4):1072–8. 

Joseph JP, Meddows TR, Webster DP, Newton JD, Myerson SG, Prendergast B, et al. Prioritizing echocardiography in Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2013 Feb;68(2):444–9. 

Barry M, Bari SA, Akhtar MY, Al Nahdi F, Erlandez R, Al Khushail A, et al. Clinical and Microbiological Characteristics of Infective Endocarditis at a Cardiac Center in Saudi Arabia. J Epidemiol Glob Health. 2021 Nov 4;11(4):435–43. 

Lakhdhar R, Chourabi C, Drissa M, Cheour M, Drissa H. [Epidomiological characteristics of infective endocarditis: a study of 135 cases]. Tunis Med. 2014 Feb;92(2):115–22. 

Mathew J, Addai T, Anand A, Morrobel A, Maheshwari P, Freels S. Clinical features, site of involvement, bacteriologic findings, and outcome of infective endocarditis in intravenous drug users. Arch Intern Med. 1995 Aug 7;155(15):1641–8. 

Zhu W, Zhang Q, Zhang J. The changing epidemiology and clinical features of infective endocarditis: A retrospective study of 196 episodes in a teaching hospital in China. BMC Cardiovasc Disord. 2017 May 8;17(1):113. 

Spies C, Madison JR, Schatz IJ. Infective endocarditis in patients with end—stage renal disease: clinical presentation and outcome. Arch Intern Med. 2004 Jan 12;164(1):71–5. 

Mano TB, Cardoso I, Costa PO, Rito T, Branco L, Agapito A, et al. Infective endocarditis in a cohort of adult CHD patients. Cardiol Young. 2023 Feb;33(2):190–5. 

Danchin N, Voiriot P, Briancon S, Bairati I, Mathieu P, Deschamps JP, et al. Mitral valve prolapse as a risk factor for infective endocarditis. Lancet Lond Engl. 1989 Apr 8;1(8641):743–5. 

Roberts WC, Kishel JC, McIntosh CL, Cannon RO, Maron BJ. Severe mitral or aortic valve regurgitation, or both, requiring valve replacement for infective endocarditis complicating hypertrophic cardiomyopathy. J Am Coll Cardiol. 1992 Feb;19(2):365–71. 

Mir T, Uddin M, Qureshi WT, Regmi N, Tleyjeh IM, Saydain G. Predictors of Complications Secondary to Infective Endocarditis and Their Associated Outcomes: A Large Cohort Study from the National Emergency Database (2016—2018). Infect Dis Ther. 2022 Feb;11(1):305–21. 

Asopa S, Patel A, Khan OA, Sharma R, Ohri SK. Non—bacterial thrombotic endocarditis. Eur J Cardio—Thorac Surg Off J Eur Assoc Cardio—Thorac Surg. 2007 Nov;32(5):696–701. 

Rajani R, Klein JL. Infective endocarditis: A contemporary update. Clin Med. 2020 Jan;20(1):31–5. 

Al—Tawfiq JA, Sufi I. Infective endocarditis at a hospital in Saudi Arabia: epidemiology, bacterial pathogens and outcome. Ann Saudi Med. 2009;29(6):433–6. 

Habib G, Thuny F, Avierinos JF. Prosthetic Valve Endocarditis: Current Approach and Therapeutic Options. Prog Cardiovasc Dis. 2008 Jan;50(4):274–81. 

Wang A, Athan E, Pappas PA, Fowler VG, Olaison L, Paré C, et al. Contemporary clinical profile and outcome of prosthetic valve endocarditis. JAMA. 2007 Mar 28;297(12):1354–61. 

	Pérez—Vázquez A, Fariñas MC, García—Palomo JD, Bernal JM, Revuelta JM, González—Macías J. Evaluation of the Duke criteria in 93 episodes of prosthetic valve endocarditis: could sensitivity be improved? Arch Intern Med. 2000 Apr 24;160(8):1185–91. 

Epidemiological, Clinical and Microbiological Profile of Infective Endocarditis and its Outcome:  Insights from a Tertiary Care Center in India

#111827

Neonatal Department, Medcare Women and Children Hospital, United Arab Emirates

Dr. Issam Abdalbari

Hemodynamic instability is common in high—risk infants admitted in NICU departments (DilekDilli, 2018); Normal hemodynamics necessities blood flow that provide adequate oxygen and nutrient delivery to the tissues. Diverse aspects may compromise hemodynamic status in preterm/term infants. The below paper highlights the management of low blood flow states in babies less than 28 weeks’ gestation. Blood pressure is an important aspect in critical care of medicine, requires to be interpreted it better, examine systolic and diastolic, and not to only look on the mean blood pressure. Furthermore, its necessary to consider its association with organ blood flow. The application of Echocardiography in NICU, led to improved understanding of the underlying pathophysiologic mechanism in infant and directing proper management with less duration and exposure to medication(Elsayed and Fraser, 2016).

Low blood flow state is defined as the state when blood flow to an organ is insufficient to meet its oxygen demand (Kluckow., 2018). Hypotension is defined as a mean blood pressure in mmHg below the numerical gestational age of the infant in weeks, although this definition is considered with least supportive evidence (Kluckow., 2018). Evidence that blood pressure alone is not sufficient to accurately assess organ perfusion, ongoing frequent assessment with perfusion is required to detect any subsequent signs of poor perfusion.

Concerning pathophysiology of low blood flow state in ELGAN, maintenance of organ perfusion and tissue oxygenation requires maintenance of adequate systematic blood flow. The two main determines of oxygen delivery for maintenance of normal tissue and organ oxygenation are volume of blood flow and atrial oxygen content. These are defined by the equation:

Systemic oxygen delivery (mls O2/min) = Cardiac output (L/min) x Hb concentration (g/L) x 1.31 (mls O2 Hb) x % saturation.

Therefore, cellular oxygen requirements must be maintained for efficient energy production and its absence results in cellular death(Paradisis, 2013).

As shown in Figure 1, the aim is to improve Oxygen delivery, while trying to correct the low blood flow states, as cardiac output equals summation of stroke volume multiplied by heart rate [COP = SV x HR].

For management of low blood flow state in babies of less than 28 weeks’ gestation,the current standard(one size fits all)pressure driven approach to manage circulatory insufficiency treat low blood pressure to achieve higher values .Nearly all NICU units use this approach as shown below, which was published in 2003, this guideline is basically considered if the child has cardiac compromised hypotension, treated with fluid bolus of normal saline 10—20 cc/kg and repeated if required. First line therapy is dopamine 5—20 mcg /kg /min, second line dobutamine 5—20 mcg / kg /min, then epinephrin should be added by 0.2 mcg / kg / min, if needed dexamethasone is added as rescue therapy. (S J Dasgupta, 2003a) (S J Dasgupta, 2003b).

This approach was used when neonatal echo is not being done routinely looking to hemodynamics in neonatal intensive care unit for sick babies. It is a blind approach which was more to increase blood pressure. there is no consideration of underlying cardiac function or physiology, compensatory mechanisms, or fluid loss. this kind of approach is neither evidenced base nor logical, this umbrella approach is not applicable to all scenarios in the clinical practice.

After introduction of neonatal echocardiography, our approach in management directed according to pathophysiology of the disease process. Now we individualized our approaches to individual circumstances looking to cardiac function, knowing the physiology, and end organ perfusion.

Our aim of treatment to improve end organ perfusion, tissue perfusion, increase oxygen delivery, and blood flow to the issue. The current dilemma is that there is not enough evidence to say Dobutamine is better than dopamine or milrinone, but there is evidence of the physiology and now after (POCUS) point of care ultrasound echo, we understand physiology better(Elsayed and Fraser, 2016b). It’s not possible to recommend a drug over another just based on evidence, because there are no randomized control trials to support that. Physiology— based approach is deliberated to be better than pressurebasedapproach(Singh and Tissot, 2018), so perhaps focused individual approach is needed.

The management of low blood flow state in babies of less than 28 weeks’ gestation infant in the first 48—72 hours of life,it depends upon the pathophysiology of the disease process. In these babies, there is diastolic myocardial dysfunction and poor compliance due to immature granular myocardium with increase left ventricular or biventricular mass. Increase sudden exposure to increase SVR after elimination of placenta, as well as persistence exposure to high pulmonary vascular resistance due to respiratory distress syndrome, wet lungs, and mechanical ventilation. Therefore, this will lead to impaired transitional circulation process with low cardiac output status, low systemic blood flow in superior vena cava and hypotension which may be due to low cardiac output and poor myocardial contractility, and persistent shunt in (PDA) patent ductus arteriosus / (PFO) patent foramen oval(Singh and Tissot, 2018).These infants also had decrease oxygen carrying capacity and oxygen extraction by tissues due to presence of high fetal hemoglobin in the first few weeks which gradually decreases, (S J Dasgupta, 2003a) (Singh and Tissot, 2018) .

Drugs used to treat circulatory compromised in babies of less than 28 weeks’ gestation infants during first 48—72 hours after birth: —
According to the physiology mentioned, we should choose drugs which could improve contractility, and improve cardiac output.


Fluid boluses 10 cc/kg and repeat if needed in case of hypovolemia or blood loss, evidenced by echocardiography(Stranaket al., 2014)

Dobutamine improve contractility and cardiac output (B1, B2) as compared to Dopamine (B) increase contractility at low doses 2.5mcg/kg/min, α at doses of (6mcg leading to increase SVR, PVR) (Dempsey et al., 2014).

	Low dose of Epinephrine < 0.3mq (B) can be used alternate to Dobutamine as it increases contractility and may increase SBF, but high doses more than 0.3mcg/kg/min, (α) will increase SVR, PVR with negative effect on which is not the case in this scenario.

Norepinephrine is predominant peripheral α effect, with more vasoconstrictor effect than epinephrine, not drug of choice in this scenario, its drug of choice in septic shock.

Milirinone phosphodiesterase III inhibitor, increases availability of cAMP, leads to improved contractility and fall in SVR, PVR, with net effect increased SBF, better to avoid in preterm infants because of its severe hypotensive effect and long half life. It can be used in post PDA ligation syndrome (Singh and Tissot, 2018).

Hence, drug of choice for this physiology is either dobutamine or low dose of epinephrin rather than dopamine or any other medication. The practitioner must beware of high dose of dopamine or vasopressor therapy in first 48—72 hours during transitional circulation, because it will increase the blood pressure and Systemic Vascular Resistance (SVR) where is not applicable in this scenario according to physiology described.

In Management of low blood flow states in septic shock, in quick and frequent monitoring, and not only blood pressure, should be with evidence of organ dysfunction (Schwarz and Dempsey, 2020).

1. Warm shock, which is due to over production of vasoactive substances cytokines which causes vasodilatation(Silveira, Giacomini and Procianoy, 2010). There will be low systemic vascular resistance, normal capillary refill time, bounding pulse, hypotension.(E.Schwarz and Dempsey, 2020).Management will include fluid boluses normal saline 30 —60cc/kg, norepinephrine at a dose of 0.05 mcg/kg/min, maximum 0.4 mcg/ kg/min., epinephrine improved blood pressure, urine output, and oxygen dependency in retrospective study of preterm infants (Rizket al) (E.Schwarz and Dempsey, 2020).

2. Cold shock, which is a constrictive physiology state with high systemic vascular resistance, cold extremities, delayed capillary refill time, diminished peripheral pulses, low or normal blood pressure (Silveira, Giacomini and Procianoy, 2010) (E Schwarz and Dempsey, 2020).
In constrictive phenotype more likely to be dealing with cardiac dysfunction and low cardiac output. Treatment will start with normal saline boluses up to 30—60 cc/kg, if the blood pressure is low, then low dose of epinephrine at 0.02mcg/kg/min (Beau Batton, 2020).If blood pressure is normal or high milrinone can be started with a dose 0.33 mcg /kg /min as negative inotrope, hydrocortisone in between if no response (E.Schwarz and Dempsey, 2020).


3. Cardiogenic shock, manifested by low systolic, diastolic, main blood pressure, and narrow pulse pressure. It occurs in hyperinflation of lungs compressing the heart in mechanical ventilation with high main airway pressure, poor filling, poor contractility of the heart, persistent pulmonary hypertension, and overdoses of inotropes affecting the myocardial performance. In cardiogenic shock, echocardiography showing poor myocardial performance.

In management, Bolus of normal saline in hypovolemia and drugs with dual effect like Dopamine or epinephrine and will not effect on the diastolic pressure. Dobutamine in low doses 5mcg/kg/min, dobutamine at doses more than 10 mcg/ kg/ min will cause vasodilatation and decrease the diastolic pressure more treatment of the cause is crucial also in management (Beau Batton, 2020).

Understanding the pathophysiologic mechanism early before worsening of hemodynamics or progression to anerobic metabolism is helpful in targeting the management. Looking at the trend of systolic, diastolic and pulse pressure before and after any deterioration and intervention. Additionally, compare the values to the normalized centile curves for blood pressure values. Furthermore, integrate the impression of systolic and diastolic pressure of other parameters of delayed organ prefusion.

Finally, Echocardiography and other non—invasive measures is crucial in directing the management.

1.	Dilli D, Soylu H, Tekin N. Neonatal hemodynamics and management of hypotension in newborns. Turk Pediatri Ars. 2018 Dec 25;53(Suppl 1):S65—S75. doi: 10.5152/TurkPediatriArs.2018.01801. PMID: 31236020; PMCID: PMC6568285.

2.	Kluckow M. The Pathophysiology of Low Systemic Blood Flow in the Preterm Infant. Front Pediatr. 2018 Feb 16;6:29. doi: 10.3389/fped.2018.00029. PMID: 29503814; PMCID: PMC5820306.

3.	Beau Batton, M. (2020) 'Assessment and management of low blood pressure in extremely preterm infants', Up to Date.

4.	Dempsey, E. M., Barrington, K. J., Marlow, N., O'Donnell, C. P., Miletin, J., Naulaers, G., Cheung, P. Y., Corcoran, D., Pons, G., Stranak, Z., Van Laere, D. and Consortium, H. I. P. (2014) 'Management of hypotension in preterm infants (The HIP Trial): a randomised controlled trial of hypotension management in extremely low gestational age newborns', Neonatology, 105(4), pp. 275—81.

5.	E.Schwarz, C. and Dempsey, E. M. (2020) 'Seminars in Fetal and Neonatal Medicine', Elsevier, pp. 7.

6.	Elsayed, Y. N. and Fraser, D. (2016a) 'Integrated Evaluation of Neonatal Hemodynamics Program Optimizing Organ Perfusion and Performance in Critically Ill Neonates, Part 1: Understanding Physiology of Neonatal Hemodynamics', Neonatal Netw, 35(3), pp. 143—50.

7.	Elsayed, Y. N. and Fraser, D. (2016b) 'Integrated Evaluation of Neonatal Hemodynamics, Part 2: Systematic Bedside Assessment', Neonatal Netw, 35(4), pp. 192—203.

8.	Paradisis, M. (2013) 'Strategies to Tackle early low flow states in the extremely preterm infant', Current Pediatric Reviews, pp. 90—98.

9.	S J Dasgupta, a. A. B. G. A. D. (2003a) 'Child Fetal Neonatal Ed', Frontiers Pediatrics.

10.	S J Dasgupta, A. B. G. (2003b) 'Hypotension in the very low birthweight infant: the old, the new, and the uncertain', Recent Advances, 88, pp. 450—454

11.	Schwarz, C. E. and Dempsey, E. M. (2020) 'Management of Neonatal Hypotension and Shock', Semin Fetal Neonatal Med, 25(5), pp. 101121.

12.	Silveira, R. d. C., Giacomini, C. and Procianoy, R. S. (2010) 'Neonatal sepsis and septic shock: concepts update and review ', Rev Bras Ter Intensiva, 22(3), pp. 280—290.

13.	Singh, Y. and Tissot, C. (2018) 'Echocardiographic Evaluation of Transitional Circulation for the Neonatologists', Front Pediatrics, 6.

14.	Stranak, Z., Semberova, J., Barrington, K., O'Donnell, C., Marlow, N., Naulaers, G., Dempsey, E. and consortium, H. I. P. (2014) 'International survey on diagnosis and management of hypotension in extremely preterm babies', Eur J Pediatr, 173(6), pp. 793—8.

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Evidence—based Guideline for the Pharmacological Management of Low Blood Flow States in Babies of Less than 28 Weeks’ Gestation

Consultant Gastroenterologist, Medcare/ Saeed Alshaikh Centre, Dubai, United Arab Emirates

Ali Alshareefy

EATL is an aggressive non—Hodgkin lymphoma that arises from T cells present in the gut who express CD103 and CD81. EATL is classified into two groups based on morphology, immunohistochemistry and genetic profile; type I which is most common (80—90%) associated with coeliac disease and is most common in those with Northern European ancestry and type II2 which is most common in Asia. This type of lymphoma is preceded by enteropathy which is the reason patients with coeliac disease (CD) are at highest risk of this condition. EATL as well as coeliac disease are highly associated with HLA—DQ2 or HLA—DQ8 haplotypes3. Other risk factors in addition to HLA—DQ2/8 haplotypes are advanced age and male sex4.EATL is a rare condition with an annual incidence of 0.5—1 million5. EATL has a poor prognosis with a 5—year survival between 8—20% due to the absence of a standard therapeutic regiment for patients for this condition6 with the only means of prevention being to adhere to a strict no gluten diet7.

 Clinico—pathologic presentation of EATL

In a study8 looking at the clinical presentation of 62 patients with EATL the following data was extracted; median age of presentation was 61 with 53% being male, 64% of patients presented with a tumor stage of IV, the small intestine was the most commonly involved location (90%) followed by the large intestine (16%). The mesenteric lymph nodes and para—aortic/iliac lymph nodes were involved in 35% and 11% of respectively. Common symptoms at presentation include abdominal pain (88%), fatigue (38%), anorexia (38%) and infection (23%). Less common symptoms include hepatomegaly (6%), splenomegaly (6%) and pruritis (3%). B symptoms (fever, night sweats and unexplained weight loss) was present in 63% of patients. 63% of tumors were greater than or equal to 5cm. Bone metastases is an uncommon feature present in only 3% of these patients. Biochemical findings include elevated LDH (35%), elevated CRP (33%), hypercalcemia (9%), 52% of the patients had a history of coeliac sprue. One of the major complications associated with EATL is small bowel perforation; perforation of any part of the bowel can result in our gut flora which normally remain intra—luminally to escape and enter the peritoneum. This can lead to peritonitis and then abdominal sepsis which is extremely dangerous as abdominal sepsis has a mortality rate of 72%9.

In a 2017 study10 conducted by Jan Delabie and colleagues the genomic and transcriptomic differences between EATL type I and EATL type II were examined. 41 patients with EATL I and 23 with EATL II were investigated and the following results were noted. It was found that the vast majority of genes studied (90%) such as TP53, BRAF, NRAS, GNAS etc. were mutated in both subtypes however there were a small number of genes that were found to be mutated frequently in one type compared to the other; DAPK3 and SOCS1 genes were found to be mutated in higher frequencies in EATL type I when compared to type II. Diagnostic guidelines derived from Arps and Smith 201311 have attributed chromosome 1q gain of function mutations to EATL type I however this study found the same gains in 20% of EATL type II cases. In regards to EATL type II, mutations that were observed in higher frequency when compared to type I include KRAS, STAT5B (>50%) in type II and SETD2 (>60%). In addition to this, gains at chromosome 8q which contains MYC gene were more frequent in type II.

In figure 1(A) we can see irregularly shaped/angulated cells with variable cytoplasm, the cells expressed CD30 as seen in 1(B), shortened villi in 1(C) and a “top heavy” intra—epithelial T cell in 1(D) via CD3 straining.

Type II lymphoma consists of monotonous—medium sized cells with round nuclei and have a stippled chromatin pattern as seen in 2(A). 2(B) shows cells expressing CD56. 2(C); mucosa adjacent to lymphoma shows villous atrophy and in 2(D) we can see intra—epithelial infiltration by lymphoma cells via CD56 staining. 

As we can see according to histological and immunohistochemistry studies EATL type I and II are two distinct entities with EATL type I being characterized by irregularly shaped/angulated cells expressing CD30 and an intra—epithelial T cell infiltration seen via CD3 staining whereas in EATL type II we see monomorphic CD56+ lymphoma cells.  

Seeing as CD is the major risk factor for EATL it is vital we understand the pathogenesis underpinning CD to explain how EATL entails as a result. CD AKA gluten—sensitive enteropathy is an autoimmune condition that results in activation of a cell mediated (T cell) and humoral (B cell) immune response. Coeliac is characterized by the presence of a specific autoantibody called anti—tissue transglutaminase (anti—ttg). The pathogenesis of CD occurs as a result of ingestion of gliadin, a peptide found in gluten which is a naturally occurring protein present in many common foods such as wheat, oats and rye. The gliadin peptide triggers an immune response which occurs as follows. Zonulin is a protein and modulator of tights junctions at the intestine which reversibly regulate intestinal permeability16 and when exposed to gluten it is upregulated causing disruption to the integrity of these tight junctions present between epithelial cells and thus results in an increase in paracellular movement of protease resistant gluten fragments17. This results in the undigested gluten peptides (gliadin) to pass through epithelial cells and enter the lamina propria where it is deaminated by tissue transglutaminase which induces a negative charge on the gliadin peptide18. This step of deamination is the key pathogenic event contributing to the immunogenicity of gliadin in CD19. These negatively charged gliadin peptides bind to positively charged amino acids on HLA—DQ2 or HLA—DQ8 molecules20. This triggers an innate immune response and also an adaptive immune response which is initiated by the presentation of these negatively charged gliadin peptides on APCs to CD4+ T Lymphocytes which causes production of pro—inflammatory cytokines namely interferon gamma21. These cytokines can either proceed to activate Th1 cells which release IL—15 and IL—21 which results in the activation of CD8+ intra—epithelial lymphocytes (IELs) and also promote the activity of CD8+ T lymphocytes22 which contributes to the intestinal lesions and damage seen in CD, or can activate Th2 cells which result in B cell antibody production such as anti—ttg and anti—endomysium which is thought of as characteristic of active CD23. IL—15 activated CD8+ IELs express NKG2D receptor which binds MIC—A on enterocyte surface causing release of granzymes and perforins resulting in enterocyte death by lysis resulting in the villous atrophy associated with CD24. 

Villous atrophy causes malabsorption resulting in a multitude of problems such as anemia from iron malabsorption, diarrhea, bloating, steatorrhea, vitamin B12 deficiency, abdominal pain, failure to thrive in infancy and other signs and symptoms that a patient with CD typically presents with. Strict adherence to a non—gluten diet can cause a reversal of symptoms however a small number of CD patients will develop refractory coeliac disease (RCD) which is defined as persistence or recurrence of malabsorptive signs and symptoms and villous atrophy despite strict adherence to a gluten free diet for > than 12 months25. RCD can be classified as follows; RCD I which is thought to represent proliferation of CD8—alpha—beta heterodimer expressing TCR—alpha—beta+ intraepithelial T cells26 and RCD II IELs are believed to be derived from CD8+ TCR—alpha—beta+ T cells due to the expression of CD103, cytoplasmic CD3 and frequent detection of TCR gene rearrangements27. As mentioned previously EATL can be classified as type I (CD associated) and II (non—CD associated). Around half of RCD II patients develop EATL28 and therefore RCD type II is considered a precursor lesion for EATL type I; partial trisomy of the one q region is highly associated with RCD type II and a gain of chromosome one q in 16% of EATLs implies a common step in lymphomagenesis29. Another possible factor in the lymphomagenesis is the overexpression of IL—15 which maintains IEL activation and promotes T cell clonal proliferation which may lead to malignant transformation.30 IL—15 has also been shown to upregulate anti—apoptotic protein BCL—xL via JAK3—STAT5 signaling pathway activation in RCD II IELs, prolonging their survival.31 Further research is needed to truly establish the link between RCD II and EATL. EATL type II as mentioned before is not associated with CD and its pathogenesis is very poorly understood as it is an extremely rare cancer with not much research behind it. As eluded to previously recent studies have a shown an association between EATL type II and SETD2 mutations;32 the tumor suppressor gene SETD2 encoding a non—redundant H3K36—specific trimethyltransferase was found to be altered (defective H3K36 trimethylation) in 14/15 cases, owing to loss of function mutations and/or loss of the associated locus 3q21.31, and according to the researchers of this paper this study describes that SETD2 inactivation is a molecular hallmark of EATL type II.

EATL may be confused with IBD due to the similar clinical presentations in terms of symptomology. Radiographic imaging is also not highly specific; gastrointestinal lymphomas typically show bowel wall thickening on CT scan which is also seen in IBD. A history of coeliac disease or non—adherence to a gluten free diet which would be noted during history taking should point the physician to a possible diagnosis of EATL. At this point when EATL is suspected capsule endoscopy may be indicated where this small video capsule swallowed then passes through the whole length of the small intestine, before being excreted. The capsule during its course takes thousands of images that can be recorded and reviewed to detect any focal irregularities or mass lesions by a specialized gastroenterologist. Such abnormalities on capsule study will subsequently be followed by double—balloon enteroscopy which may be used to visualize the lesion in real time and to obtain a sample that can be sent for histological analysis which provides the definitive diagnosis of EATL via presence of histological/immunohistochemistry markers as discussed above.

There is not yet a standardized form of therapy for EATL with physicians using a mix of chemotherapy, surgical resection, radiotherapy and autologous stem cell transplantation.33 Surgical resection of the tumor remains the mainstay of management however due to the tumors’ location in the gastrointestinal tract surgical resection can often lead to other gastrointestinal related issues such loss of absorptive function of the small bowel where malabsorption is often encountered and in addition to surgical issues related to stoma formation such as high stoma output which can negatively impact a patients wellbeing and quality of life.34 Strict adherence to a gluten free diet remains the only means of prevention. 

EATL is a rare but serious complication of CD. It is subdivided into two distinct entities via genetic analysis where genes such SETD2 and KRAS are mutated in much higher frequency in type II when compared to type I, however in EATL type I we see genes such as DAPK3 and SOCS1 mutated in high frequency. In addition, histological analysis and immunophenotyping also show clear differences in the two subtypes; type I is characterized by irregularly shaped/angulated cells expressing CD30 and an intra—epithelial T cell infiltration seen via CD3 staining while type II EATL is characterized by CD56+ lymphoma cells. The 2 subtypes also differ in their pathogenesis with current research showing EATL type I follows a linear route of progression from RCD as a precursor lesion, in contrast to EATL type II which is non coeliac associated and has been associated with SETD2 loss of function mutations as a molecular hallmark. It is clear EATL has a complex pathogenesis with multiple factors involved, research thus far has highlighted a clear difference in the pathogenesis pathways of EATL subtypes however much more work is needed to be done. Currently there is no standard therapy used in the management of EATL as stated previously and there is lack of targeted therapies mostly due to a lack of understanding of the molecular basis underpinning this condition. Further research is required to identify novel molecular targets which can be used to develop targeted therapies that can treat this condition with high specificity and efficacy, until then the prognosis of patients afflicted with this condition will remain poor. Equally as important, more emphasis is required on the awareness and early detection of EATL in the appropriate clinical context like RCD.

Delabie J.M.A. (2020) Enteropathy—Associated T—Cell Lymphoma. Hematopathology. Encyclopedia of Pathology, 2020 

N. Majid, Z. Bernoussi, H. Mrabti, H. Errihani. Celiac Disease, Enteropathy—Associated T—Cell Lymphoma, and Primary Sclerosing Cholangitis in One Patient: A Very Rare Association and Review of the Literature,2013

Delabie J.M.A. Enteropathy—Associated T—Cell Lymphoma. Hematopathology. Encyclopedia of Pathology, 2020

	Zakiah Al Somali, Mehdi Hamadani, Moahamed Kharfan— Dabaja, Ana Sureda, Riad El Fakih, Mahmoud Aljurf. Enteropathy—Associated T cell Lymphoma, 2021

Jan Delabie, Harald Holte, Julie M.Vose, Fred Ullrich, Elaine S. Jaffe, Kerry J. Savage et al. Enteropathy—associated T—cell lymphoma: clinical and histological findings from the International Peripheral T—Cell Lymphoma Project, 2011

Petula Nijeboer, Laura R. de Baaij, Otto Visser, Birgit I. Witte, Saskia A.G.M. Cillessen, Chris J Mulder, Gerd Bouma. Treatment response in enteropathy associated T—cell lymphoma; survival in a large multicenter cohort, 2015

Antonio Di Sabatino, Federico Biagi, Paolo G Gobbi, Gino R Corazza. How I treat enteropathy—associated T—cell lymphoma, 2012

M H Schoenberg, M Weiss, P Radermacher. Outcome of patients with sepsis and septic shock after ICU treatment, 1998

Andrea B. Moffitt, Sarah L. Ondrejka, Matthew McKinney, Rachel E.Rempel, John R. Goodlad, Chun Huat Teh et al. Enteropathy—associated T cell lymphoma subtypes are characterized by loss of function of SETD2, 2017

Arps D.P., and Smith L.B.. Classic versus type II enteropathy—associated T—cell lymphoma: Diagnostic considerations, 2013

Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications, 2012

Menard S, Lebreton C, Schumann M, Matysiak—Budnik T, Dugave C, Bouhnik Y, et al. . Paracellular versus transcellular intestinal       permeability to gliadin peptides in active celiac disease, 2012

De Re V, Magris R, Cannizzaro R. New insights into the pathogenesis of celiac disease. Front Med, 2017

Husby S, Murray JA. Diagnosing coeliac disease and the potential for serological markers. Nat Rev Gastroenterol Hepatol, 2014

Ciccocioppo R, Di Sabatino A, Corazza GR. The immune recognition of gluten in coeliac disease. Clin Exp Immunol, 2005

Qiao SW, Sollid LM, Blumberg RS. Antigen presentation in celiac disease. Curr Opin Immunol, 2009

Troncone R, Jabri B. Coeliac disease and gluten sensitivity. J Intern Med, 2011

A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Sophie Hue, Jean—Jacques Mention, Renato C Monteiro, ShaoLing Zhang, Christophe Cellier, Jacques Schitz et al, 2004

Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2013

Verbeek WH, Goerres MS, von Blomberg BM, Oudejans JJ, Scholten PE, Hadithi M, et al. Flow cytometric determination of aberrant intra—epithelial lymphocytes predicts T—cell lymphoma development more accurately than T—cell clonality analysis in Refractory Celiac Disease. Clin Immunol. 2008

Udit Chander, Rebecca J. Leeman—Neill, Govind Bhagat. Pathogenesis of Enteropathy—Associated T Cell Lymphoma, 2018

A. Al—Toma, W.H. Verbeek, M. Hadithi, et al. Survival in refractory coeliac disease and enteropathy—associated T—cell lymphoma: retrospective evaluation of single—centre experience, Gut, 2007

V. Verkarre, S.P. Romana, C. Cellier, et al. Recurrent partial trisomy 1q22—q44 in clonal intraepithelial lymphocytes in refractory celiac sprue, Gastroenterology, 2003

J.J. Mention, A.M. Ben, B. Begue, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease, Gastroenterology, 2003

Malamut G, El Machhour R, Montcuquet N, Martin—Lanneree S, Dusanter—Fourt I, Verkarre V, et al. IL—15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease—associated inflammation and lymphomagenesis, 2010

Annalisa Roberti, Maria Pamela Dobay, Bettina Bisig, David Vallois, Cloe Boechat, Evripidis Lanitis.Type II enteropathy—associated T—cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations, 2016

Peutla Nijeboer, Laura R. de Baajj  Otto Visser, Birget I. Witte, Saskia A.G.M. Cillessen, Chris J. Mulder, Gerd Bouma, Treatment response in enteropathy associated T—cell lymphoma; survival in a large multicentre cohort, 2015

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Molecular Pathogenesis of Enteropathy Associated T—Cell Lymphoma (EATL)

Consultant and Head of the Department, Aster Hospital, Doha, Qatar.

Dr Manoj Mohan

Evidence—based medicine, clinical research methodology, well—built questionnaire.

This first paper in this clinical research methodology series focuses on understanding the need for evidence—based medicine, its applicability and how we should use it in our everyday clinical practice. The paper provides an overview of the evolution of evidence—based medicine and the five—step approach to simplify its use. Clinical research evolves through evidence—based medicine, and this paper assists a busy practitioner with the fundamentals of clinical research. Future papers in the clinical research methodology series will cover all relevant aspects of clinical research.

Evidence—based medicine (EBM) is a systematic approach to clinical problem—solving that integrates the best available research evidence with clinical expertise and patient values. This paper explains the concepts of EBM and also introduces the five—step approach of EBM. Health practitioners must base their clinical decisions on the best available evidence. The clinical research methodology series aims at all health practitioners to understand the principles of research methodology to incorporate EBM in their practises. This first paper on the approach to evidence—based medicine provides the basic understanding and the reasoning for clinical research. The subsequent articles in the series will focus on principles and approaches for evidence—based practice, including methodology of systematic reviews, meta—analysis, randomised controlled trials, observational studies and all other clinical research methodologies required for healthcare practitioners.

EBM began as a movement in the 1990s(1) and is defined as the integration of the "best research evidence with clinical expertise and patient values"(2) (Fig i)(3). The evidence—based working group showed a paradigm shift in teaching and training since the introduction of EBM(4), and the concept is embedded in the current clinical practice with clinical practice guidelines and guidance based on EBM. The Cochrane Collaboration was founded in 1993 by Ian Chalmers and a group of 70 other international colleagues based on EBM to establish a concrete approach for clinical trials.(5) Similarly, methodology setting and publication standards(6) have changed and evolved around the development of EBM. The need for EBM is growing as new research and evidence are coming out daily, and the need to stay current in clinical practice(7). The task of reading every single paper out there and appraising it to use in clinical practice is highly impossible for clinicians. 

Commonly, there are questions in clinical practice about diagnosis, prognosis, and treatment that often arise, and we need the answers to these questions. EBM allows the integration of good quality published evidence, clinical expertise, and the options and values of the patients and their families or carers. The alternative practices, including textbook description, basic scientific principles, clinical judgement, experiences, and clinical idiosyncrasies, continue as a challenge for EBM(8). Therefore, incorporating an evidence—based approach should fulfil factors such as personal experience, judgement skills, and, more importantly, patient values and preferences can all be considered together in EBM.

The most important reason for practising EBM is for physicians to make decisions and patient outcomes(9) to improve the quality of care by identifying and promoting practices that work and eliminating ineffective or harmful ones. EBM provides a platform for critical thinking and reasoning to caregivers. It demands the effectiveness of clinical interventions, the accuracy and precision of diagnostic tests, and the power of prognostic markers that can be scrutinised for their usefulness in clinical practice. It requires clinicians to be open—minded and explore new methods and scientifically proven effective methods and, at the same time, to discard methods that are ineffective or harmful. EBM has a hierarchy of evidence, and getting the proper evidence to the question is challenging, especially when we need help understanding the context of the clinical entity. Grades and levels of evidence have been debated because of the complexity of their applicability in clinical practice (10). Therefore, healthcare professionals must develop EBM skills, including effectively finding, critically appraising, and incorporating evidence—based knowledge and practice. Therefore, there is a need to use the five—step approach as a practical solution for every healthcare practitioner and provider.

The EBM five—step approach involves converting information in clinical practice through a stepwise approach to ask the right question as the framework for EBM. The five—step approach (Figure 2) (11) allows the transformation of the answerable question to find the relevant evidence—based reasoning and the structure to provide an evidence—based answer to the question which can be applied in practice and allows a possibility of appraising our performance, which improves our clinical practice.

The most critical and challenging task in practising EBM may be translating a clinical problem into an answerable question. When we come across a patient with a particular problem, various questions may arise for which we would like the answers. These questions are frequently not structured, are usually complex and may need more clarity in one's mind. In the practice of EBM, we should begin with a well—formulated clinical question. We should develop the skill to convert the information we need into an answerable question. Good clinical questions should be straightforward, directly focused on the problem and answerable by searching the medical literature.

The PubMed PICO tool (12) assists in framing the correct clinical question as below:

The intervention, test, or exposure of interest

Therefore, an answerable clinical question should be structured in the PICO (Patient or Problem, Intervention, Comparison, Outcome/s) or PIO (Patient or Problem, Intervention, Outcome/s) format.
For example, 


Patients with Bell's Palsy (Patient / Problem)

Facial function at three months (Outcome)

A four—part clinical question can be formulated: In patients with Bell's Palsy, do corticosteroids, compared to placebo or no treatment, improve facial function at three months?

Once we have formulated the clinical question, the next step is to seek the relevant evidence to help us find the answer. Many sources of information are available to answer this question; traditional sources suggest textbooks and journals are often outdated, and we may resort to asking a colleague or an expert, but again, the quality of information from these sources is variable. Other reliable sources are summarised evidence that can help, including UpToDate (13) and Best Practice from BMJ 

Other critical electronic bibliographic databases allow thousands of articles to be searched relatively quickly. The ability to search these databases effectively is an essential aspect of EBM. Effective searches help to maximise the potential of retrieving the relevant article within the shortest possible time. Studies(15,16) have shown that, even in countries where hospitals have facilities for Internet access allowing healthcare professionals access to several electronic databases, many people are not familiar with the process of carrying out efficient searches and often conduct searches, which results in too few or too many articles. Therefore, healthcare providers need to undergo basic training and skills, either through their local library services or by attending formal courses.

A clinician must understand the basic search methods to derive the correct number of articles relevant to the clinical question.

Keywords can be generated based on the clinical question. For example, the following keywords could be used for the previous clinical question: Bell's palsy, Corticosteroids, Facial function. It is essential for the keywords as they form the base of the search strategy.

Numerous online databases are available; we must know which database to search for relevant articles. The databases which we should search include The Cochrane Library, MEDLINE(PubMed) (17), Embase (18) and CINAHL(19). If one needs to gain the expertise or access to all the above databases, it is advisable to focus on PubMed initially.

First, the keywords are formed, and then we can use PubMed to run the search. There are basic combining strategies of the keywords using specific combining words called "Boolean operators". There are three specific Boolean operators: "AND", "OR" and "NOT". When we do a search combining two words/ terms, we use AND, which allows articles containing both terms to be retrieved, while OR allows articles containing either term to be retrieved, and when we use NOT, then the articles with the first word but not the second word will be retrieved (Figure 3).

When too many articles come up after the initial search, PubMed has a feature that allows you to limit your search results. You can modify your search by publication type (for example, randomised controlled trials or review articles) by publication date, language, study population, etc. PubMed Also has a feature called "clinical queries", which allows a straightforward approach to evidence—based search within the Medline database. "Clinical queries" is a preprogrammed research methodology filter that helps busy practitioners access the best available evidence by providing quick access to reliable clinical studies relating to therapy, diagnosis, aetiology, or prognosis.
You should build your initial search by forming and trying the keywords in PubMed. A Detailed approach to using PubMed, which includes all the search strategies, will be covered in the upcoming future series of clinical research methodologies.


Research evidence is appraised in three main areas: the article's validity, its importance, and applicability to the patient or patients of interest. Critical appraisal provides a simple, structured method for assessing research evidence in all three areas. Developing critical appraisal skills involves learning how to ask a few key questions about the validity of the evidence and its relevance to a particular patient or group of patients. Such skills may be learned through small tutorials, workshops, interactive lectures and at the bedside.

Several tools for appraising technical research articles are available. The CEBM tool "Critical Appraisal Skills Programme (CASP), Oxford, UK, is a simple and practical tool that can be easily assessed and used by anyone(20). These include specific CASP tools for appraising randomised control trials, systematic reviews, case—control studies, and cohort studies. 

A detailed approach to how these tools are to be used will be discussed in the upcoming series on each of the different methodologies of clinical studies.

After critically appraising the evidence and understanding that it is valid and essential, we use it in our clinical practice. When we use this evidence, we consider the patient's values, circumstances, and the evidence we have appraised. The evidence regarding efficiency and risk should be thoroughly discussed with the patient or patients to allow them to make an informed decision. This approach enables a therapeutic alliance to be formed with the patient, and the principles of EBM are integrated with the clinical expertise and patient values in EBM. Many international bodies that develop guidelines for clinical practice go through this step, which allows us to apply the pre—appraisal evidenced by expertise and complete Step 4 in EBM.

As we routinely incorporate EBM into our practice, we also need to evaluate the applicable evidence in our practice and different methodologies are used for evaluating performances. One of the common methods is auditing the performance against benchmarked standards. It is essential to reflect on the performance evaluation and show that the response in one clinical practice is similar to the evidence obtained. By doing this, we understand that the evidence is factual. However, when there is a deviation, we realise that the evidence may not be appropriate to one's practice, which will be the reasoning for further research and changes in practice.

Evidence—based medicine forms the base of clinical research as the continuing process that allows unanswered questions for further research or when there is a deviation in practice or changes noted, allowing scope for further research and newer evidence. Each practitioner needs to understand EBM, which helps evolve clinical practice.

1.	PubMed EBM PICO and Well—Built questionnaire: https://pubmedhh.nlm.nih.gov/ebm/index.

2.	Centre for Evidence—Based Medicine EBM tools: https://www.cebm.ox.ac.uk/resources/ebm—tools 

PubMed EBM PICO and Well—Built questionnaire: https://pubmedhh.nlm.nih.gov/ebm/index.php 

Sackett DL. Evidence—based medicine. Semin Perinatol. 1997 [cited 2023 Nov 12];21(1):3–5. Available from: https://pubmed.ncbi.nlm.nih.gov/9190027/

What is Evidence—Based Practice — Evidence—Based Practice: Nursing — Seton Hall University Libraries at Seton Hall University. Available from: https://library.shu.edu/c.php?g=1008106&p=7308538

Group EBMW. Evidence—Based Medicine: A New Approach to Teaching the Practice of Medicine. J Am Med Assoc. 2015;268(17):327–31. 

Shah H, surgery KC—P and reconstructive, 2009  undefined. Archie Cochrane and his vision for evidence—based medicine. ncbi.nlm.nih.gov; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746659/

Simera I, Moher D, Hirst A, Hoey J, Schulz KF, Altman DG. Transparent and accurate reporting increases reliability, utility, and impact of your research: Reporting guidelines and the EQUATOR Network. BMC Med. 2010 Apr 26;8. 

	Steves R, Hootman JM. by the National Athletic Trainers. Vol. 39, Journal of Athletic Training 83, Journal of Athletic Training. Association, Inc; 2004. Available from: www.journalofathletictraining.org

Greenhalgh T, Howick J, Maskrey N, Brassey J, Burch D, Burton M, et al. Evidence based medicine: A movement in crisis? BMJ. 2014;348(June):1–7. Available from: http://dx.doi.org/doi:10.1136/bmj.g3725

Goodin DS. Disease—modifying therapy in MS: A critical review of the literature. Part II: Assessing efficacy and dose—response. J Neurol Suppl. 2004 Sep;251(5). 

Murad MH, Asi N, Alsawas M, Alahdab F. New evidence pyramid. Evid Based Med. 2016 Aug 1;21(4):125–7. Available from: https://pubmed.ncbi.nlm.nih.gov/27339128/

	LibGuides: PubMed @ UMSL: Search Basics; Available from: https://libguides.umsl.edu/pubmed/searchbasics

Brown D. A Review of the PubMed PICO Tool: Using Evidence—Based Practice in Health Education. Health Promot Pract. 2020 Jul 1;21(4):496–8. Available from: https://pubmed.ncbi.nlm.nih.gov/31874567/

UpToDate. Available from: https://www.uptodate.com/login

BMJ Best Practice. Available from: https://bestpractice.bmj.com/info/evidence—

Rosenberg W, Deeks J, Luscher A, Gordon D, Sackett D. Improving Searching Skills and Evidence Retrieval. J R Coll Physicians Lond. 1998 Nov;32(6):557. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662986/

Jordaan M, Jones R. Adoption of Internet technology by UK postgraduate centres: a questionnaire survey. Health Libr Rev. 1999;16(3):166–73. Available from: https://pubmed.ncbi.nlm.nih.gov/10620851/

	PubMed. Available from: https://pubmed.ncbi.nlm.nih.gov/

	Embase. Available from: https://www.embase.com

CINAHL Database | EBSCO. Available from: https://www.ebsco.com/products/research—databases/cinahl—database

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