A DISSERTATION SUBMITTED TO THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY In partial fulfilment of the regulations for the award of the degree of M.D

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(1)‘A STUDY ON HYPERURICEMIA AS AN EARLY MARKER FOR SEVERITY OF ILLNESS IN SEPSIS IN IMCU OF A TERTIARY CARE CENTRE’ A DISSERTATION SUBMITTED TO THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY In partial fulfilment of the regulations for the award of the degree of M.D. GENERAL MEDICINE – BRANCH I. DEPARTMENT OF GENERAL MEDICINE GOVERNMENT VELLORE MEDICAL COLLEGE AND HOSPITAL. THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY, TAMILNADU, INDIA APRIL 2020.

(2) CERTIFICATE. This. is. to. certify. that. the. dissertation. titled “A STUDY ON. HYPERURICEMIA AS AN EARLY MARKER FOR SEVERITY OF ILLNESS IN SEPSIS IN IMCU OF A TERTIARY CARE CENTRE” is a genuine work done by DR.N.BHARGAVI SINDHUJA, Post Graduate student (2017-2020) inthe Department of General Medicine, Government Vellore Medical College, Vellore under the guidance of Prof. Dr.H.SRIPRIYA M.D., in partial fulfilment of the regulations laid down by the Tamilnadu Dr.M.G.R. Medical University, Chennai, for M.D., General Medicine Degree Examination.. Prof.Dr. H. Sripriya M.D.,. Prof.Dr.S.P.Kumaresan. M.D.(G.M). D.C.H., Guide & Chief Medical Unit – IV,. Head of The Department,. Department of General Medicine,. Department of General Medicine,. Government Vellore Medical. Government Vellore Medical. College &Hospital.. College &Hospital.. Prof. Dr.R.Selvi M.D., The Dean, Government Vellore Medical College, Vellore -632011..

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(4) CERTIFICATE – II. This is to certify that this is the dissertation work titled ‘A STUDY ON. HYPERURICEMIA AS AN EARLY MARKER FOR SEVERITY OF ILLNESS IN SEPSIS IN IMCU OF A TERTIARY CARE CENTRE’ of the candidate DR.N.BHARGAVI. SINDHUJA with registration number. 201711651 for the award of M.D. DEGREE in the branch of GENERAL MEDICINE. I personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 11% of plagiarism in the dissertation.. Guide & Supervisor sign with Seal.

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(7) DECLARATION I, DR.N.BHARGAVI SINDHUJA. solemnly. declare that. this. dissertation titled ‘A STUDY ON HYPERURICEMIA AS AN EARLY MARKER FOR SEVERITY OF ILLNESS IN SEPSIS IN IMCU OF A TERTIARY CARE CENTRE’ is a bonafide work done by me in Department of General Medicine,. Government Vellore Medical College And Hospital, Vellore under the guidance and supervision of Prof. Dr. H.SRIPRIYA M.D.,. This dissertation is submitted to the Tamil Nadu Dr. M.G.R. Medical University ,Chennai in partial fulfilment of the university regulation for the award of M.D., Degree in General Medicine (Branch – 1).. Place: Vellore Date: SINDHUJA. DR. N. BHARGAVI.

(8) SPECIAL ACKNOWLEDGEMENT. I gratefully acknowledge and thank. Prof. Dr.R.SELVI M.D., DEAN GOVERNMENT VELLORE MEDICAL COLLEGE AND HOSPITAL, VELLORE. For granting me permission to utilise the resources of this institution for my study..

(9) ACKNOWLEDGEMENT It gives immense pleasure for me to thank everyone who has helped me during the course of my study and in preparing dissertation.. I am very thankful to the Chairman of the Ethical Committee and members of the Ethical Committee, Government Vellore Medical College and Hospital for their guidance and help in getting the ethical clearance for this work.. I consider it a privilege to have done this study under the supervision of my beloved teacher, guide and unit chief Prof. Dr. H. SRIPRIYA M.D. and my former teacher, guide and Head of the Department Prof.Dr. D. ANBARASU M.D., who has been a source of constant inspiration and encouragement to accomplish this work.. I express my deepest sense of thankfulness to my Assistant Professors Dr.S. KARTHIKEYAN M.D., Dr. S. BALACHANDER M.D., Dr. RAMESH M.D., Dr. V. SATHI M.D., Dr. GOWRIPATHY M.D., for their valuable inputs and constant encouragement without which this dissertation could not have been completed.. I express my sincere gratitude to Prof. Dr. S.P. KUMARESAN M.D. (G.M.) DCH., Professor & Head of the Department of General Medicine. I also thank Prof.Dr.M. RANGASWAMI M.D.(G.M.),DMRD., Associate Professor of General.

(10) Medicine and Prof. Dr.D.ANBARASU M.D., Former Professor & Head of the Department of General Medicine. I am particularly thankful to my fellow postgraduate colleagues Dr. L. Vasanth and Dr. R. K. Renish for their valuable support in the time of need throughout the study.. I thank my junior Post Graduates & CRRIs for helping me in the preparation of this dissertation.. It is my earnest duty to thank my friends and family members without whom accomplishing this task would have been impossible.. I am extremely thankful to my patients who consented and participated to make this study possible..

(11) TABLE OF CONTENTS LIST OF TABLES LIST OF CHARTS ABBREVIATIONS. S.NO. TITLE. PAGE NO. 1. INTRODUCTION. 1. 2. REVIEW OF LITERATURE. 3. 3. AIMS AND OBJECTIVES. 53. 4. MATERIALS AND METHODS. 54. 5. OBSERVATION AND RESULTS. 58. 6. DISCUSSION. 82. 7. LIMITATION. 87. 8. CONCLUSION. 88. 9. BIBLIOGRAPHY. 89. APPENDIX. 10. i.. STUDY PROFORMA. 97. ii.. INFORMED CONSENT FORM. 99. iii.. MASTER CHART. 102.

(12) LIST OF TABLES TABLE TOPIC NO 1 Age distribution of study population. PAGE NO. 58. 2. Age distribution of study population. 58. 3. Gender distribution of study population. 60. 4. Distribution of hyperuricemia in study population. 61. 5. Distribution of comorbidities among study population. 63. 6. Duration of stay in the IMCU among the study population. 65. 7. Distribution of complications among the study population. 66. 8. Distribution of outcome among the study population. 68. 9. Distribution of hyperuricemia among various age groups in the. 69. study population 10. Comparison of hyperuricemia and gender. 71. 11. Comparison of hyperuricemia and duration of stay. 73. 12. Comparison of hyperuricemia and comorbidities. 75. 13. Comparison of hyperuricemia and complications of sepsis.. 76. 14. Comparison of hyperuricemia and outcome of patients. 78.

(13) LIST OF FIGURES FIGURE NO. TOPIC. PAGE NO. 1. Pathogenesis of sepsis. 9. 2. An overview of pathogenesis of sepsis. 13. 3. Structure of uric acid. 20. 4. Pathophysiology of acute kidney injury in hyperuricemia. 22. 5. Mechanism of hyperuricemia and its consequences. 24. 6. The phases of pathophysiology of ARDS. 30. 7. Pathophysiology of sepsis induced ARDS. 32. 8. Progression of sepsis and AKI. 38. 9. Pathophysiology of sepsis induced AKI. 39. 10. Age distribution of study population. 59. 11. Gender distribution of study population. 60. 12. Distribution of hyperuricemia among study population. 62. 13. Distribution of comorbidities among study population. 64. 14. Duration of stay in the IMCU among the study population. 65. 15. Distribution of complications among the study population. 67. 16. Distribution of outcome among the study population. 68. 17. Distribution of hyperuricemia among various age groups in the study population. 70. 18. Comparison of hyperuricemia and gender. 72. 19. Comparison of hyperuricemia and duration of stay. 74. 20. 77. 21. Comparison of hyperuricemia and complications of sepsis. Comparison of hyperuricemia and outcome of patients. 22. Comparison of mechanical ventilation with ARDS. 80. 23. Comparison of mechanical ventilation and outcome of patients. 81. 79.

(14) ABBREVIATIONS Ach. Acetylcholine. AKI. Acute Kidney Injury. AKIN. the Acute Kidney Injury Network. ARDS. Acute Respiratory Distress Syndrome. APTT. Activated Partial Thromboplastin Time. ATP. Adenosine Triphosphate. CD4. Cluster Differentiation 4. DAMPs. Damage Associated Molecular Patterns. DIC. Disseminated Intravascular Coagulation. GCS. Glasgow Coma Scale. HIV. Human Immunodeficiency Virus. ICD. International Classification Of Diseases. ICDSC. Intensive Care Delirium Screening Checklist. IMCU. Intensive Medical Care Unit. INR. International Normalised Ratio. KDIGO. Kidney Disease: Improving Global Outcome. NO. Nitric Oxide. NOD. Nucleotide -Binding Oligomerization Domain- Like Receptors. PAMPs. Pathogen Associated Molecular Patterns. RIFLE. Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease. RIG- I. Retinoic Acid Inducible Gene-I-Like Receptors. QSOFA. Quick Sequential Organ Failure Assessment. SCr. Serum Creatinine. SIRS. Systemic Inflammatory Response Syndrome. TLR. Toll Like Receptors.

(15) INTRODUCTION Sepsis is a serious medical condition characterized by a whole-body inflammatory state (systemic inflammatory response syndrome) and the presence of a known or suspected infection that has severe consequences. Hence majority of intensive care unit patients undergo ischemic-reperfusion injury and inflammation to varying degrees during their hospitalization.. In the past 20 years, research has revealed that infection can cause multiple organ dysfunction but without a measurable inflammatory excess (i.e., without the systemic inflammatory response syndrome [SIRS]). In fact,both pro- and antiinflammatory responses are present along with significant changes in other pathways. To clarify terminology and reflect the current understanding of the pathobiology of sepsis, the Sepsis Definitions Task Force in 2016 proposed the Third International Consensus Definitions specifying that sepsis is a dysregulated host response to infection that leads to acute organ dysfunction.Septic shock is defined as a complication of sepsis resulting in derangements in circulatory and metabolic pathways in the body. Allantoin is the end product of purine metabolism in animals whereas uric acid in human beings. Purines can be endogenous or exogenous. Purines are nitrogenous compounds found in the body as well as food. Uric acid passes through the liver, enters the blood stream and most of it excreted in urine[1,2]. Some uric acid is degraded in the body after reaction with oxidants [1]. Over the last ten years, strong association has been found betweenatherosclerosis[3-7], hypertension, hyperinsulinemia[8,9] and chronic kidney disease [10] and uric acid..

(16) Oxidative stress is found out by the presence of elevated serum uric acid which is a poor prognostic sign in case of patients with sepsis as multi organ dysfunction occurs as a result of high oxygen free radicals.Increased levels of serum uric acid causes acute activation of many transcription factors in patients with severe infection and is a poor prognostic sign in case of severe infection. Chronic conditions is also associated with elevated serum uric acid.. Hence this study was conducted to bring out the correlation between hyperuricemia in clinically diagnosed sepsis patients and morbidity and mortality and also to find out the correlation between hyperuricemia in sepsis patients and acute kidney injury, ARDS and duration of stay in medical intensive care patients. The study was conducted at Government Vellore Medical College & Hospital, a tertiary care centre, among patients who were admitted at the IMCU with a clinical diagnosis of sepsis based on quick SOFA score. Hyperuricemia was defined as >7 mg/dl in males and females[13]. Acute kidney injury was defined as an absolute increase >0.3 mg/dl increase in creatinine above the baseline in both males and females.. REVIEW OF LITERATURE.

(17) Sepsis term was derived from the Greek word sepo meaning decay or putrefaction.Severe sepsis is acute organ dysfunction due to infection.Septic shock was derived from the French word choquer meaning ‘to collide with’[14]. Sepsis and septic shock are major healthcare problems all over the world. The incidence of sepsis and related syndromes is increasing around the globe. Every year millions of people are affected by sepsis world over and most of them succumb to it.. Though the existence of sepsis and related disorders were known since time immemorial, formal definitions for the same were laid by the American College of Chest Physicians (ACCP)and Society of Critical Care Medicine (SCCM) Consensus Conference in 1991. With advances in the understanding of the pathophysiological aspects of septic shock and the dissatisfaction in several quarters regarding these,a Consensus Sepsis Definitions Conference was convened in 2001 under the auspices of ACCP, SCCM, the European Society of Intensive Care Medicine, and the Surgical Infection Societies re-visited the definitions of sepsis and related conditions. The key change was regarding the definition of systemic inflammatory response syndrome (SIRS) [manifested by (but not limited to) 2 or more of the following conditions: temperature> 38 °C or, < 36 °C; heart rate > 90 beats/min; respiratory rate >20/min or (PaCO2) < 32 mmHg; white blood cell count >12.0 ×109/L, < 4:0 × 109/L, or > 10% immature (band) forms] which was expanded to include longer list of possible signs of sepsis. As per the new guidelines, sepsis is defined as infection plus systemic manifestations of infection. Severe sepsis is defined as sepsis plus sepsis-induced organ dysfunction or.

(18) tissuehypoperfusion.. Septic shock is defined as sepsis-induced hypotension. persisting despite adequate fluid resuscitation.. HISTORICAL REVIEW: Ancient Greece scriptures first mentioned about sepsis. The word sepsis is derived from the Greek word “sepo” meaning “I rot”[14]. The words were first used in medical context in Homer’s poems.. Hippocrates, a physician and a philosopher,has mentioned about sepsis in his writings around 400 BC.. Initially, the decay in sepsis was believed to occur in the colon as the basic biological principles were not understood well. They believed the decay releases various substances that caused “auto-intoxication”.. The alcohol in wine and vinegar was found to have antisepsis properties by Hippocrates. He tried to identify pharmacological response based on these actions.. After Hippocrates, a Roman physician and philosopher, worked on sepsis in 129-199 AD. Galen developed theories about pus and wound healing which lasted for 1500 years. Romans believed that sepsis was caused by some invisible creatures that secreted fumes and laid the foundation for the Roman public health system. They emphasised on the hygiene practices.. Golden age of germ theory was considered to begin in the 1800s. Semmelweis was a pioneer of that age who made credible studies on puerperal.

(19) sepsis. During his period he noticed that in his ward, the rate of puerperal sepsis in deliveries conducted by midwives was found to be 2% whereas the rate was 16% of the time when deliveries were conducted by medical students. The cause of the difference struck him when his colleague died due to an infection he acquired during autopsy. This made him think on the terms that the high rate of puerperal sepsis due to deliveries conducted by medical students was because, they performed autopsies and then deliver babies without washing their hands. Henceforth, he made his medical students wash their hands before conducting deliveries and found the rates of puerperal sepsis declined progressively to less than 3%. But his policies were not accepted and he was fired from his position.. Following his efforts Joseph Lister, Louis Pasteur and Robert Koch did tremendous jobs in the field for understanding of microbiology and infectious disease.Pasteur’s experiments disproved the theory of spontaneous development of diseases. Lister also formulated his theories on wound sepsis. Lister postulated that wound sepsis occurs by entry of pathogens through breaks in the skin and hence he developed carbolic acid dressings. This led to a tremendous decrease in wound sepsis and sepsis related deaths.. In 1964, Dr. Edward Frank a Boston surgeon, framed a management strategy for septic shock. The strategy included continuous monitoring of cardiac output, urine output, systemic pressure, blood volume, blood chemistries, pH, electrolytes and central venous pressure..

(20) In 2003, an international committee published latest guidelines for severe sepsis and septic shock.. AETIOLOGY: Both community acquired and hospital acquired infections can cause sepsis.Pneumonia is the most common cause of sepsis which constitutes about half of all cases followed by intra abdominal and genitourinary infections as the next common causes[15]. Blood cultures are positive in only one third of patients while the remaining are culture negative in all sites. Most commonly isolated gram positive bacteria are Staphylococcus aureus and Streptococcus pneumoniae. Escherichia coli, Klebsiella. species, and. Pseudomonas aeruginosa. are most. common gram-negative bacteria isolated. In recent years, gram-positive infections are being reported more often than gram-negative infections. The risk factors for sepsis are related to both the predisposition to develop an infection and, the likelihood of developing acute organ dysfunction once the infection develops. Common risk factors for high risk of infection include chronic diseases like HIV infection, chronic obstructive pulmonary disease, cancers and immunosuppression. Risk factors for the progression from infection to organ dysfunction are not well understood, but may include underlying health status, organ function prior to infection, and timeliness of treatment. Age, sex, and race/ethnicity influence the incidence of sepsis, which is highest at both younger and older age groups, higher in males than females, and higher in blacks than whites. The difference in risk of sepsis by race is not fully explained by the socioeconomic factors or access to health care, raising the possibility that other factors, such as genetic differences.

(21) among individuals in susceptibility to infection or in expression of. proteins. necessary for the host response, may play a role.. EPIDEMIOLOGY: The incidences of sepsis and septic shock depend on how acute organ dysfunction and infection are defined as well as on which data sources are studied. Disparate estimates come from administrative data, prospective cohorts with manual case identification, and large electronic health-record databases. Organ dysfunction is often defined by the provision of supportive therapy, in which case epidemiological studies count the “treated,” rather than the actual, incidence. In the United States, recent cohort studies using administrative data suggest that upwards of 2 million cases of sepsis occur annually. Shock is present in ~30% of cases.The incidences of sepsis and septic shock also reported to be increasing (according to ICD9-CM diagnosis and procedure codes), with a rise of almost 50% in the past decade. While the data demonstrate that sepsis is a significant public-health burden in high- income countries, its impact on the populations of low- and middle-income countries is probably even more substantial because of the increased incidence of infectious diseases and the high prevalence of HIV in some parts of the developing world. Although there are fewer high-quality studies on sepsis in these countries, the available data support sepsis as a major public-health problem. In India, large studies not sufficient enough to get an overview of the incidence and prevalence of sepsis. In a recent study involving 5 years duration in a hospital, it was found that the mortality among sepsis patients was 63.6% out of which 56% died in the ICU [15]..

(22) PATHOGENESIS: Since long time, the clinical features of sepsis were considered to be the result of an excessive inflammatory host response (SIRS)[16]. More recently, it has become evident that infection triggers a much more complex, and prolonged host response than that was previously thought. The specific response of each and every patient is dependent on the pathogen (load and virulence) causing sepsis and the host (genetic composition and comorbidity), with different types of responses at local and systemic levels. The systemic and local response of the host evolves over time with the patient’s clinical course. Generally, pro inflammatory reactions are responsible for “collateral” tissue damage in sepsis, whereas anti-inflammatory response is instituted in the enhanced susceptibility to secondary infections which occur later in the course. These mechanisms can be characterised by direct damage to organs by the microbes and damage to organs arising from the host’s immune response. The ability of the host to resist as well as tolerate both direct, pathological and immunologic damage will determine whether uncomplicated infection becomes sepsis.. Figure-1. showing the pathogenesis of sepsis.

(23) INFLAMMATORY RESPONSE:.

(24) Over the past decade, our knowledge about pathogen recognition has increased tremendously. Pathogens generally activate immune cells by an interaction with the pattern recognition receptors. Four main classes of pattern recognition receptors are known. TLRs, RIG-I-like receptors, C-type lectin receptors, and NOD-like receptors. The activity of the NOD like receptors occurs partially in protein complexes called inflammasomes.. The structures conserved across microbial species are recognised by socalled pathogenassociated molecular patterns (PAMPs) and this results in upregulation of the inflammatory gene transcription and the initiation of innate immunity. A common type of PAMP is the lipid A moiety of lipopolysaccharide (LPS or endotoxin), which gets attached to the LPS-binding protein present on the surface of monocytes, macrophages and neutrophils. Signals from LPS are transferred via TLR4 to produce and release cytokines such as TNF that grow the signal and alert other cells and tissues. As many as 10 TLRs have been identified in humans.. Meanwhile, these receptors also sense endogenous molecules that are released from injured cells that are called as damage-associated molecular patterns (DAMPs), like high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and histones. The release of DAMPs during injuries that are non infectious or sterile such as those incurred during trauma leads to the concept that pathogenesis of multiple-organ dysfunction may be similar in both sepsis and noninfectious critical illness.The inflammatory responses implicated in the.

(25) pathogenesis of sepsis also activate the complement system, PAF, arachidonic acid metabolites, and NO, in addition to activating the pro inflammatory response.. COAGULATION DISORDERS: Sepsis is commonly associated with coagulation disorders. Sepsis leads to disseminated intravascular coagulation. The abnormalities in coagulation are thought to isolate the invading microorganisms and prevent the spread of infection to other tissues and organs. Coagulation drives the excess fibrin deposition via tissue factor, a transmembrane glycoprotein that is expressed by various types of cells; by impaired anticoagulant mechanisms, like the protein C system and antithrombin; and by diminished fibrin removal due to depression of the fibrinolytic system. Coagulation and other inflammatory proteases further enhance inflammation via protease-activated receptors. In infections which have endothelial predominance (e.g., meningococcemia), these mechanisms can be common and deadly.. ORGAN FAILURE: Impaired tissue oxygenation plays a key role in organ dysfunction and failure in sepsis, even though the mechanisms are only partially known. Many factors contribute to decreased oxygen delivery in sepsis and septic shock, like hypotension, reduced red-cell deformability, and microvascular thrombosis. Inflammation leads to dysfunction of the vascular endothelium. Cell death and loss of barrier integrity ensues due to vascular endothelial dysfunction giving rise to subcutaneous and body-cavity edema. An uncontrolled and excessive release of NO.

(26) causes vasomotor collapse, arteriovenous shunts opening, and pathologic shunting of oxygenated blood from susceptible tissues. Additionally, mitochondrial damage due to oxidative stress and many other mechanisms impair cellular oxygen utilization. The decline in oxidative metabolism, along with impaired oxygen delivery, reduces oxygen extraction at cellular level. Yet energy (i.e., ATP) is still needed to support the basal and vital cellular function, which is derived from glycolysis and fermentation and thus yields Hydrogen ionsand lactate. With severe or prolonged insult, production of ATP falls below a critical threshold, bioenergetic failure occurs, toxic reactive oxygen species are released, and apoptosis causes irreversible cell death and organ failure. The mechanisms and actual morphologic changes in sepsis-induced organ failure are complex. Generally, organs such as lungs undergo multiple and extensive microscopic changes, while other organs undergo rather few histologic changes. In fact, organs like the kidney may lack significant structural damage but still have significant tubular-cell changes that impair function.. Figure-2 An overview of the pathogenesis of sepsis.

(27) ANTI-INFLAMMATORY MECHANISMS:.

(28) The immune system undergoes humoral, cellular, and neural mechanisms that may aggravate the potentially harmful effects of proinflammatory response. Phagocytes can switch over to an anti-inflammatory phenotype which promotes tissue repair, while regulatory T lymphocytes and myeloid-derived suppressor T cells further reduce inflammation. The neuroinflammatory reflex may also contribute to the mechanism Sensory input is relayed through the afferent vagus nerve to the brainstem, after which the efferent vagus nerve activates splenic nerve in the celiac plexus, with subsequent norepinephrine release in the spleen and Ach release from a subset of CD4+ T cells. The acetylcholine thus released targets α7 cholinergic receptors on macrophages, thereby reducing proinflammatory cytokine release. Experimental disruption of this neural-based system by vagotomy leaves animals more vulnerable to endotoxin shock. By stimulating the efferent vagus nerve or α7 cholinergic receptors systemic inflammation is attenuated in experimental sepsis.. IMMUNE SUPPRESSION: Patients who have survived early sepsis and remain dependent on intensive care occasionally demonstrate an evidence of suppressed immune system. These patients may have ongoing infectious foci despite antimicrobial therapy or may experience the reactivation of latent viruses. Many investigations have documented decreased responsiveness of blood leukocytes to pathogens in sepsis diagnosed patients. These findings have been corroborated by post-mortem findings revealing strong functional impairment ofsplenocytes taken from ICU patients who died of.

(29) sepsis. Spleen and the lungs are the two organs mainly immune suppressed; in both organs, there was increased expression of ligands for T cell–inhibitory receptors on parenchymal cells . Elevated apoptotic cell death, especially of CD4+ T cells, follicular dendritic cells and B cells has been associated with sepsis-associated immune suppression and death. The most common secondary infections were found to be catheter-related bloodstream infections like urinary tract infections and cystitis causing urosepsis, ventilator-associated infections like ventilator associated pneumonia and abdominal infections. Similarly, it is not known whether the dysfunctional immune system is causing organ dysfunction and secondary infections or the immune system itself is just another dysfunctional organ.. CLINICAL MANIFESTATIONS: The clinical manifestations of sepsis occur as a consequence of complex interactions among the immune, coagulation and neuroendocrine systems in response to severe infection[15]. Septic shock is suspected whenever a patient with fever or hypothermia, tachycardia and tachypnoea and evidence of decreased organ perfusion develops hypotension. The factors that predispose to infections are the patients on immunosuppressive drugs and chronic debilitating diseases like diabetes mellitus, cirrhosis of liver and chronic kidney disease. Cellulitis, pustules, bullae or hemorrhagic lesions occur due to hematogenous seeding of skin and underlying soft tissue. Evidence of impaired organ perfusion, altered mental status, jaundice, gastrointestinal bleed, DIC, ARDS also point towards septic shock. FACTORS INDICATING POOR PROGNOSIS IN SEPTIC SHOCK:.

(30) PRE EXISTING FACTORS  Old age  Nature of co-existing illness  Number of failed organs CARDIOVASCULAR  Lack of ventricular dilatation  Persistence of tachycardia and raised cardiac output OTHERS  Delay in institution of treatment  Acute respiratory distress syndrome  Disseminated intravascular coagulation  Hypothermia  Leucopenia  Hyperglycemia  Hyperuricemia  Metabolic acidosis  Renal failure  Polymicrobial infection. DIAGNOSTIC CRITERIA FOR SEPSIS.

(31) GENERAL VARIABLES ‫סּ‬. Fever (core temperature >38.30 Celsius). ‫סּ‬. Hypothermia (core temperature <360 Celsius). ‫סּ‬. Tachycardia. ‫סּ‬. Tachypnoea. ‫סּ‬. Altered mental status. ‫סּ‬. Significant oedema. ‫סּ‬. Hyperglycemia (plasma glucose >120 mg/dl) in the absence of diabetes. INFLAMMATORY VARIABLES ‫סּ‬. Leucocytosis (>12000/ml). ‫סּ‬. Leucopenia (<4000/ml). ‫סּ‬. Normal WBC count with >10% immature forms. ‫סּ‬. Plasma C- reactive protein > 2 SD above the normal value. ‫סּ‬. Plasma procalcitonin>2 SD above the normal value. HEMODYNAMIC VARIABLES ‫סּ‬. Arterial hypotension (SBP <90 mmHg, MAP<70, or SBP decrease >40 mmHg). ‫סּ‬. Cardiac index > 3.5 L/min/m2. ORGAN DYSFUNCTION VARIABLES.

(32) ‫סּ‬. Arterial hypoxaemia. ‫סּ‬. Acute oliguria (urine output <0.5 ml/kg/h for at least 2 hrs). ‫סּ‬. Creatinine increase >0.5 mg/dl. ‫סּ‬. Coagulation abnormalities( INR> 1.5 or APTT >60 sec). ‫סּ‬. Ileus. ‫סּ‬. Thrombocytopenia (platelet count < 100000/ microliter). ‫סּ‬. Hyperbilirubinemia. TISSUE PERFUSION VARIABLES ‫סּ‬. Hyperlactatemia (>1 mmol/L). ‫סּ‬. Decreased capillary refill or mottling. qSOFA SCORE: In this study, quick SOFAScore was used to diagnose sepsis and predict the outcome and severity in all patients at the time of admission in the intensive medical care unit with suspected sepsis. The quick Sequential Organ Failure Assessment score takes into account three parameters. The Glasgow coma scale or altered sensorium, respiratory rate and systolic BP. It is calculated as one point each for altered mental status; GCS < 15, RR>=22, SBP <=100. A score of 2-3 prompts a high risk for sepsis. The quick SOFA score was introduced in February 2016 by the Third International Consensus Definitions for Sepsis and Septic Shock task force as a rapid bedside clinical score to identify patients with suspected infection that are at a great risk for a poor outcome.in patients with qSOFA score of 2 or higher, there was a 3-14 fold increase in the rate of in hospital mortality[17]..

(33) In our hospital, for all the patients admitted in the IMCU with suspicion of sepsis were applied for the quick SOFA score and taken into study.. SOFA SCORE: The sequential organ failure assessment score is based on scores for six systems. The Sepsis Definitions Task Force has recommended that once infection is suspected, clinicians could consider organ dysfunction by determining a SOFA Score. The SOFA Score ranges from 0-24, with upto 4 points given across six systems. It is widely used in ICU. With >=2 new points, the infected patient is considered septic.. SOFA VARIABLES are Systolic blood pressure <=100 mmHg, serum creatinine>=1.2 mg/dl, PaO2/ FiO 2<=300, platelets <=150k/microliter, GCS<15, bilirubin>=1.2 mg/dl, mechanical ventilation present or absent, vasopressors present or absent, vasopressors more than one.. URIC ACID Humans convert adenosine and guanosine to uric acid. Adenosine is first converted to inosine by adenosine deaminase. In mammals, other than higher primates, uric acid is converted to water soluble product allantoin by uricase enzyme. As humans lack uricase, uric acid is the end product of purine catabolism in human beings. The enzyme involved in the formation of uric acid is xanthine oxidase. The daily synthesis rate is estimated to be 1.8 mmol, with a total body pool.

(34) of approximately 7.2 mmol (1200 mg in adult males and about one half that in females) Figure-3 showing the structure of uric acid.

(35) Approximately 70% of uric acid will be excreted by kidneys. The remaining 30% is excreted by the gastrointestinal tract. Additionally, some uric acid is degraded after reaction with oxidants or peroxynitrite. Uric acid is predominantly found as urate anion in physiological pH. Urate is readily filtered by the glomerulus and reabsorbed by the proximal tubular cells of the kidney. 10% is the normal fractional excretion of uric acid in the body.. The normal value of uric acid is 3.4 – 7.2 mg/dlin males and 2.4 – 6.1in females. Hyperuricemia is defined as increased levels of uric acids and its accumulation that occurs due to overproduction, underexcretion or both[13]. Oflate, raised uric acid levels are seen in chronic kidney disease[10], hypertension, hyperinsulinemia[8,9] and atherosclerosis[3-7]. Uric acid is also elevated during hypoxic states like obstructive pulmonary diseases[18,19] and chronic heart failure[1,11,12].. Uric acid gets accumulated beyond its point of solubility and results in acute inflammation of renal epithelial cells by uric acid crystals. Even without formation of crystals, elevated uric acid levels can cause deleterious effects. Uric acid can cause endothelial dysfunction. Hyperuricemia causes afferent renal arteriolopathy and tubulointerstitial fibrosis by activating the renin angiotensin aldosterone system in the kidneys[20]. It activates various inflammatory transcription factors[21] and systemic cytokine production[22]. Chemical mediators like tumor necrosis factor,.

(36) monocyte chemotactic protein 1 and cyclooxygenase 2 are elevated in hyperuricemia causing the systemic inflammatory effects.. Figure-4showing the pathophysiology of acute kidney injury in hyperuricemia.

(37) When there is sepsis, elevated uric acid occurs due to cellular breakdown and many other mechanisms as discussed. Elevated uric acid then causes acute kidney injury by both crystal dependent and crystal independent pathway. The crystals formed by uric acid precipitates within the renal tubules. Some uric acid doesn’t cyrstallise and results in vasoconstriction, decreased renal blood flow, impaired autoregulation and triggers the inflammatory response leading to acute kidney injury[23].Similarly, hyperuricemia is associated with the development of ARDS. Various studies have been undergone to prove the relationship between the two[29] [30].. Since sepsis is a systemic inflammatory response, majority of intensive care patients undergo inflammation of varying degrees and ischemic reperfusion injury during their stay in hospital. Uric acid , having both oxidant and antioxidant properties, is found to play a role in these processes. Multiorgan failure in sepsis is due to high levels of oxyradicals and low levels of antioxidants. Hence measurement of uric acid can be used as a marker of oxidative stress in patients diagnosed to have sepsis[24]..

(38) Figure-5 showing the mechanism of hyperuricemia and its consequences.

(39) CAUSES OF HYPERURICEMIA:. OVERPRODUCTION OF URIC ACID: GENETIC: inborn errors of purine metabolism. INCREASED NUCLEIC ACID TURNOVER:  Malignancies: myelo or lymphoproliferative  Excessive alcohol, purine, fructose intake  Psoriasis, haemolytic disorders  Obesity  Hypertriglyceridemia  Heavy exercise DECREASED EXCRETION OF URIC ACID:  Chronic kidney disease, polycystic kidney disease  Hypertension  Chronic Lead intoxication DRUGS CAUSING HYPERURICEMIA: Aspirin (low dose), amiloride, alcohol, chlorthalidone, cisplatin, cyclosporine A, ethacrynic acid, ethambutol, frusemide, levodopa, niacin, pyrazinamide, parathyroid hormone, tacrolimus, thiazide, theophylline, cytotoxic drugs..

(40) MAJOR COMPLICATIONS OF SEPSIS: Cardiopulmonary - Acute lung injury, Acute respiratory distress syndrome Depression of myocardial function Renal – Acute kidney injury Drug induced renal damage Disseminated intravascular coagulation Neurological – critical illness polyneuropathy Multiorgan dysfunction syndrome. CARDIORESPIRATORY FAILURE: Respiratory and cardiovascular systems are the two most commonly affected organ systems in sepsis. When respiratory system is affected, it classically manifests as acute respiratory distress syndrome (ARDS), which is defined as hypoxemia and bilateral infiltrates of lung fields of noncardiac origin that arise within 7 days of beginning of the suspected infection. ARDS can be classified by Berlin criteria as mild (PaO2/FiO2, 201–300 mmHg), moderate (101–200 mmHg), or severe (≤100 mmHg). A close differential diagnosis is hydrostatic oedema due to cardiac failure or fluidoverload. Although usually identified by an increased pulmonary capillary wedge pressures from a pulmonary artery catheter (>18 mmHg), cardiac failure is objectively evaluated based on clinical judgment or focused echocardiography.. When there is a Cardiovascular compromise, it typically presents as hypotension. The cause can be frank hypovolemia, diffuse capillary leakage.

(41) causing maldistribution of blood flow, decreased systemic vascular resistance, or depressed myocardial function. After necessary volume expansion, hypotension frequently persists, requiring vasopressor usage in patients. In early shock, when volume status is reduced, there is low cardiac output and a very high systemic vascular resistance; after volume repletion, however, this picture may rapidly revert back to low systemic vascular resistance and high cardiac output.. ACUTE RESPIRATORY DISTRESS SYNDROME: PATHOPHYSIOLOGY AND COURSE OF THE DISEASE: There are three phases in the natural history of ARDS as exudative, proliferative and fibrotic. *Exudative Phase In exudative phase, both alveolar capillary endothelial cells and alveolar epithelial cells called the type I pneumocytes are injured. This leads to consequent loss of the normal alveolar barrier to macromolecules and fluids. Protein richfluid gets collected in the interstitial and alveolar spacescausing oedema. Proinflammatory cytokines like interleukin 1, interleukin 8, and tumour necrosis factor α [TNF-α] and lipid mediators like leukotriene B4 are increased in this acute phase, leading to the retaining of leukocytes (mainly. neutrophils) into the. pulmonary interstitium and alveoli.. Additionally, hyaline membrane whorls are formed in the air spaces by the aggregation of condensed plasma proteins with cellular debris and dysfunctional pulmonary surfactant. Vascular obliteration by fibrocellular.

(42) proliferation and microthrombi occurs early in ARDS, leading on to pulmonary vascular injury. Alveolar oedemamajorly involves dependent portions of the lung with decreased aeration. Such a collapseof large sections of dependent lung can causereduced lung compliance. Intrapulmonary shunting and hypoxemia develop as a result of these changes and the work of breathing increases, leading to dyspnea. On top of these pathophysiologic alterations in alveolar spaces, microvascular occlusion occurs that results in decreased pulmonary arterial blood flow to ventilated portions of the lung, increase in dead space of lungs and in pulmonary hypertension.In addition to severe hypoxemia, hypercapnia happens secondary to an increased pulmonary dead space and this becomes prominent in early ARDS.. The exudative phase lasts for the first 7 days of illness after exposure to a precipitating ARDS risk factor, with the patient experiencing the onset of respiratory symptoms. Although usually ARDS presents within 12–36 h after the initial insult, there could be a delayed presentation by5–7 days. Dyspnea develops, with a sensation of rapid shallow breathing and an inability to get enough air. Tachypnea causes increased work of breathing resulting in respiratory fatigue and ultimately in respiratory failure. Laboratory values are generally nonspecific and are primarily indicative of underlying clinical disorders. The chest radiograph usually reveals opacities consistent with pulmonary edema and often involves at least three-quarters of the lung fields. While characteristic for. ARDS, these. radiographic findings are not specific and can be indistinguishable from cardiogenic pulmonary edema. Unlike the latter, however, the chest x-ray in ARDS may not demonstrate cardiomegaly, pleural effusions, or pulmonary.

(43) vascular redistribution as is often present in pure cardiogenic pulmonary edema. If no ARDS risk factor is present, then some objective evaluation is required (e.g., echocardiography) to exclude a cardiac etiology for hydrostatic edema. Chest computed tomography (CT) in ARDS also reveals the presence of bilateral pulmonary infiltrates and demonstrates extensive heterogeneity of lung involvement. Because the early features of ARDS are nonspecific, alternative diagnoses must be considered. In the differential diagnosis of ARDS, the most common disorders are cardiogenic pulmonary edema, bilateral pneumonia, and alveolar hemorrhage. Less common diagnoses to consider include acute interstitial lung diseases (e.g., acute interstitial pneumonitis) acute immunologic injury (e.g., hypersensitivity pneumonitis), toxin injury (e.g., radiation pneumonitis), and neurogenic pulmonary edema..

(44) Figure-6 the phases in pathophysiology of ARDS. *Proliferative Phase This phase of ARDS usually lasts from day 7 to day 21. Most patients recover rapidly and are liberated from mechanical ventilation during this phase. Despite this improvement, many patients still experience dyspnea, tachypnea, and hypoxemia. Some patients develop progressive lung injury and early changes of pulmonary fibrosis during the proliferative phase. Histologically, the first signs of resolution are often evident in this phase, with the initiation of lung repair, the organization of alveolar exudates, and a shift from neutrophil- to lymphocytepredominant pulmonary infiltrates. As part of the reparative process, type II pneumocytes proliferate along alveolar basement membranes. These specialized epithelial cells synthesize new pulmonary surfactant and differentiate into type I pneumocytes..

(45) *Fibrotic Phase While many patients with ARDS recover lung function 3–4 weeks after the initial pulmonary injury, some enter a fibrotic phase that may require long-term support on mechanical ventilators and/or supplemental oxygen. Histologically, the alveolar edema and inflammatory exudates of earlier phases convert to extensive alveolar-duct and interstitial fibrosis. Marked disruption of acinar architecture leads to emphysema-like changes, with large bullae. Intimal fibroproliferation in the pulmonary microcirculation causes progressive vascular occlusion and pulmonary hypertension. The physiologic consequences include an increased risk of pneumothorax, reductions in lung compliance, and increased pulmonary dead space. Patients in this late phase experience a substantial burden of excess morbidity. Lung biopsy evidence for pulmonary fibrosis in any phase of ARDS is associated with increased mortality risk..

(46) Figure-7 showing the pathophysiology of sepsis induced ARDS.

(47) TREATMENT OF ARDS: In the appropriate clinical setting, a high index of clinical suspicion is necessary to diagnose ARDS early. Efforts directed at establishing the cause of ARDS must be actively pursued to facilitate institution of specific treatment.. *General therapeutic measures: Patients with ARDS should be admitted in an ICU equipped with facilities for invasive monitoring and providing assisted MV. Ideally, pulmonary and systemic arterial lines should be inserted for haemodynamic monitoring and rational fluid replacement therapy. SpO2 monitoring by pulse oximetry, periodic ABG analysis must also be done. Adequate nutrition should be ensured; enteral route is preferred to the parenteral route as it does not cause the serious risk of catheter induced sepsis. If sepsis is presumed to be the cause of ARDS, empirical antibiotic treatment may be started in the early phase of the disease as detailed above.. *Ventilatory support While some patients with ARDS can be managed with conservative measures and non-invasive ventilation, tracheal intubation and assisted MV are required in a majority of thepatients. Aim of MV is to maintain gas exchange with minimal complications. Initially, spontaneous ventilation using a face mask with a high flow gas delivery system can be used to deliver a FiO2 of up to 0.5 to 0.6. Continuous positive airway pressure (CPAP) may be added to improve PaO2 without increasing FiO2. If a FiO2 of more than 0.6 and CPAP of more than 10 cm.

(48) H2O are needed to achieve a PaO2 of more than 60 mmHg, tracheal intubation and MV must be considered. The maximal clinical benefit is likely to occur if MV is initiated early, i.e. within 96 hours of the onset of ARDS, a time when alveolar recruitment potential is the greatest. Recent evidence suggests that, whatever mode of ventilation is used, tidal volume should be set in the region of 6 mL/kg (‘lung protective ventilation’) and the peak pressure should be limited to 30 to 35 cm H2O to prevent lung over distension. Presently, in the absence of routine static pressure-volume curve measurement, positive end expiratory pressure (PEEP) is set at a relatively high level such as 15 cm H2O in patients with ARDS. It is also a common practice to increase the I:E ratio to 1:1 or 2:1 (inverse ratio ventilation) with close monitoring of intrinsic PEEP and haemodynamics during pressure control ventilation. The usefulness of recruitment manoeuvres such as the high function where intermittent breaths of larger tidal volume are administered either via the mechanical ventilators or by hand, sustained inflation or CPAP aimed at increasing alveolar recruitment are also being studied.. *Other ventilatory strategies: Other alternative approaches to conventional MV include prone positioning of the patient, high frequency ventilation (HFV, rate> 60/min) techniques such as high frequency jet ventilation (HFJV) and high frequency oscillatory ventilation (HFOV), and liquid ventilation, among others. The relative merits of these alternative methods of MV must be critically weighed against the potential sideeffects in every setting. Extracorporeal respiratory support in extracorporeal.

(49) membrane oxygenation (ECMO), venous blood is removed via a cannula in the inferior vena cava or right atrium, passed through a heart/lung machine, and is returned to either the right atrium (veno-venous bypass) or aorta (veno-arterial bypass). Extracorporeal carbon dioxide (CO2) removal (ECCOR) involves use of an extracorporeal venovenous circuit with lower blood flow and oxygenation still occurring via the patient’s lungs. These modalities may be useful in selected patients and, studies with a large sample size are required to clarify their role in the management of ARDS.. *Pharmacological therapies: Though. various. pharmacological. therapies. are. directed. at. the. pathophysiologic mechanisms of ARDS. These include neuromuscular blockade, inhaled. nitric. oxide,. vasoactive. agents. (intravenous. phenylephrine,. inhaledprostacyclins, almitrine, among others. The therapeutic potential of these strategies needs further study.. *Corticosteroids: The role of corticosteroid treatment. in. the management of ARDS is. controversial. The studies published in the 1980s had employed high-dose corticosteroids (1 to 8 doses of 30 mg/kg methylprednisolone) for short durations (< 48 hours). Compared with placebo, corticosteroid treatment resulted in either no difference or increased the incidence of ARDS. In more recent studies, low-tomoderate doses of corticosteroids (methylprednisolone 1 to 2 mg/kg per day to start) for longer duration (mean 25 to 32 days), with gradual tapering has been.

(50) evaluated. Presently, corticosteroid therapy is not considered to be beneficial before the onset of ARDS or early in its course. A difference of opinion exists among experts regarding the efficacy of corticosteroids for late-stage ARDS. Even though lowdose corticosteroid therapy improves lung function and shortens the duration of MV in persistent ARDS, the impact on long-term mortality is unclear. More data are required from clinical trials before they can be recommended for routine use in patients with unresolved ARDS.. *Nutritional supplementation: Enteral feeding with omega-3 fatty acids, such as, eicosapentanoic acid, γlinolenic acid,. and antioxidants was shown to facilitate improvement in. oxygenation and reduction in mortality in earlier trials. However, this benefit has not been replicated in more recent clinical trials.. ACUTE KIDNEY INJURY: Acute kidney injury (AKI) is defined by the impairment of kidneyfiltration and excretory function over days to weeks, resulting in theretention of nitrogenous and other waste products normally cleared by the kidneys. Acute kidney injury (AKI) increases the risk of in hospital death by six to eight fold. AKI complicates more than 50% of cases of severe sepsis and greatly increases the risk of death. Sepsis is also a very important cause of AKI in the developing world. Decreases in GFR with sepsis can occur even in the absence of overt hypotension, although most cases of severe AKI typically occur in the setting of hemodynamic collapse.

(51) requiring vasopressor support. While there is clearly tubular injury associated with AKI in sepsis as manifest by the presence of tubular debris and casts in the urine, postmortem examinations of kidneys from individuals with severe sepsis suggest that other factors, perhaps related to inflammation, mitochondrial dysfunction, and interstitial edema, must also be considered in the pathophysiology of sepsisinduced AKI.. The hemodynamic effects of sepsis—arising from generalized arterial vasodilation, mediated in part by cytokines that upregulate the expression of inducible NO synthase in the vasculature—can lead to a reduction in GFR. The operative. mechanisms. particularly early in. the. may be excessive efferent arteriole course. of. vasodilation,. sepsis, or renal vasoconstriction from. activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, vasopressin, and endothelin. Sepsis may lead to endothelial damage, which results in increased microvascular leukocyte adhesion and migration, thrombosis, permeability, increased interstitial pressure, reduction in local flow to tubules, and activation of reactive oxygen species, all of which may injure renal tubular cells..

(52) Figure-8 shows how inflammation and oxidative stress both cause the progression of sepsis and AKI.

(53) Figure-9 pathophysiology of sepsis induced AKI.

(54) More than 50% of the septic patients present with acute kidney injury. The clinical features of AKI are oliguria, azotemia, and rising serum creatinine levels frequently requiringdialysis. The mechanism for sepsis-induced AKI is incompletely understood. If there is no overt hypotension, AKI may occur in up to 25% of patients. Current mechanistic work suggests that other than organ ischemia, a combination of diffuse microcirculatory blood-flow abnormalities, cellular responses to injury and inflammation contribute to sepsis-induced AKI.. AKI is defined as any one of the following: (KDIGO DEFINITION)  Increase in serum creatinine by >=0.3 mg/dl within 48 hours  Increase in serum creatinine to >=1.5 times baseline, which is known or presumed to have occurred within the prior 7 days  Decrease in urine output <0.5 ml/kg/h for 6 hours. In this study, the definition for acute kidney injury by KDIGO is used The other definitions are: RIFLE CRITERIA Increase in serum creatinine by 1.5 times or GFR decrease by more than 25% AKIN CLASSIFICATION: Increase in SCr>=0.3 mg/dl or Increase of >= 150% to 200% (1.5 to 2 fold increase) from baseline within 48 hours.

(55) COMPLICATIONS OF AKI: The kidney plays a central role in homeostatic control of volume status, blood pressure, plasma electrolyte composition, and acid-base balance, and for excretion of nitrogenous and other waste products. Complications associated with AKI are, therefore, protean, and depend on the severity of. AKI. and other associated. conditions. Mild to moderate AKI may be entirely asymptomatic, particularly early in the course.  URAEMIA Buildup of nitrogenous waste products, manifested as an elevated BUN concentration, is a hallmark of AKI. BUN itself poses little direct toxicity at levels <100 mg/dL.. At higher concentrations, mental status changes and bleeding. complications can arise. Other toxins normally cleared by the kidney may be responsible for the symptom complex known as uremia. Few of the many possible uremic toxins have been definitively identified. The correlation of BUN and Serum creatinine concentrations with uremic symptoms is extremely variable, due in part to differences in urea and creatinine generation rates across individuals..  HYPERVOLEMIA AND HYPOVOLEMIA Expansion of extracellular fluid volume is a major complication of oliguric and anuric AKI, due to impaired salt and water excretion. The result can be weight gain, dependent edema, increased jugular venous pressure, and pulmonary edema; the latter can be life threatening. Pulmonary edema can also occur from volume overload and hemorrhage in pulmonary renal syndromes. AKI may also induce or.

(56) exacerbate acute lung injury characterized by increased vascular permeability and inflammatory cell infiltration in lung parenchyma. Recovery from AKI can sometimes be accompanied by polyuria, which, if untreated, can lead to significant volume depletion. The polyuric phase of recovery may be due to an osmotic diuresis from retained urea and other waste products as well as delayed recovery of tubular reabsorptive functions.  HYPONATREMIA Abnormalities in plasma electrolyte composition can be mild or life threatening. The dysfunctional kidney has limited ability to regulate electrolyte balance. Administration of excessive hypotonic crystalloid or isotonic dextrose solutions can result in hypoosmolality and hyponatremia, which, if severe, can cause neurologic abnormalities, including seizures..  HYPERKALEMIA An. important. complication. of. AKI. is. hyperkalemia.. Marked. hyperkalemia is particularly common in rhabdomyolysis, hemolysis, and tumor lysis syndrome due to release of intracellular potassium from damaged cells. Muscle weakness may be a symptom of hyperkalemia. Potassium affects the cellular membrane potential of cardiac and neuromuscular tissues. The more serious complication of hyperkalemia is due to effects on cardiac conduction, leading to potentially fatal arrhythmias..

(57)  ACIDOSIS Metabolic acidosis, usually accompanied by an elevation in the anion gap, is common in AKI, and can further complicate acid-base and potassium balance in individuals with other causes of acidosis, including sepsis, diabetic ketoacidosis, or respiratory acidosis..  HYPERPHOSPHATEMIA AND HYPOCALCEMIA AKI can lead to hyperphosphatemia, particularly in highly catabolic patients or those with AKI from rhabdomyolysis, hemolysis, and tumor lysis syndrome. Metastatic deposition of calcium phosphate can lead to hypocalcemia. AKI-associated hypocalcemia may also arise from derangements in the vitamin D– parathyroid hormone–fibroblast growth factor-23 axis. Hypocalcemia is often asymptomatic but can lead to perioral paresthesias, muscle cramps, seizures, carpopedal spasms,. and. prolongation. of. the. QT. interval. on. electrocardiography. Calcium levels should be corrected for the degree of hypoalbuminemia, if present, or ionized calcium levels should be followed. Mild, asymptomatic hypocalcemia does not require treatment.  BLEEDING Haematological complications of AKI include anaemia and bleeding, both of which are exacerbated by coexisting disease processes such as sepsis, liver disease, and disseminated intravascular coagulation. Direct haematological effects from AKI-related uremia include decreased erythropoiesis and platelet dysfunction..

(58)  INFECTIONS Infections are a common precipitant of AKI and also a dreaded complication of AKI. Impaired host immunity has been described in end-stage renal disease and may be operative in severe AKI..  CARDIAC COMPLICATIONS The major cardiac complications of AKI are arrhythmias, pericarditis, and pericardial effusion. In addition, volume overload and uraemia may lead to cardiac injury and impaired cardiac function. In animal studies cellular apoptosis and capillary vascular congestion as well as mitochondrial dysfunction have been described in the heart after renal ischemia reperfusion..  MALNUTRITION AKI is often a severely hypercatabolic state, and therefore, malnutrition is a major complication. PREVENTION AND TREATMENT: Several agents have been tested and have failed to show benefit in the treatment of acute tubular injury. These include atrial natriuretic peptide, low-dose dopamine, endothelin antagonists, erythropoietin, loop diuretics, calcium channel blockers, a-adrenergic receptor blockers, prostaglandin analogs, antioxidants, antibodies against leukocyte adhesion molecules, and insulin-like growth factor, among many others. Most studies have enrolled patients with severe and wellestablished AKI, and treatment may have been initiated too late. Novel kidney.

(59) injury biomarkers may provide an opportunity to test agents earlier in the course of AKI.AKI due to acute glomerulonephritis or vasculitis may respond to immunosuppressive agents and/or plasmapheresis. Allergic interstitial nephritis due to medications requires discontinuation of the offending agent. Glucocorticoids have been used, but not tested in randomized trials, in cases where AKI persists or worsens despite discontinuation of the suspected medication. AKI due to scleroderma (scleroderma renal crisis) should be treated with ACE inhibitors. Idiopathic TTP-HUS is a medical emergency and should be treated promptly with plasma exchange. Pharmacologic blockade of complement activation may be effective in atypical HUS.Early and aggressive volume repletion is mandatory in patients with rhabdomyolysis, who may initially require 10 L of fluid per day. Alkaline fluids (e.g., 75 mmol/L sodium bicarbonate added to 0.45% saline) may be beneficial in preventing tubular injury and cast formation, but carry the risk of worsening hypocalcemia.. Diuretics may be used if fluid repletion is adequate but unsuccessful in achieving urinary flow rates of 200–300 mL/h. There is no specific therapy for established AKI in rhabdomyolysis, other than dialysis in severe cases or general supportive care to maintain fluid and electrolyte balance and tissue perfusion. Careful attention must be focused on calcium and phosphate status because of precipitation in damaged tissue and release when the tissue heals..

(60) SUPPORTIVE MEASURES FOR AKI: Hypervolemia in oliguric or anuric AKI may be life threatening due to acute pulmonary edema, especially because many patients have coexisting pulmonary disease, and AKI likely increases pulmonary vascular permeability. Fluid and sodium should be restricted, and diuretics may be used to increase the urinary flow rate. There is no evidence that increasing urine output itself improves the natural history of AKI, but diuretics may help to avoid the need for dialysis in some cases. In severe cases of volume overload, furosemide may be given as a bolus (200 mg) followed by an intravenous drip (10–40 mg/h), with or without a thiazide diuretic. In decompensated heart failure, stepped diuretic therapy was found to be superior to ultrafiltration in preserving renal function. Diuretic therapy should be stopped if there is no response. Dopamine in low doses may transiently increase salt and water excretion by the kidney in pre-renal states, but clinical trials have failed to show any benefit in patients with intrinsic AKI. Because of the risk of arrhythmias and potential bowel ischemia, the risks of dopamine outweigh the benefits if used specifically for the treatment or prevention of AKI.. *Electrolyte and Acid-Base Abnormalities: Metabolic acidosis is generally not treated unless severe (pH <7.20 and serum bicarbonate <15 mmol/L). Acidosis can be treated with oral or intravenous sodium bicarbonate, but overcorrection should be avoided because of the possibility of metabolic alkalosis, hypocalcemia, hypokalaemia, and volume overload. Hyperphosphatemia is common in AKI and can usually be treated by limiting intestinal absorption of phosphate using phosphate binders (calcium.

(61) carbonate, calcium acetate, lanthanum, sevelamer, or aluminium hydroxide). Hypocalcemia does not usually require therapy unless symptoms are present. Ionised calcium should be monitored rather than total calcium when hypoalbuminemia is present. Malnutrition, protein energy wasting is common in AKI, particularly in the setting of multi-system organ failure. Inadequate nutrition may lead to starvation ketoacidosis and protein catabolism. Excessive nutrition may increase the generation of nitrogenous waste and lead to worsening azotemia. Total parenteral nutrition requires large volumes of fluid administration and may complicate efforts at volume control.. According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, patients with AKI should achieve a total energy intake of 20–30 kcal/kg per day. Protein intake should vary depending on the severity of AKI: 0.8–1.0 g/kg per day in non catabolic AKI without the need for dialysis; 1.0– 1.5 g/kg per day in patients on dialysis; and up to a maximum of 1.7 g/kg per day if hyper catabolic and receiving continuous renal replacement therapy. Trace elements and water-soluble vitamins should also be supplemented in AKI patients treated with dialysis and continuous renal replacement therapy.. *Anaemia The anaemiaseen in AKI is usually multifactorial and is not improved by erythropoiesis-stimulating agents, due to their delayed onset of action and the presence of bone marrow resistance in critically ill patients. Uremic bleeding may respond to desmopressin or estrogens, but may require dialysis for treatment in the.

(62) case of long-standing or severe uraemia. Gastrointestinal prophylaxis with proton pump inhibitors or histamine (H2) receptor blockers is required. It is important to recognise, however, that protein pump inhibitors have been associated with AKI from interstitial nephritis, a relationship that is increasingly being recognised. Venous thromboembolism prophylaxis is important and should be tailored to the clinical setting; low-molecular-weight heparins and factor Xa inhibitors have unpredictable pharmacokinetics in severe AKI and should be avoided.. DIALYSIS INDICATIONS AND MODALITIES Dialysis is indicated when medical management fails to control volume overload, hyperkalemia, or acidosis; in some toxic ingestions; and when there are severe. complications. of. uremia. (asterixis,. pericardial rub or effusion,. encephalopathy, uremic bleeding). The timing of dialysis is still a matter of debate. Late initiation of dialysis carries the risk of avoidable volume, electrolyte, and metabolic complications of AKI. On the other hand, initiating dialysis too early may unnecessarily expose individuals to intravenous lines and invasive procedures, with the attendant risks of infection, bleeding, procedural complications, and hypotension. The initiation of dialysis should not await the development of a life-threatening complication of renal failure. Many nephrologists initiate dialysis for AKI empirically when the BUN exceeds a certain value (e.g., 100 mg/dL) in patients without clinical signs of recovery of kidney function..

(63) The available modes for renal replacement therapy in AKI require either access to the peritoneal cavity (for peritoneal dialysis) or the large blood vessels (for hemodialysis, hemofiltration, and other hybrid procedures). Small solutes are removed across a semipermeable membrane down their concentration gradient (“diffusive” clearance) and/or along with the movement of plasma water (“convective” clearance). The choice of modality is often dictated. by. the. immediate availability of technology and the expertise of medical staff.. Hemodialysis can be used intermittently or continuously and can be done through convective clearance, diffusive clearance, or a combination of the two. Vascular access is through the femoral, internal jugular, or subclavian veins. Hemodialysis is an intermittent procedure that removes solutes through diffusive and convective clearance. Hemodialysis is typically performed 3–4 h per day, three to four times per week, and is the most common form of renal replacement therapy for AKI. One of the major complications of hemodialysis is hypotension, particularly in the critically ill, which can perpetuate AKI by causing ischemic injury to the recovering organ. Continuous intravascular procedures were developed in the early 1980s to treat hemodynamically unstable patients without inducing the rapid shifts of volume, osmolarity, and electrolytes characteristic of intermittent hemodialysis. Continuous renal replacement therapy (CRRT) can be performed by convective clearance (continuous venovenous hemofiltration [CVVH]), in which large volumes of plasma water (and accompanying solutes) are forced across the semipermeable membrane by means of hydrostatic pressure; the plasma water is then replaced by a physiologic crystalloid solution..

(64) CRRT can also be performed by diffusive clearance (continuous venovenoushemodialysis [CVVHD]), a technology similar to hemodialysis except at lower blood flow and dialysate flow rates. A hybrid therapy combines both diffusive and convective clearance (continuous venovenoushemodiafiltration [CVVHDF]). To achieve some of the advantages of CRRT without the need for 24h staffing of the procedure, some physicians favor slow low-efficiency dialysis (SLED) or extended daily dialysis (EDD). In this therapy, blood flow and dialysate flow are higher than in CVVHD, but the treatment time is reduced to ≤12 h. The optimal dose of dialysis for AKI is not clear. Daily intermittenthemodialysis and high-dose CRRT do not confer a demonstrable survival or renal recovery advantage, but care should be taken to avoid under treatment. Studies have failed to show that continuous therapies are superior to intermittent therapies. If available, CRRT is often preferred in patients with severe hemodynamic instability, cerebral edema, or significant volume overload.. Peritoneal dialysis can be performed through a temporary intraperitoneal catheter, although it is rarely used in the United States for AKI in adults. Peritoneal dialysis has enjoyed widespread use internationally, particularly when hemodialysis technology is not as readily available. Dialysate solution is instilled into and removed from the peritoneal cavity at regular. intervals in order to achieve. diffusive and convective clearance of solutes across the peritoneal membrane; ultrafiltration of water is achieved by the presence of an osmotic gradient across the peritoneal membrane achieved by high concentrations of dextrose in the dialysate solution. Because of its continuous nature, it is often better tolerated.

(65) than intermittent procedures like hemodialysis in hypotensive patients. Peritoneal dialysis may not be sufficient for hyper catabolic patients due to inherent limitations in dialysis efficacy.. NEUROLOGIC COMPLICATIONS Typical central nervous system dysfunction presentation is coma or delirium.. There. are. electroencephalographic. no. focal. findings. are. lesions usually. in. imaging consistent. studies. with. The. nonfocal. encephalopathy. Sepsis-associated delirium is due to a diffuse cerebral dysfunction that is considered to be caused by the inflammatory response to infection without any evidence of a primary central nervous system infection. Consensus guidelines recommend delirium screening with valid and reliable tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and theIntensive Care Delirium Screening Checklist ICDSC. Patients with a prolonged course of sepsis tend to have critical illness polyneuropathy and myopathy. Neurologic complications can be severe for survivors of sepsis.. ADDITIONAL MANIFESTATIONS Apart from the above mentioned organ dysfunctions, sepsis can also lead to ileus,. increased. aminotransferase. levels,. altered. glycemic. control,. thrombocytopenia and disseminated intravascular coagulation, adrenal dysfunction, and sick euthyroid syndrome. Reversible dysfunction of the hypothalamic–pituitary axis or tissue glucocorticoid resistance is thought to be related to adrenal dysfunction in sepsis rather than direct damage to the adrenal gland. The diagnosis.

(66) is difficult to establish. Recent clinical practice guidelines don’t recommend the use of Adrenocorticotropic hormone stimulation test or determination of the plasma cortisol level to detect relative glucocorticoid insufficiency..

(67) AIMS AND OBJECTIVES: AIM: To study the correlation between hyperuricemia and mortality and morbidity in patients with clinically diagnosed sepsis.. OBJECTIVES: 1) Primary end point is morbidity and mortality 2) Secondary end point is AKI, ARDS, duration of stay in IMCU.

(68) MATERIALS AND METHODS. STUDY DESIGN: PROSPECTIVE COHORT STUDY STUDY SETTING: IMCU IN GOVERNMENT VELLORE MEDICAL COLLEGE, ADUKAMPARAI, VELLORE. STUDY PERIOD: SEP’2018 TO AUG’ 2019. SAMPLE SIZE: 75. STUDY CRITERIA: INCLUSION CRITERIA: 1. Age more than 18 years 2. Admission to IMCU with a working diagnosis of sepsis. EXCLUSION CRITERIA: 1. Patients denying consent 2. Pregnant females 3. Known case of kidney disease 4. Patients who have already been in IMCU in an outside facility for more than 24 hrs 5. Patients who are known case of gout 6. Patients on drugs causing hyperuricemia.

(69) URIC ACID MEASUREMENT: Blood samples were taken from the patient for measuring uric acid levels.. COLLOBORATING DEPARTMENT: Department of Biochemistry, Govt Vellore Medical College and Hospital. METHODOLOGY: This study was conducted over a period of one year in the IMCU of Government Vellore Medical College and Hospital among 75 patients who were more than 18 years old and admitted in the IMCU with a clinical diagnosis of sepsis based on the quick SOFA (qSOFA) score.. Once the patient met the inclusion criteria, consent was obtained from the study participants. Clinical proforma for the study including demography was meticulously collected from the study participants.. History of comorbidities such as Diabetes mellitus (Type I and II), Cerebrovascular accident, Tuberculosis, Malignancy, Mental retardation etc,were collected.. Basic vitals at admission heart rate, respiratory rate, blood pressure, oxygen saturation were recorded.Thorough general and systemic examination performed.. Quick SOFA score is based on three parameters; glassgow coma scale, systolic blood pressure and respiratory rate, assigning one point each to:.

(70) 1. Low blood pressure SBP <= 100 mmHg, 2. High respiratory rate (>=22 breaths per minute) and 3. GCS <15. Blood samples were then obtained for uric acid, urea, creatinine, complete blood count, serum electrolytes and chest xray was taken.. The patient’s creatinine at admission to IMCU was taken as the baseline value. Hyperuricemia was defined as value more than 7 mg/dl in males and females. Parameters such as requirement of mechanical ventilation, Acute kidney injury (as defined by KDIGO), Acute respiratory distress syndrome and duration of stay in the IMCU were noted. Outcome of the sepsis event was classified as either death or discharge from the intensive care unit...

(71) Patients > 18 years admitted to IMCU with suspicion of sepsis included.. History including demography and comorbidities collected. Vitals and thorough systemic examination done. qSOFA score calculated.. Basic blood investigations including sepsis screen done.. Parameters: Mechanical ventilation, AKI, ARDS, Dura tion of IMCU stay noted.. Outcome of the sepsis Death or discharge from IMCU taken into account..

(72) OBSERVATION AND RESULTS. AGE AND GENDER DISTRIBUTION: In the study population, the median age was 55.37 years (Table 1). 6.67% were under 30 years, 56% belonged to 30-65 years age group and contributed to the whole lot as shown in Table 2 and Figure 10, followed by 37.33% in the ≥ 65years age group .. AGE RANGE. 18-85. MEAN. 55.37. S.D. 15.251. AGE GROUP(yrs) NUMBER. PERCENTAGE. <30. 5. 6.7. 30-65. 42. 56. ≥65. 28. 37.3. Table-1 and 2 showing age distribution of study population.

(73) AGE DISTRIBUTION. 7%. 37%. 56%. < 30 YEARS. 30-65 YEARS. ≥ 65 YEARS. Figure-10 Pie chart showing age distribution of study population.

(74) GENDER: Our study population had a slight male preponderance at 52% as shown in Table-3 and Figure-11 SEX. NUMBER. PERCENTAGE. MALES. 39. 52%. FEMALES. 36. 48%. Table-3 showing sex distribution in study population. GENDER DISTRIBUTION. 48%. 52%. MALE. FEMALE. Figure-11 Chart showing gender distribution of study population.

(75) URIC ACID:. Among the 75 study participants, 32 had elevated uric acid levels which constitutes about 42.7%, whereas 43 patients constituting 57.3% had normal uric acid levels.. URIC ACID LEVEL. FREQUENCY, PERCENTAGE. (mg/dL). N=75. ≥7. 32. 42.7. <7. 43. 57.3. Table-4 showing the distribution of hyperuricemia in study population.

(76) URIC ACID LEVELS IN STUDY POPULATION. 43% 57%. ≥7. <7. Figure-12 Pie chart showing distribution of hyperuricemia in study population.

(77) COMORBIDITIES PRESENT:. COMORBIDITY. FREQUENCY, N=75. PERCENTAGE. TYPE 2 DIABETES MELLITUS. 30. 40. TYPE 1 DIABETES MELLITUS. 3. 4.0. MENTAL RETARDATION. 3. 4.0. DECOMPENSATED LIVER DISEASE. 4. 5.3. TYPE 2 DM WITH SYSTEMIC. 2. 2.7. MALIGNANCY. 1. 1.3. CEREBROVASCULAR ACCIDENT. 2. 2.7. TUBERCULOSIS. 1. 1.3. CHRONIC KIDNEY DISEASE. 2. 2.7. NO COMORBIDITIES. 27. 36. HYPERTENSION. Table-5 showing distribution of comorbidities among the sepsis patients or the study population.. It can be inferred that among the study population, patients had type 2 diabetes mellitus as the most common comorbidity at 40%. The most prevalent comorbidities among the patients with hyperuricemia were diabetesmellitus type 2 and type 1, decompensated liver disease and cerebrovascular accident.Patients without any comorbidities about 36% of the study population also developed sepsis..

(78) Figure-13 Chart showing the distribution of comorbidities among the study population. 45 40. 40. 35. 36. 30 25 20 15 10 5 0. 4. 4. 5.3. 2.7. 1.3. 2.7. 1.3. 2.7.

(79) DURATION OF STAY IN IMCU:. DURATION OF STAY. FREQUENCY, N=75. PERCENTAGE. >72 hrs. 41. 54.7. ≤72 hrs. 34. 45.3. Table-6 showing duration of stay in the intensive care in sepsis patients. DURATION OF STAY IN IMCU. 45% 55%. > 72 HOURS. ≤ 72 HOURS. Figure-14 Pie chart depicting 54.7% of the study population sepsis patients stayed for more than 72 hours in the intensive care unit..

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