Symposium

DOI-10.21304/2018.0504.00406

Symposium Understanding Sepsis Guest Editorial Vinayak Patki *, Kundan Mittal** *Chief Consultant, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, Maharashtra, India ** Senior Professor & Head of Unit, Pediatric Intensive Care, Respiratory Services & Genetic Clinic and Molecular Diagnostics, Department of Pediatrics, PGIMS, Rohtak Received: 03-Jul-18/Accepted: 15-Aug-18/Published online: 30-Aug-18

Sepsis is now officially defined as a dysregulated host response to an infection,causing life-threatening organ dysfunction. Since the days of Hippocrates sepsis and septic shock are leading causes of morbidity and mortality across the world and infection is still among top 10 causes of mortality in today’s world. Although epidemiology of sepsis is changing (from country to country for various reasons) but the incidence has not come down. Severe sepsis and septic shock are major health care challenge despite advancement in various area of management and prevention of infection.1,2 Developing antimicrobial resistance and hospital associated infection are also posing great threat to public health. Although definition of sepsis appeared 3500 years ago but till today it is not clear. Controversy is still going on regarding definition of sepsis and Surviving Sepsis Campaign Guidelines (SSCG) has published “Sepsis-3” diagnostic criteria/definition in 2017. Sepsis-1 and Sepsis-2 had some limitations. Still the quality of evidence is missing to define sepsis and also latest version did not focus on pediatric sepsis.

Most of the data has been extrapolated from adult studies. Over the last 27 years, the focus on systematic inflammatory response syndrome (SIRS) for sepsis definition has shifted to PIRO (PredispositionInfection-Response-Organ Dysfunction) Model and then to Sequential Organ Failure Assessment [SOFA] score.The major implications of the new definition include the recognition of role of dysregulated host response in pathogenesis of sepsis and septic shock, the use of increment of SOFA score by 2 to identify the patients with sepsis, and the use of quick SOFA (qSOFA) score to identify septic patients outside of ICU.3 Over a period of time with the availability of more than 2000 biomarkers and better understanding of symptomatology and pathophysiology, diagnosis of sepsis has become very difficult. CRP and Procalcitonin are still the main acute phase reactants being used in clinical practice. Newer biomarkers and combination of biomarkers are needed with better sensitivity and specificity for early recognition of septic infants and children. It is unlikely that any single biomarker will be able to predict with complete certainty the presence or absence of a disease with specific outcome. All biomarkers must be used in their appropriate clinical context as adjuncts to decision making process. 4,5

Correspondence: Dr.Vinayak Patki, MB,DNB,FCCP,FIAP. Chief, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, 416410, Maharashtra, India. Phone:+919822119314, [email protected]

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The normal host response to infection is a complex process that localizes and controls bacterial invasion, while initiating the repair of injured tissue. It involves the activation of circulating and fixed phagocytic cells, as well as the generation of proinflammatory and anti-inflammatory mediators.6 Sepsis results when the response to infection becomes generalized and involves normal tissues remote from the site of injury or infection. Sepsis-induced immune suppression is likely a major contributor to the morbidity and mortality associated with sepsis. It is characterized by a decrease in immune effector cell number as well as loss of function, which results in increased susceptibility to secondary infections. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Though there are uncertainties in hemodynamic management and several treatments that have failed in clinical trials, many investigational therapies increasingly targeted on sepsis induced organ and immune dysfunction.7,8 Though outcome in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in providing supportive care for critically ill patients but still scientisthave to workhard (specially pediatric sepsis) on various aspect of sepsis management. This symposium includes articles for better

understanding of sepsis in critical care settings. Renowned pediatric intensivists from India have contributed to this symposium focusing on recent updates in basic aspects of sepsis. We hope you will find these articles interesting and helpful. Conflict of Interest:Nil Source of Funding: Nil References 1. 2.

3.

4. 5.

6. 7. 8.

Mehta Y, Kochhar G.Sepsis and Septic Shock.J Card Crit Care TSS 2017;1:1-3. Todi S, Chatterjee S, Sahu S, Bhattacharyya M. Epidemiology of severe sepsis in India: an update. Crit Care 2010;14(Suppl 1):382. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care 2010;14(1):R15.doi:10.1186/cc8872. Schuetz P, Wirz Y, Sager R et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2017 ;10:CD007498. Cinel I, Dellinger RP. Advances in pathogenesis and management of sepsis. Curr Opin Infect Dis 2007; 20:345. Gotts Jeffrey E, Matthay Michael A. Sepsis: pathophysiology and clinical management BMJ 2016; 353 :i1585. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targetsan updated view. Mediators Inflamm. 2013;2013:165974.

How to cite this article: Patki V, Mittal K.Understanding Sepsis. J Pediatr Crit Care 2018;5(4):24-25. How to cite this URL: Patki V, Mittal K.Understanding Sepsis. J Pediatr Crit Care 2018;5(4):24-25. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504003.html


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DOI-10.21304/2018.0504.00407

Symposium Sepsis Definitions - Changing Perspectives Vinayak Patki* *Chief Consultant, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, Maharashtra, India Received: 28-July-18/Accepted: 08-Aug-18/Published online: 30-Aug-18

ABSTRACT The evolving changes in the “definition” of sepsis reflect both a new emphasis on precision, needed for research, and an ever-expanding knowledge of its pathophysiology. Even with the recent revision of sepsis definitions, identification of patients with early sepsis remains a significant challenge. Newer definitions and clinical criteria should clarify longused descriptors and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing it. This process, however, remains a work in progress. Keywords: Sepsis, Septicshock, PIRO, SOFA, Diagnosis, Infection

Introduction It is very important for physicians and patients both, to name or label a specific collection of signs and symptoms. To reach an accurate diagnosis and to offer optimal medical therapy, precise definition of the disease process is required. Over the years many disease processes have become well defined and are easy to diagnose with the appropriate set of symptoms and test results. The ability to form a specific diagnosis and attempt to institute therapies to benefit patients is limited by vague or indefinite definitionsand maysometimes cause harm. Sepsis is a complex process which can originate from multiple sites, caused by multiple microorganisms and can affect any individual. It can present with vast signs and symptoms, of which many are nonspecific for sepsisand all of which can vary among patients and within the same patient over time. The severity of the symptoms can fluctuate from a mild, short-lived fever to fatal septic shock. Attempts to provide clear and accurate definitions have been madebut with poor universal support. Because of its complexity and variation, a single, simple definition for sepsis will never be possible and we should focus on types of infection rather than on sepsis per se. History of the Definition of Sepsis the original Greek Sepsis is derived from

word for the decomposition ofanimal or vegetable organic matter.1 First used more than 2700 years ago by Homer, and referenced by Hippocrates, Aristotle, Plutarch, and Galen, it was only approximately 100 years ago, that the link between bacteria and systemicsigns of disease was made;2 sepsis then became almost synonymous with severe infection. Sepsis Syndrome Roger Bone and his colleagues introduced the concept of the “sepsis syndrome” in 1989, which became the foundation of our systemic inflammatory response syndrome (SIRS) criteria.3 Sepsis syndrome was defined as hypothermia (less than 960 F [35.50C]) or hyperthermia (greater than 1010 F [38.30C]); tachycardia (greater than 90 beat/min); tachypnea (greater than 20 breath/min); clinical evidence of an infection site; and the presence of at least one end-organ demonstrating inadequate perfusion or dysfunction expressed as poor or altered cerebral function, hypoxemia (PaO2 less than 75 torr on room air), elevated plasma lactate, or oliguria (urine output less than 30 mL/h or 0.5 mL/kg body weight/h without corrective therapy). However, although it has been used as an entry criterion for clinical trials,3 sepsis syndrome does not successfully define a homogeneous group of patients. 1991 International Consensus Conference (Sepsis 1) SIRS Criteria The terminology “sepsis” which is currently used, was born out of the 1991 International Consensus Conference: Distinctions in the Definition of

Correspondence: Dr. Vinayak Patki, MB,DNB,FCCP,FIAP. Chief, Advanced Pediatric Critical are Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, 416410, Maharashtra, India. Phone: +919822119314, E-Mail- [email protected]


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at an increased risk of developing complications and with increased mortality7, they have been criticized for being too sensitive and nonspecific to be of much clinical use.8 Most ICU patients and many general ward patients meet the SIRS criteria.9,10 Sprung CL et al 11 found up to 90% of patients admitted to the ICU fit the criteria for SIRS. Moreover, each of the SIRS criteria can be present in many different conditions, so that little or no information about the underlying disease process is provided by a label of SIRS. Use of the SIRS criteria to identify patients for enrolment in clinical trials has been disappointing and has likely contributed to the negativity of almost all these trials. Multiple organ dysfunction syndrome MODS was defined as ‘‘the presence of altered organ function in an acutely ill patientsuch that homeostasis cannot be maintained without intervention”.4 The 1991 ACCP-SCCM Consensus.The term ‘‘multiple organ dysfunction syndrome’’ was introduced with the awareness that severe sepsis is frequently associated with the development of multiple organ dysfunction (MODS) and that multiple organ failure is the most common cause of death in patients who have severe sepsis.Since then, many systems have been developed to characterize and quantify MODS, like the sequential organ failure assessment, which are increasingly used as measures of morbidity in clinical trials.12 2001 Sepsis Definitions Conference (Sepsis 2) A Consensus Sepsis Definitions Conference of 29 international experts in the field of sepsis was convened in 2001 under the auspices of SCCM, the European Society of Intensive Care Medicine, ACCP, and the Surgical Infection Societies,13 to give a satisfactory definition of sepsis based on the advanced understanding of its pathogenesis and pathophysiology. The conference participants concluded that the definitions of sepsis, severe sepsis, and septic shock, as defined in the 1991 North American Consensus Conference,4 may still be useful in clinical practice and for research purposes. The use of the SIRS criteria, which were considered too sensitive and nonspecific was the key change. The participants suggested that other signs and symptoms be added to reflect the clinical response to infection in better way (Table 2). Sepsis is now defined as the

Severe Sepsis (hosted by the Society of Critical Care Medicine, European Society of Intensive Care Medicine, the American College of Chest Physicians, the American Thoracic Society and Surgical Infection Society)4 Thirty-five experts in the field of sepsis came together to provide a framework to define the systemic inflammatory response to infection (i.e., sepsis). The result of this conference was the introduction of the term ‘‘systemic inflammatory response syndrome’’ (SIRS). SIRS was an attempt to differentiate sepsis from the non-infectious causes that cause the same inflammatory response, such as acute pancreatitis, trauma, ischemia/reperfusion injury and burns. According to the ACCP-SCCM Consensus Conference,4 infection was defined as a microbial phenomenon characterized by the invasion of microorganisms or microbial toxins into normally sterile tissues. SIRS was defined, by consensus, as the presence of at least two of four clinical criteria (Table 1). Table 1 • • •

Body temperature >38_C or 90 beats/min Respiratory rate >20 breaths/min or hyperventilation with a PaCO2 12,000/ mm3, 10% immatureneutrophils According to the guidelines, sepsis is SIRS with suspected or proven infection, while severe sepsis describes patients who fulfil the criteria forsepsis and in addition have organ dysfunction. In its most severe manifestation,5 septic shock is defined as “acute circulatory failure characterized by persistent arterial hypotension [including systolic 2). Previously, this was the definition of Severe Sepsis, a term that will no longer be used. This change was instituted primarily because the field was already using sepsis to imply a patient deteriorating with infection and organ dysfunction, leading to considerable confusion between the terms sepsis and

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management (Figure 2). Components of SOFA (such as creatinine or bilirubin level) require laboratory testing and thus may not promptly capture dysfunction in individual organ systems. Neither qSOFA nor SOFA is considered to be a stand-alone definition of sepsis. It is crucial, however, that failure to meet 2 or more qSOFA or SOFA criteria should not lead to a deferral of investigation or treatment of infection or to a delay in any other aspect of care deemed necessary by the practitioners. qSOFA can be rapidly scored at the bedside without the need for blood tests, and it is hoped that it will facilitate prompt identification of an infection that poses a greater threat to life. This may prompt testing to identify biochemical organ dysfunction, if appropriate laboratory tests have not already been done. These data will primarily aid patient management but will also enable subsequent SOFA scoring. Other elements, such as the cardiovascular score, can be affected by iatrogenic interventions. However, SOFA has widespread familiarity within the critical care community and a well-validated relationship to mortality risk. It can be scored retrospectively, either manually or by automated systems, from clinical and laboratory measures often performed routinely as part of acute patient management.

severe sepsis. The definition of Septic Shock refers to patients with infection who also have hypotension (MAP 2 mmol/L. Because SOFA is better known and simpler than the Logistic Organ Dysfunction System, the guideline recommends using a change in baseline of the total SOFA score of 2 points or more to represent organ dysfunction. The baseline SOFA score should be assumed to be zero unless the patient is known to have pre-existing (acute or chronic) organ dysfunction before the onset of infection. The overall mortality risk was approximately 10% in a general hospital population with presumed infection18 in patients with a SOFA score of 2 or more. A SOFA score of 2 or greater identified a 2- to 25-fold increased risk of dying compared with patients with a SOFA score less than 2,18 depending on a patient’s baseline level of risk. qSOFA (Quick SOFA) Criteria • Respiratory rate ≥22/min • Altered mentation • Systolic blood pressure ≤100 mm Hg SOFA score is intended to be used to clinically characterise a septic patient and not as a tool for patient


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Figure 2 : Operationalization of Clinical Criteria Identifying Patients with Sepsis and Septic Shock (Adapted from Singer M et al,JAMA.2016;315(8):801–10) and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20(6):864–74.

Future The Guidelines noted that there are several novel biomarkers that can identify renal and hepatic dysfunction or coagulopathy earlier than the elements used in SOFA, but these require broader validation before they can be incorporated into the clinical criteria describing sepsis. Future repetition of a process of the sepsis definitions should either include an updated SOFA score with more optimal variable selection, cut off values, and weighting, or a superior scoring system. Conflict of Interest :Nil Source of Funding :Nil References 1.

Geroulanos S, Douka ET. Historical perspective of the word ‘‘sepsis’’ [letter]. IntensiveCare Med 2006;32:2077.

2.

Schottmueller H. Nature and Management of sepsis. Inn Med 1914;31:257–80.

3.

Bone RC, Fisher Jr CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA. Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study Group. Crit Care Med.1989;17(5):389–93.

4.

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/ SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101(6):1644–55.

6.

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med 2003;29(4):530–8.

7.

Malone DL, Kuhls D, Napolitano LM. Back to basics: validation of the admission systemic inflammatory response syndrome score in predicting outcome in trauma. J Trauma 2001;51:458–63.

8.

Vincent JL. Dear sirs, I’m sorry to say that I don’t like you. Crit Care Med 1997;25:372–4.

9.

Bossink AW, Groeneveld J, Hack CE. Prediction of mortality in febrile medical patients: how useful are systemic inflammatory response syndrome and sepsis criteria? Chest 1998;113:1533–41.

10. Sprung CL, Sakr Y, Vincent JL. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely ill Patients (SOAP) study Intensive Care Med 2006;32:421–7.

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis


5.

11. Sprung CL, Sakr Y, Vincent JL, Le Gall JR, Reinhart K,

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Ranieri VM, et al. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely Ill Patients (SOAP) study. Intensive Care Med 2006;32(3):421–7.

14. Moreno RP, Metnitz B, Adler L. Sepsis mortality prediction based predisposition, infection and response. Intensive Care Med 2008;34:496–504.

12. Vincent JL, de Mendonca A, Cantraine F. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on ‘‘sepsis-related problems’’ of the European Society of Intensive Care Medicine. Crit Care Med 1998;26:1793–800.

16. Czura CJ. “Merinoff symposium 2010: sepsis”—speaking with one voice. Mol Med 2011;17:2–3.

15. W.O. The Evolution of Modern Medicine. 1904.

17. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016;315(8):801–10.

13. Levy MM, Fink MP, Marshall JC. 2001 SCCM/ ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250–6.

18. Seymour CW, Liu V, Iwashyna TJ. Assessment of clinical criteria for sepsis. JAMA. doi:10.1001/jama.2016.0288.

How to cite this article: Patki V. Sepsis Definitions - Changing Perspectives. J Pediatr Crit Care 2018;5(4):26-32. How to cite this URL: Patki V. Sepsis Definitions - Changing Perspectives. J Pediatr Crit Care 2018;5(4):26-32. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504004.html


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Symposium Biomarkers in Sepsis Amita Kaul*, Sachin Shah** *Consultant PICU, **Chief Consultant and Director, Surya Mother and Child Superspecialty hospital, Pune, India Received: 21-Jul-18/Accepted: 02-Aug-18/Published online: 30-Aug-18

ABSTRACT Sepsis in children is a global problem causing significant mortality and morbidity. Early identification and prompt treatment is the key to better survival. Sometimes the symptoms are not clear cut and culture sensitivity takes time. Infections lead to synthesis of various biomarkers. These biomarkers can be used as a screening tool to diagnose infections. Some of the markers can help in risk stratification of the disease. Use of biomarkers to monitor drug response is also an important function. The commonly used biomarkers are erythrocyte sedimentation rate, C-reactive protein and Procalcitonin, which have been studied well in children. There are many more biomarkers which are being evaluated. Key Words: Sepsis, biomarkers ,C-reactive Protein, Procalcitonin

Qualities of an ideal biomarker • Fast and specific increase in sepsis. • Rapid decrease after effective therapy. • Short half life. • Easy and wide availability and quick turnaround time. • Reliable method of determination. • Cost effectiveness. • Reproducibility of result. Overview Biomarker may be defined as a characteristic that can be objectively measured assessed as an indicator of normal biological processes, pathological processes and or pharmacological responses to a therapeutic intervention. There are a lot of biomarkers which are being evaluated in diagnosis and prognosis of sepsis. There are 178 biomarkers being studied till date.1 Of the 178 biomarkers, 18 had been evaluated in experimental studies only, 58 in both experimental and clinical studies, and 101 in clinical studies only. Thirty-four biomarkers were identified that have been considered for use specifically in the diagnosis of sepsis. Types of biomarkers Acute Phase Reactants • Amyloid • C-reactive protein (CRP)

Introduction Sepsis is leading cause of morbidity and mortality in infants and children. The diagnosis of sepsis and evaluation of its severity is complicated by the highly variable and non specific nature of signs and symptoms of sepsis. However early diagnosis and stratification of the severity of sepsis is important in increasing the possibility of starting timely and prompt antibiotic therapy.Biomarkers can be useful in identifying or ruling out sepsis. It helps to categorize patients who may benefit from specific therapies or assessing the response to therapy. The diagnosis of infection is based on cultures and biomarkers of inflammation. Microbiology results take several days and are negative in one-third of patients especially if they have received prior antibiotics. Potential uses of sepsis biomarkers • Rule out sepsis • Provide early intervention • Guide antimicrobial therapy • Assess response to therapy • Distinguish between viral and bacterial infections • Differentiate sepsis from other non infectious causes of systemic inflammatory response syndrome • Predict multiorgan failure Correspondence: Dr. Sachin Shah MD, DM, Chief Consultant and Director, Surya Mother and Child Superspecialty hospital, Pune, India. Phone:+919850566196, Email: [email protected]


• Erythrocycte sedimentation rate (ESR) • ferritin

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• procalcitonin

Miscellaneous • vascular endothelial damage markers (ADAMTS-13, Endocan, ICAM etc) • vasodilation markers (Adrenomedullin, ACE activity, copeptin, nitricoxide, VIP organ dysfunction markers (ANP, BNP, Troponin )

• ceruloplasmin • pentraxin 3 • hepcidin

Cell Markers • CD types: CD10,CD11b,CD11c,CD18,CD40,CD 64,CD80,CD165 • mHL-DR

Pathophysiology of sepsis and synthesis of biomarkers It starts as a dysregulated response to infection when the innate immune mechanism recognizes pathogen associated molecular pattern (PAMP) of the invasive microorganism.PAMP are antigen of viral or bacterial origin and recognized by four class of receptors: Toll like receptors, C-type lecithin receptors, retinoic acid inducible gene-1 like receptors and nucleotidebinding oligomerization domain like receptors.2 The resulting inflammatory response activates a number of complex intracellular and extracellular cascades which cause cell lysis and spill over of intracellular molecules to extracellular space. Extensive trauma release damage associated molecular pattern which have similar effect of PAMP on the host immune response, can induce cascade of inflammatory response. Concominantly body induces compensatory anti inflammatory reactions that are mediated through a number of pathways resulting in increased release of glucocorticoids, a strong inducer of anti-inflammatory cytokines, including IL-10. Inflammatory response leads to increased capillary permeability and vasodilation causing hypotension, tissue hypoperfusion. Coagulation abnormalities further compromise the situation. In sepsis there is upregulation of tissue factor resulting in downregulation of anti-thrombin and a subsequent increase in plasma thrombin. Fibrinolysis is induced by downregulation of protein C and upregulation of plasminogen activator inhibitor type one.3 These changes lead to hypercoaguable state.Increased coagulation disorder along with hypotension is a sinister combination leading to life threatening multiorgan dysfunction. A large number of molecular mechanisms are involved in sepsis and these are investigated for their clinical utility in diagnosis and prognosis of sepsis.

Receptors • • • • • • • • •

Toll-like

receptors TNF receptors IL-2 receptors TREM-1 CC chemokine receptor (CCR)2 CCR 3 C5L2 CRTh2 GP130

Cytokines • interleukins (e.g. IL-27,IL1β,IL2,IL4,IL6,IL8,IL1 0,IL12,IL13,IL18 • macrophage inflammatory proteins • monocyte protein • TNF • Osteoponitin • RANTES • MCP1 and 2 Coagulation factors • APTT • protein C and S • fibrin • antithrombin • d-dimer • thrombomodulin • plasminogen activator inhibitor 1


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PATHOPHYSIOLOGY OF SEPSIS Pathogen associated molecular pattern (PAMP) of the invasive microorganism

Innate immune mechanism

Dysregulated response to infection

Activates a number of complex intracellular and extracellular cascades

Cell lysis and spill over of intracellular molecules to extracellular space.

Compensatory anti inflammatory reactions

Inflammatory response leads to increased capillary permeability and vasodilation causing hypotension, tissue hypo perfusion

Coagulation abnormalities further compromise the situation.

Hypercoaguable state

Hypotension

Multiorgan Dysfunction Figure 1 :Pathophysiology of Sepsis


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Erythrocyte sedimentation rate ESR is a non specific marker of inflammation. It has very limited specificity. ESR measures the distance that a vertical column of anticoagulated blood has fallen in one hour. Any condition that affects red cells and fibrinogen will affect the value of ESR.4 (Table 1)

on immunosupression. If an immunosupressed patient on corticosteroids develops an infection CRP would rise and help in diagnosis. Accuracy to diagnose severe infection in patients with cancer and febrile neutropenia is less as compared to markers like procalcitonin, IL -6.10 It can be used as an inflammatory marker in patients with renal dysfunction. Its value remains unaffected by renal replacement therapy and can be used in patients undergoing dialysis.11 CRP cannot differentiate between an inflammatory process and infectious process. For example in burns it would very high even if there is no infection. It is also elevated in inflammatory diseases like Junvenile rheumatoid arthrititis, systemic lupus erythematosus etc. CRP is the most widely used biomarker. It is easy to perform. Most of the laboratories offer this test, it is low cost and easy to interpret. Procalcitonin PCT precursor of calcitonin hormone is normally secreted by neuroendocrine cells of the thyroid gland. During bacterial systemic infections it is believed to be secreted by neuroendocrine cells in the lungs and intestine. Its release is mediated by cytokines like TNF-α and IL-6. In viral infections it gets downregulated by production of interferon gamma. Serum concentration of PCT is less than 0.05ng/ml. PCT levels become detectable within 3-4 hours of infection and peak within 6-24 hours. Elevated PCTs are not seen in inflammatory conditions like systemic lupus eythematosus, gout, juvenile rheumatoid arthritis, inflammatory bowel disease. But PCT values may rise transiently in massive trauma like severe burns (Table 2).

Table 1 : Variations in ESR Conditions causing high ESR (non inflammatory) Anemia Pregnancy Drugs Obesity

Conditions causing low ESR Sickle cell disease Hereditary spherocytosis Severe liver disease Low fibrinogen levels

ESR rises within 24-48 hours of the onset of inflammation and falls back slowly with resolution of inflammation. ESR levels >100mm/hour should prompt a search for underlying etiology. High ESR has high specificity: 0.96 for malignant neoplasms, 0.97 for infections, and 0.99 as sickness indicator. Positive predictive value for an identifiable cause of marked elevation of ESR is 90 %.5 C-reactive protein It is widely used marker of acute inflammation and one of the most studied sepsis markers. It has a halflife of 19 hours. Post inflammatory exposure it starts to increase in 4-6 hours, doubles in 8 hours and peaks at 36-50 hours. It is produced in the liver in response to cytokines mainly IL-6. Normal value of CRP is generally less than 2mg/L but can be considered normal upto 10mg/L.6,7 In a systematic review its sensitivity and specificity to diagnose serious bacterial infection in non hospitalized children is 77% and 79% respectively.8 Serial measurement of CRP have a better predictive value. Positive CRP will increase the probability of infection by 11%, a negative CRP decreases probability of infection by 33%.9 CRP measurement could be a good predictor of adequate empirical antibiotic use. If CRP remains same or increases even after 48 hours of antibiotic use it is suggestive of antibiotic failure. A study done in neonates with sepsis using serial CRP to assess the antibiotic response in first 48 hrs of therapy. Fall in CRP identified whether the organism was sensitive to the given antibiotic with 89% sensitivity and 90% specificity.9 CRP values donot get suppressed in case of a patient


Table 2 : Comparision between CRP and Procalcitonin.8 C-reactive protein Begins to rise 12-24 hours and peaks Within 2-3 days High in other inflammatory conditions like SLE,JRA, etc As a marker of sepsis sensitivity :0.75 (95% CI, 0.62-0.84) Specificity :0.67( 95%CI, 0.56-0.77)

Procalcitonin Detectable with 3-4 hours and peaks within 6-24hours Doesn’t rise in these inflammatory conditions 0.88 (95% CI -0.8-0.93) 0.81( 95% CI,0.67-0.90)

As it peaks early some studies have shown that it

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IL-6 is indicator of severe bacterial infection.17 It is not being used regularly as it is costly, it is not freely available and there is not a robust data justifying its use.

is a better tool than CRP in picking up bacterial infections.12 Serum concentrations of PCT are valuable to monitor the clinical response to therapy for sepsis and has a role in de-escalating antibiotics in ICU (Table 3).

Table 5 : Acute phase reactants in specific infections.16

Table 3 : Procalcitonin guidance inacute respiratory tract infection.13 Acute respiratory tract infection Including community acquired Pneumonia

PCT values (ng/ml) 0.50: strongly encourage antibiotics

Good quality evidence suggests that PCT guidance reduces antibiotic duration and prescription rates.13Moderate to good quality evidence suggests that use of PCT to guided therapy did not increase mortality, hospital length of stay or ICU admission rates. Studies have shown that in neonates PCT shows a moderate diagnostic accuracy at the cut off 2-2.5ng/ ml for diagnosis of sepsis in neonates with SIRS and suspected sepsis.14 At a cut off of 2-2.5ng/ml sensitivity is 0.85(95% CI 0.76;0.90) and specificity is 0.54(95% CI 0.38;0.70). Using a PCT cut off >2.5ng/ml, sensitivity and specificity is 0.68(95% CI 0.52;0.80) and 0.85(95% CI 0.70;0.93) respectively (Table 4).14

0.5-2.0 2.0-10 >10

Cellulitis, erysipelas Necrotising skin and soft Tissue infections (NSSTIs) Meningitis Neurosurgical infections

CRP>70,ESR>50 high predictive value for duration of hospital stay CRP > 150 suggestive of NSSTIs

Pyelonephritis

Bone related infections

Risk category Low risk of systemic bacterial or fungal infection High risk of systemic bacterial or fungal infections High risk of sepsis and progression to septic shock High risk of septic shock

Serum and CSF PCT have a high diagnostic accuracy in bacterial meningitis PCT>0.15 in post operative neurosurgical patient has high diagnostic value for bacterial infection Initial PCT >0.5 is a predictor of poor outcome.High level CRP >120 after first week of treatment and slow decline are indicators of poor outcome PCT >0.5 is associated with high likelihood of renal scars and pyelonephritis in children with Urinary tract infection CRP>32 ESR >70 are helpful in differentiating osteomyelitis and cellulitis. CRP and PCT decrease rapidly after treatment, fall in ESR which takes usually 6-8 weeks, is a marker of response to treatment

Interleukin -8 Interleukin 8 is a pro-inflammatory cytokine that may predict the survival of critically ill children. Higher Il-8 levels were seen in children with septic shock who died than in survivors based on 28 day mortality data. Il-8 300pg/ml, along with high CRP in children more than 12 yrs of age associated

Interleukin -6 IL-6 is a pro-inflammatory cytokine. It has been widely studied in adult population as a biomarker of sepsis. There are just a few studies in pediatric population. It is higher in children with sepsis than in patients with non infectious systemic inflammation. Its diagnostic accuracy increases when combined with CRP.High Il-6 is associated with severe sepsis. Even in child with febrile neutropenia and cancer high


Acute phase reactant: ESR mm/hour, CRP mg/l, PCT ng/dl

Infective endocarditis

Table 4 : Risk categories according to PCT values.15 PCT value (ng/mL) 1) and cardiovascular efficiency isimpaired leading to poor tissue perfusion. In these cases, there is decrease in Ees (intrinsic myocardial contractility) and arterial elastance may be low or high (disease related or induced by therapy). An optimal Ea/Ees coupling may be obtained by balancing volume, inotropic, and vasoconstrictor therapies.25 Assessment of LVEF being simple bedside tool, has become most widely used surrogate index of LV contractility. However, LVEF is “loaddependent” parameter and represents the interaction between the left ventricle and the arterial system (VA coupling). As explained, load-dependant indices like LVEF, cardiac index (CI) and stroke volume index may be observed as normal in septic patients even when intrinsic myocardial contractility is poor in presence of severely reduced arterial tone. Considering that myocardial depression is constant in patients with sepsis and septic shock, LV systolic function should be considered more as a reflection of the vascular tone status than of intrinsic LV contractility.22 Use of pulmonary artery catheter and echo doppler techniques like tissue doppler imaging have greater diagnostic accuracy for myocardial depression. Recent echocardiographic studies have also suggested that diastolic dysfunction is common in patients with severe sepsis and septic shock however, its impact in prognosis and management is still unclear and more


studies are needed.26 Vincent et al found significantly lower right ventricular ejection fraction in patients with septic shock using thermodilution technique in a series of 127 consecutive critically ill patients. RVEF can be reduced due to peripheral vasodilation and preload reduction in early phase of septic shock. However, both myocardial depression and pulmonary artery hypertension may also be responsible for RV dysfunction.27 Hemodynamic changes Reduced preload Sepsis induced hemodynamic alterations are due to intravascular volume depletion, loss of vascular tone, inhomogeneous distribution of blood flow between organs, microcirculatory imbalance, VO2/ DO2 dependency, and high lactate levels. The decreased intravascular volume is due toabsolute or relative hypovolemia leading to reduced preload. Microvascular barrier dysfunction and increased capillary permeability due to sepsis related cytokines and other inflammatory mediators leads to absolute volume loss whereas endotoxemia related venous pooling, especially in the splanchnic compartment, leads to reduction in the effective compliance of the total vascular bed and relative hypovolemia.28 Decreased vascular tone (reduced afterload) As explained above, decreased vascular tone may temporarily mask myocardial depression, allowing maintained LVsystolic function despite myocardial depression in early phase of septic shock. Normal LVEF may be observed, despite seriously impaired intrinsic LV contractility if arterial tone is severely depressed. Altered systemic resistance is related to autonomic dysregulation and an imbalance between vasoconstrictor and vasodilator factors. Various vasodilating factors released during sepsis are NO, TNF-α, histamine, kinins, and prostaglandins. Vascular hyporesponsiveness in the form of lower vasoconstrictor response to angiotensin II, catecholamines, serotonin, and potassium chloride is reported in experimental models of sepsis related conditions.22, 29 State of catecholamine “desensitization” could be

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pressure, pulmonary artery occlusion pressure and mixed SvO2 helps bedside clinician for assessing the RV function and response to therapy. PAC can be used to measure CO using thermodilution techniques.34, 35 Tissue Doppler imaging Echocardiography is the most commonly used bedside tool to assess myocardial function in sepsis and septic shock. Global systolic function can be assessed by quantitative metrics such as fractional shortening (FS) and ejection fraction (EF). Various load dependant echocardiographic parameters toassess LV function such as ejection fraction, cardiac index (CI), and stroke volume index may be inaccurate because they are influencedby changes in heart rate, preload, and afterload as discussed earlier. Tissue Doppler Imaging (TDI) and two-dimensional strain echocardiography (SE) is a contemporary angle-independent method for evaluating cardiac function by tracking cardiac tissue deformation. TDI provides quantitative information about myocardial motion with high temporal and spatial resolution. It is less load dependent and has greater diagnostic and prognostic use compared with conventional echocardiography.36,37 Myocardial performance index (MPI) also known as Tei index represents global myocardial performance and provides an evaluation of both systolic and diastolic function. Peak systolic velocity measured at the mitral annulus reflects the systolic motion of the ventricle long axis, whereas the early diastolic velocity of the mitralannulus reflects the rate of myocardial relaxation.38 These values have been demonstrated to be useful in diagnosis and prognosis of different cardiovascular diseases, however careful interpretation is needed in relation to preload variations, common in patients with sepsis and septic shock undergoing resuscitation and optimization of hemodynamic status. In many studies, blood troponin concentration is reported to correlate well with poor cardiac functionand response to therapy in children with septic shock.39 Laboratory markers of cardiac function and oxygen delivery: utilization balance include troponin and lactate. Lactate is recommended as an important laboratory testfor both diagnosis and subsequent monitoring of patient with septic shock. However, it primarily reflects balance of oxygen

a result of either down-regulation of α1-adrenergic receptor or uncoupling between receptors and their intracellular messengers. Decreased plasma vasopressin levels and down-regulated V1 receptor expression has also been reported in sepsis. Other reported factors causing vasoplegia in sepsis are increased production of superoxide anion, peroxynitrite, and prostacyclin; decreased steroid sensitivity; corticosteroid insufficiency and activation of ATP-sensitive (KATP) potassium channels.22, 30,31 Microcirculatory alterations Microcirculatory changes in the form of reduction in functional capillary density and altered perfusion (intermittent, reduced, or stopped blood flow) have been reported to appear much before the macrocirculatory changes (clinical signs of altered hemodynamics) in severe sepsis and septic shock. Persisting changes are related to poor survival outcome.32 Microcirculatory alterations leading to impaired oxygen extraction explain the dissociation between myocardial depression and elevated mixed venous oxygen saturation(ScvO2) values observed in septic patients. VO2/DO2 dependency Poor perfusion in sepsis frequently leads to dependence of tissue oxygen uptake (VO2 ) on tissue oxygen delivery (DO2); so-called VO2/DO2 dependency. Lactate Serum lactate values greater than 2 mEq/L reflect the presence of circulatory failure. Increased lactate levels may also be due to seizures, hyperventilation or altered metabolism (liver failure, mitochondrial inhibition). High lactate is related to poor survival outcome however “lactate clearance” (rate necessary to metabolize lactate ina certain time) has been reported to have better predictive value for organ failureand mortality.33 Investigations Use of the pulmonary artery catheter (PAC) and echoDoppler techniques are promising in the diagnostic approach to sepsis related myocardial depression. Although the benefits of PAC use on patient outcome have never been convincingly demonstrated, continuous monitoring of central venous pressure, right-sided intracardiac pressure, pulmonary artery


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settings.35Non-invasive methods to monitor cardiac output also need expertise. Measuring Scvo2 may act as surrogate marker to estimate CO as discussed later. Cardiac index (CI) is a haemodynamic parameter that relates the cardiac output (CO) from left ventricle in one minute to body surface area (BSA). It can be derived as CI = CO/BSA = (HR X SV)/ BSA (L/min/ m2). A CI between 3.3 and 6.0 L/min/m2 is reported to have best outcomes in patients with septic shock compared to patients without septic shock for whom a CI above 2.0 L/min/m2 is sufficient.35 Because CO = HR × SV, targeted CO is often dependent on attaining threshold HRs. Myocardial perfusion through coronary arteries occurs during diastolic phase. If there is significant tachycardia, there is not enough time to fill the coronary arteries during diastole, causing further myocardial depression, poor contractility and low CO. Coronary perfusion is further compromised if diastolic blood pressure (DBP) is low and/or end diastolic ventricular pressure is high. Fluid bolus may restore end-diastolic volume and improve coronary perfusion pressure. Addition of inotrope will improve myocardial contractility (SV) and CO and will reflexively reduce HR. This will be evident in improvement of the shock index (HR/ systolic blood pressure) as well as CO Reported normal cut off values of Pediatric Adjusted shock index (SIPA) are 1.2 for 4-6 years; 1 for 6-12 years; and 0.9 for > 12 years. For normal healthy adults it is 0.5 to 0.7.42 Increased systemic vascular resistance (SVR) is clinically identified by cool extremities, prolonged capillary refill, absent or weak distal pulses and narrow pulse pressure with relatively increased DBP. Vasodilator therapy is useful in this scenario as it reduces after load and increases vascular capacitance for which additional fluid volume should be given. Additional fluid volume to restore filling pressure results in a net increase in end-diastolic volume (i.e., preload) and improved CO. If the HR is below the threshold minimum HR, then CO will also be too low (CO = HR × SV). Use of inotrope with chronotropic property such as epinephrine will be helpful in such cases. If diastolic blood pressure or DBP – CVP is too low, an inotrope/

delivery and utilization in body rather than cardiac dysfunction. Treatment As myocardial dysfunction is part of a systemic dysregulated response to infection, causal line of therapy remains sepsis control using prompt and adequate antibiotic therapy along with measures to control source of infection including surgical removal of infectious focus. Myocardial dysfunction being reversible process in most of the cases, organ support remains lifesaving strategy. Optimum fluid therapy, vasopressors and inotropic agents along with good supportive care is crucial to improve outcomes. Surviving sepsis guidelines may be taken as good starting point in treatment of septic shock and sepsis associated myocardial dysfunction.40 Adults are more likely to have vasomotor dysfunction in sepsis where vasopressor therapy shows good response. However, mechanism of sepsis related cardiac dysfunction is not well elucidated in children and management of septic shock in children is based on predominant pathophysiological status (warm shock or cold shock). Children respond well to inotropic and at times to vasodilating agents suggesting that myocardial dysfunction is a major player in children as compared to vasomotor dysfunction in adults. With evolving evidence and better understanding of pathophysiological changes, management of septic shock is going through a paradigm shift from protocolized guidelines-based approach like surviving sepsis bundle or early goal-directed therapy to an individualized physiology-based management strategy. It is important to acheive therapeutic targets with background understanding of cardiovascular interaction in sepsis and septic shock. Septic shock treatment should target restoration of normal mental status, threshold HRs, peripheral perfusion (capillary refill < 3 s), palpable distal pulses, and blood pressure for age.41 Further evaluation and treatment should also be guided by hemodynamic variables including perfusion pressure (MAP – CVP) and CO to maintain effective blood flow in individual organs. Measurement of cardiac outputand accurate blood pressure needs invasive catheter placement though it may not be feasible in most of the


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perfusion pressure.In children perfusion pressure of MAP – CVP is calculated using formula 55 + age x 1.5. Here CVP is considered 0 but in setting of higher CVP or intra abdominal pressure (IAP), appropriate correction of targeted perfusion pressure should be done by adding actual value of CVP or IAP to this formula. Other targets are Scvo2 greater than 70% and/or CI 3.3–6.0L/min/m2. 35 In view of marked individual variability, patients should undergo frequent clinical evaluation of shock parameters to adjust targets for clinical variables of shock management. Fluid therapy There is no myocardial protector fluid and SSC guidelines recommend use of crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock.40 In view of increasing concern of hyperchloremia and acute kidney injury with ‘chloride liberal’ normal saline, balanced solutions are being investigated as a better alternative, though, normal saline remains the standard of care till we get more evidence in this area.49, 50 Inotropes Low-dose epinephrine (0.05–0.3μg/kg/min) is suggested by many authors as first-line choice for cold hypodynamic shock for its β2-adrenergic effects in the peripheral vasculature with little α-adrenergic effect at this dose.35,40 Dopamine (5–9 μg/kg/min), being time tested in children is still first line in otropic support in children at most of the centres. Dobutamine may be used when there is a low CO state with adequate or increased SVR. Epinephrinestimulates gluconeogenesis and glycogenolysis, and inhibitsthe action of insulin, leading to increased blood glucose concentrations and increasedplasma lactateconcentrations independent of changes in organ perfusion. In an emergency, it may be infusedthrough a peripheral IV route or through an intraosseous needlewhile attaining central access.35, 51,

vasopressor agent such as norepinephrine will be required to improve diastolic coronary blood flow. In significant myocardial depression or in fluid overload, a diuretic may be required to improve stroke volume (SV) by moving leftward on the overfilled Starling function curve. One of the targets of initial resuscitation in EGDT protocol was achievement of Scvo2 > 70%. Scvo2 < 70% indicates poor CO. In contrast, supra-normal Scvo2 (> 80–85%) that reflects narrowed arteriovenous difference in oxygen content is indicator of either mitochondrial dysfunction (poor oxygen extract), a high CO state, or overly aggressive resuscitation (35, 43). Serial monitoring of multiple variables (multimodal monitoring) such as HR/SBP shock index, CO, and SVR along with clinical signs such as distal pulses, skin temperature, capillary refill, serum lactate level and urine output is important to determine the underlying hemodynamic status and response to therapy. 44 Hemodynamic stabilization In adults, sepsis and septic shock is often characterized by a hyperdynamic circulation having higher cardiac output in response to systemic vasodilatation and relative and/or absolute hypovolemia. However, hypodynamic pattern is also quite common, more so in children usually due to myocardial dysfunction related to sepsis. Rapid and effective fluid therapy to restore adequate volemia is most important. Early goal directed therapy protocol has been standard of care for management of septic shock in emergency for more than a decade, however recently conducted large multicentre randomized controlled trials failed toreplicate the mortality benefit of EGDT.45-47 The above trials challenged the necessity of targeting each of the components of the 6-hour resuscitation bundle of EGDT. Similar outcomes with usual standard care in these studies, indicate towards importance of individualized clinical judgement and care based on physiologic status of the patient and setting in which patient is being treated. As we target cerebral perfusion pressor in management of raised intracranial pressure, importance of targeting organ perfusion pressor is equally valid for other organs during management of septic shock.48 The primary therapeutic target is to restore tissue perfusion by ensuring targeted


52, 53

Vasopressors Norepinephrine is recommended as the first line agent in adults with fluid-refractory shock. Use of low-dose norepinephrine as a first-line agent for fluid-refractory hypotensive hyperdynamic shock has also been

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suggested in children by many authors. Vasopressors should be used in pediatric septic shock as per the pathophysiological scenario discussed above (warm shock or hyperdynamic septic shock with flash capillary refill, warm extremities, low diastolic pressure, and bounding pulses) however, excessive vasoconstriction compromising microcirculatory flow should be avoided. Dopamine > 15 μg/kg/min, epinephrine > 0.3 μg/kg/min, or norepinephrine have vasopressor effect and there is no sufficient evidence to support one drug over another.35, 54, 55 Vasodilators In children with fluid-refractory septic shock, who are normotensive with a low CO and high SVR, initial treatment consists of the use of an inotropic agent such as epinephrine or dobutamine that tends to lower SVR. A short-acting vasodilator such as sodium nitroprusside or nitro glycerine may also be added judiciously to recruit microcirculation.35,40 Type III phosphodiesterase inhibitors (PDEIs) including milrinone and inamrinone improve myocardial contractility and reduce SVR (inodilator effect). PDEIs have a synergistic effect with β-adrenergic agonists and they maintain their action even when the β-adrenergic receptors are down-regulated or have reduced functional responsiveness (state of catecholamine desensitization in sepsis). At times these drugs may cause arrythmia and hypotension and should be discontinued immediately due to longe limination half-life. Hypotension can be potentially overcome by promptly beginning vasopressor such as norepinephrine.56,57 Enoximone is another type III PDEI which is reported to have more β1 cAMP hydrolysis inhibition than β2 cAMP hydrolysis inhibition. Hence, it can be used to increase cardiac performance with less risk of undesired hypotension.35 One of the pathogenic mechanisms of sepsis induced cardiac dysfunctionis desensitization of Ca++ / actin / tropomyosin complex binding as discussed above. Levosimendan is a promising drug that increases Ca++ / actin / tropomyosin complex binding sensitivity and has some type III PDEI and adenosine triphosphate– sensitive K+ channel activity.58 Vasopressin and terlipressin have been shown to increase MAP, SVR, and urine output in patients with vasodilatory septic shock and hypo-responsiveness to catecholamines.35


Vasopressin’s action being independent of catecholamine receptor stimulation, its efficacy is not affected by α-adrenergic receptor down-regulation often seen in septicshock. Angiotensin, Phenylephrine, Nitric oxide (NO) inhibitors and methylene blue are considered investigational therapies in septic shock refractory to norepinephrine.35 Conclusion Sepsis is a major cause of mortality worldwide and SIMD is a frequent consequence in severe sepsis and septic shock. Alterations in preload, afterload and myocardial contractility due to dysregulated response to infection lead to failure of cardiovascular system in sepsis and septic shock. The pathogenesis involves a complex mix of systemic factors apart from genetic, molecular, metabolic, autonomic and structural alterations. In septic shock adults are more likely to have vasomotor dysfunction where as children are more likely to have myocardial dysfunction. SIMD is reversible entity most of the time, if timely causal treatment of sepsis (antibiotics and source control) and organ support for failing cardiovascular system can be provided. EGDT protocol advocates time bound achievement of ‘goals’ in management of septic shock however, findings of recent large trials have challenged this approach and indicate towards a paradigm shift from protocolized guidelines-based approach to an individualized pathophysiology-based management strategy. Conflict of Interests:Nil Source of Funding:Nil References 1. Wolfler A, Silvani P, Musicco M. Incidence of and mortality due to sepsis, severe sepsis and septic shock inItalian Pediatric Intensive Care Units: a prospective national survey. Intensive Care Med 2008;34:1690–7. 2. Hollenberg SM, Ahrens TS, Annane D. Practice parameters for hemodynamic support of sepsis in adults patients: 2004 update.Crit Care Med 2004; 32:1928-48. 3. Brierly J, Thiruchelvan T, Peters MJ. Hemodynamics of early pediatric fluid resistant septic shock using non-invasive cardiac output(USCOM) distinct profiles of CVC infection and community acquired sepsis. Crit Care Med 2006; 33:171I 4. Deep A, Goonasekera CD, Wang Y. Evolution of haemodynamics and outcome of fluid-refractory septic shock in children. Intensive Care Med 2013; 39:1602–9.

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How to cite this article: Tiwari L, Chaturvedi J, Anand C.Myocardial Dysfunction in Sepsis. J Pediatr Crit Care 2018;5(4):41-49. How to cite this URL: Tiwari L, Chaturvedi J, Anand C.Myocardial Dysfunction in Sepsis. J Pediatr Crit Care 2018;5(4):41-49. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504006.html


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DOI-10.21304/2018.0504.00410

Case Report Arterial Tortuosity Syndrome in a Neonate *Indu Khosla,**Tanushri Mukherjee *Consultant Pediatric Pulmonology, **Consultant Pediatrics and Neonatology, Cloud nine Hospital, Malad West, Mumbai, India Recieved: 07-Jul-18,/Accepted:09-Aug-18/Published Inline:30-Aug-18

ABSTRACT Background : Arterial Tortuosity Syndrome (ATS) is a rare, autosomal recessive connective tissue disorder characterized by elongated and tortuous large and medium-sized arteries involving aorta and pulmonary arteries along with dysmorphic facial features, skin and joint laxity and hernia formation. We present here one case of ATS. Key words: Arterial Tortuosity Syndrome (ATS)

pulmonary artery and tortuous left arch with patent foramen ovale and intact ventricular septum with no evidence of PPHN. The patient was advised CT angiography for further evaluation. The baby was discharged home on day 12 of life on breast feeds. The baby readmitted on 25th day of life with excessive projectile non-bilious vomiting, weight loss and severe dehydration. He was resuscitated with intravenous fluid and was started on supportive management. X ray of abdomen was normal. Ultrasonography of abdomen showed thickened pylorus, elongated pyloric canal and “dough sign” suggestive of infantile hypertrophic pyloric stenosis. After initial stabilisation, modified Ramstedtpylorotomy was done on the 27th day of life. He continued to have unexplained oxygen dependency and was discharged after 15 days post operatively. On follow up there was an incisional hernia. CT pulmonary angiography showed significant elongation of aortic arch with tortuosity of the arch vessels without any stenosis or aneurysm. There were early bifurcation of main and branch pulmonary arteries. CT was suggestive of arterial tortuosity syndrome. The patient was advised to do a CT angiography brain and genetic work up. He is 7 months old now and is doing well. Discussion Arterial Tortuosity Syndrome is a connective tissue disorder associated with various vascular and nonvascular characteristics. Arterial narrowing involving the pulmonary artery and the Aorta both locally and over long stretches, may be associated. A loss-of-function mutation of the SLC2A10 gene leads to a decreased transcription of decorin, which is the inhibitor of the transforming growth factor beta (TGFB) signalling pathway. This leads to improper

Introduction Arterial Tortuosity Syndrome (ATS) is a rare, autosomal recessive connective tissue disorder characterized by elongated and tortuous large and medium-sized arteries involving either the aorta, the pulmonary arteries, or both with a propensity for aneurysm, stenosis and dissection of arteries leading to ischemic events. This was first described in 1967 by Ertugrul(1). Additional characteristics include dysmorphic facial features, ocular involvement cutis laxa, and signs of a generalized connective tissue disorder. The skeletal manifestations of the connective tissue disorder includes joint laxity, hernias and muscular hypotonia. Here we are discussing one neonate who presented with ATS. Case A full-term male new-born presented at 2 hours of age with progressively increased respiratory distress since birth. There was history of meconium stained amniotic fluid but the baby was vigorous and did not need any resuscitation. On admission he had severe distress with impending respiratory failure. He was intubated and after relevant blood work up was started on antibiotics, intravenous fluid and inotropic support. His clinical condition improved over the next 24 hours. He required ventilator support for 3 days and then was weaned to high flow oxygen which was continued till the 10th day. In view of prolonged oxygen dependency in a child with meconium aspiration, 2 D Echo was done to rule out secondary pulmonary hypertension. Echo was suggestive of proximal bifurcation of Correspondence: Dr Indu Khosla, Consultant, Cloudnine Hospital, Malad West, Mumbai - 400064 Email id: [email protected], Phone: 9820144593


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Arterial tortuosity syndrome in a neonate

CASE REPORT

formation of extracellular matrix, causing tortuosity of arterial vessels.2 Characteristic facial features include hypertelorism, micrognathia, elongated face, high palate, beaked nose and down slanting palpebral fissures. Our case has hypertelorism and elongated face (Figure 1)

premature aging. Hernias like diaphragmatic hernias, hiatal hernias and inguinal hernia are common but our patient had an incisional hernia. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Initial reports describe a poor prognosis with mortality rates up to 40% before the age of 5 years4 but subsequent series suggest a milder course.5 So these patients require regular surveillance for early detection of aortic root aneurysm and stenosis. Causes of death are pulmonary infection, myocarditis and organ infarction.

Figure 1: Hypertelorism and elongated face Figure 2: CT angiography showed severe tortuosity and meandering of aortic arch with areas of hairpin bend involving right subclavian and right common carotid arteries. Tortuosity of aorta noted at diaphragmatic levels.

A review of 71 cases of ATS described in the literature revealed that consanguinity was present in 46% of cases which corroborates with autosomal recessive inheritance pattern. Our baby also had a history of consanguinity. In a recent study of review of 40 cases by Beyens et al,3 about half of all patients presented with cardiovascular manifestations, the most common being coarctation of the isthmus aorta or a functional cardiac murmur. Six term probands manifested with infant respiratory distress syndrome and recovered well. Five cases had pyloric stenosis. Our case presented with respiratory distress at birth requiring mechanical ventilation followed by prolonged oxygen support and pyloric stenosis later on. Post operatively he developed incisional hernia also suggestive of poor tone of abdominal wall. Other features of ATS are cleft palate or bifid uvula and muscular hypotonia. Skeletal manifestations included joint laxity, pectus excavatum, arachnodactyly and scoliosis. Several patients had ocular involvement like myopia, corneal thinning, keratoconus and keratoglobus. Skin involvement ranged from a thin, hyperextensible skin with a velvety texture, marked cutis laxa and


Due to intrinsic defect in the vascular collagen, blood vessels tends to show increased fragility and tendency for rupture so in the evaluation of these patients, non-invasive modalities like sonography, magnetic resonance imaging and computed tomography angiography are preferred.6 In large vessel involvement, most striking observations are noted in the tortuosity and dilatation of the aortic arch. Findings can range from elongation of the aortic arch, clustering of vessels, to gross meandering of the aorta to almost reaching the lateral thoracic wall. Our patient had significant tortuosity and meandering of aortic arch with areas of hairpin bend involving right subclavian and right common carotid arteries and tortuosity of vertebral arteries and aorta at diaphragmatic level (Figure 2). Other important vessel to get affected are pulmonary arteries which tend to show areas of narrowing and dilatation. Relative

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Arterial tortuosity syndrome in a neonate

CASE REPORT

narrowing at the origin and early division of the main pulmonary artery lead to “V” configuration of the pulmonary bifurcation. Our patient showed early bifurcation of main pulmonary artery into branch pulmonary artery and the branch pulmonary artery showed early branching into lobar arteries with tortuous course (Figure 3). The differential diagnosis for ATS are other inherited defects of connective tissue like Marfan syndrome, Williams Beuren syndrome, Ehlers Danlos syndrome and hereditary cutis laxa syndromes.

Conclusion ATS though rare, is a very fatal disease. Neonate and infants presenting with features of aortic aneurysm and pulmonary stenosis with or without typical craniofacial characteristics should be screened for ATS. CT angiography being a noninvasive modality should be used for diagnosis and surveillance. Conflict of Interest :Nil Source of Funding :Nil References 1. Ertugrul A. Diffuse tortuosity and lengthening of the arteries. Circulation 1967;36:400-7. 2. Marwah A, Shah S, Suresh PV. Arterial tortuosity syndrome: a rare entity. Ann Pediatr Cardiol 2008;1:62-4. 3. BeyensA, AlbuissonJ. Arterial tortuosity syndrome: 40 new families and literature review, Genet Med. 2018 Jan 11. 4. Wessels MW, Catsman-Berrevoets CE, Mancini GM. Three new families with arterial tortuosity syndrome. Am J Med Genet A 2004;131:134–43. 5. Callewaert BL, Willaert A, Kerstjens-Frederikse WS. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat2008;29:150-8. 6. Bhat V, Arterial Tortuosity Syndrome: An Approach through Imaging Perspective. J Clin Imaging Sci. 2014; 4: 44.

Figure 3: CT scan showing early bifurcation of main pulmonary artery into branch pulmonary artery leading to “V” configuration and tortuous course of branch pulmonary arteries. How to cite this article: Khosla I, Mukherjee T.Arterial tortuosity syndrome in a neonate.J Pediatr Crit Care 2018;5(4):50-52. How to cite this URL: Khosla I, Mukherjee T. Arterial tortuosity syndrome in a neonate. J Pediatr Crit Care 2018;5(4):50-52. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504007.html


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DOI-10.21304/2018.0504.00411

Case Report Retropharyngeal abscess in Neonate - A misdiagnosed entity Virender Kumar Gehlawat*, Kundan Mittal**, Vandana Arya*** *Associate professor,**Senior Professor,***Assistant professor, Department of Pediatrics, Pt B D Sharma, PGIMS, Rohtak,Haryana,India Received:25-Jul-18/ Accepted:12-Aug-18/Published Online:30-Aug-18

ABSTRACT Respiratory distress is common problem seen in new born and infants due to anatomical and physiological differences from adult. Infant can present with respiratory distress, inspiratory stridor, feeding difficulty, and cyanosis. At birth usually congenital malformation, hyaline membrane diseases, nasal block are common disorders leading to respiratory distress. Retropharyngeal abscess is uncommon in neonatal period. Key words: Respiratory distress, newborn, retropharyngeal abscess

Introduction Retropharyngeal abscessis a rare deep neck infection that usually affects young children. It usually follows an upper respiratory tract infection. Theinfection can spread from infected lymph nodes secondary to infections in nasopharynx (e.g. adenoiditis, nasopharyngitis), oropharynx (e.g. tonsillitis, pharyngitis, dental infection or foreign body trauma) or sinusitis. The etiology in adults or older children is mainly tubercular, whereas in younger children the bacterial pathology is more common.1 Retropharyngeal lymph nodes usually get atrophied by 3 to 4 years of age.2 We are reporting a case of neonate with retropharyngeal abscess, managed successfully by surgical drainage and conservative management. Case report One-month old exclusively breast fed male infant weighing 4 kg delivered per vaginally, presented to emergency department with history of noisy breathing for last 15 days, fever, refusal to feed and difficulty in respiration for last 5 days. Infantwas being treated in a private hospital but infant gradually deteriorated and referred to higher centre.There was no history ofcyanosis. At presentation of child was sick and febrile. Physical examination revealed heart rate 160/ minute, respiratory rate 62/minute with subcostal and intercostals retraction with SpO2 of 96 % with oxygen

2 L/min via nasal prongs. On auscultation chest was clear but inspiratory stridor was present. Throat examination revealed congestion of the posterior pharyngeal wall without any obvious swelling. There was a visible swelling over the left side of the neck (2x2 cm), compressible with no signs of inflammation. There was no cervical lymphadenopathy. Rest of the systemic examination was essentially normal. The Child was started with injectable antibiotics (Amoxiclav + amikacin) and shifted to intensive care unit with a provisional diagnosis of pneumonitis with septicaemia or some congenital malformation of larynx. Child was put on mechanical ventilation for 20 days in view of marked respiratory distress and not maintaining saturation. But clinical diagnosis could not be made. Chest X-ray was performed and showed slight shift in trachea, clear lung field with no evidence of pneumothorax. Complete blood count performed was essentially unremarkable (Hb 12.1 g/dL and TLC 14,000/cmm with neutrophilic predominance). C-reactive protein was highly positive. Liver and renal function tests were within the normal limit. Ultrasound neck swelling revealed a cystic fluid filled cavity not communicating with other adjacent structures.Antibiotics upgraded to meropenem and vancomycin in view of worsening condition of the child and failed extubation trial. Urgent CT chest and neck was performed which showed peripherally enhancing hypodense collection in retropharyngeal spaceextending upto para-pharyngeal space with compression of the trachea (Figure 1). These findings were suggestive of retropharyngeal abscess. Surgical

Correspondence: Dr. Kundan Mittal, Senior Professor Pediatrics, Pt B D Sharma, PGIMS, Rohtak Haryana, India, Phone-+919416514111, [email protected]


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Retropharyngeal abscess in Neonate

CASE REPORT

Figure 1: Urgent CT chest showingretropharyngeal space extending up to para-pharyngeal space with compression of the trachea.

swallowing), trismus, neck swelling, refusal to move the neck. muffling of voice, stridor or respiratory distress. The physical signs include fever (100%), cervical adenopathy (69%), retropharyngeal bulge (43%), neck pain (38%) stridor (23%), torticollis (18%) and rarely cyanosis.4 Acute epiglottitis, foreign body aspiration, pharyngitis, cervical adenitis, meningitis should be considered as differential diagnosis of retropharyngeal abscess. The organisms usually isolated in acute retropharyngeal abscess are Staphylococcus aureus, Streptococcus viridians, Klebsiella-pneumoniae, Escherichia coli, beta-haemolytic Streptococcus Group A, and Haemophilus species.5 In the literature, β-hemolytic streptococci group A is the single most commonly isolated pathogen cultured in pediatric retropharyngeal infections.6,7 So it is of utmost importance to identify antibiotic with good sensitivity toeradicate the organisms. A lateral neck radiographis the first line investigation in the stable child. CTneck and thorax is useful in confirming retropharyngeal abscess, extent of the

drainage of abscess was done via intraoral route under general anaesthesia and pus was send for culture and sensitivity. Pus culture turned out to be sterile may be due to antibiotic therapy. Child improved and successfully extubatedwithin 72 hours of drainage of abscess. Discussion The retropharyngeal space lies behind the pharynx bounded anteriorly by the buccopharyngeal fascia, posteriorly by the prevertebral fascia, and laterally by the carotid sheaths. The retropharyngeal space extends superiorly upto the base of the skull and inferiorly upto the mediastinum.3 The retropharyngeal space contains two paramedial chains of lymph nodes which drain the nose, paranasal sinuses, nasopharynx, and adenoids. As the retropharyngeal space communicates with the parapharyngeal space and the posterior mediastinum, infection can spread to these areas.1 The children usually present with symptoms of upper respiratory tract infection (fever, sore throat, irritability, decreased oral intake, drooling, pain on


54


Retropharyngeal abscess in Neonate

CASE REPORT

abscess or any complications such as mediastinitis to help us in planning surgery.8,9 Up to 25% of retropharyngeal infection have been successfully treated with antibiotics alone.10 This small percentage of response to medical treatment makes many surgeons adopt immediate surgical intervention (Incision and drainage) along with antibiotics.As our case was managed successfully by surgical drainage of pus by intraoral route and intravenous antibiotics. In present case there was compression of trachea leading to respiratory distress. Mortality is high in retropharyngeal abscesses if associated with compression of airway, aspiration pneumonia, rupture of abscess (mediastinitis, pericarditis, tamponade), epidural abscess, jugular venous thrombosis, necrotizing fasciitis, vertebral subluxation, sepsis, and erosion into the carotid artery.11 Conclusion The clinical presentation of retropharyngeal abscess can be insidious and variable. To maintain a high index of suspicion especially in patients with upper respiratory illnesses that do not appear to be resolving over a normal time course or with conventional therapy. Conflict of Interest :Nil Source of Funding :Nil

References 1. Velankar HK. Retropharyngeal abscess. Bombay Hospital Journal2001; 43(3): 365-73. 2. Millan SB, Cumming WA. Supraglottic airway infections. Prim Care 1996;23:741–58. 3. Lafitte FN, Duverneuil M, Brunet E. Rhinopharynx et espacesprofonds de la face :anatomie et applications a la pathologie. Journal of Neuroradiology 1997; 24(2):98–107. 4. Mallik SVS, Rao A, Adwani MA, Bharti C. Retropharyngeal candidal abscess in a neonate: case report and review of literature. Kuwait Medical Journal 2007; 39: 177-80. 5. Asmar BI. Bacteriology of retropharyngeal abscess in children. Pediatr Infect Dis J 1990; 9: 595-7. 6. Ungkanont K, Yellon RF, Weissman JL. Head and neck space infections in infants and children. Otolaryngol Head Neck Surg 1995;112:375–82. 7. Nicklaus PJ, Kelley PE. Management of deep neck infection. Pediatr Clin North Am 1996;43:1277–96. 8. Frances WC and Jeff ES. Retropharyngeal abscess in children: clinical presentation, utility of imaging, and current management. Pediatrics 2003; 111: 1394-98. 9. Ravindranath T, Janakiraman N, Harris V. Computed tomography in diagnosing retropharyngeal abscess in children. Clin Pediatr (Phila).1993; 32: 242-4. 10. Nagy M, Pizzuto M, Backstrom J, et al. Deep neck infections in children: a new approach to diagnosis and treatment. Laryngoscope 1997;107:1627–34. 11. Herzon FS and Martin AD. Medical and surgical treatment of peritonsillar, retropharyngeal, and para-pharyngeal abscesses. Current Infectious Disease Reports, vol. 8, no. 3, pp. 196– 202, 2006.

How to cite this article: Gehlawat VK, Mittal K, Arya V.Retropharyngeal abscess in Neonate- misdiagnosed entity.J Pediatr Crit Care 2018;5(4):53-55. How to cite this URL: Gehlawat VK, Mittal K, Arya V. Retropharyngeal abscess in Neonate- misdiagnosed entity. J Pediatr Crit Care 2018;5(4):53-55. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504008.html


55


DOI-10.21304/2018.0504.00412

Case Report Triple “A” syndrome presenting as recurrent chronic sinusitis with Pneumonia, septic shock and meningoencephalitis in a child Ramaning Loni*, Priyanka Agrawal**, Prashant Rajebhosale***, Mrutyunjaya Panda****, Prashant Darveshi*****, Prakash Valse****** *Pediatric Intensivist & In charge Pediatric ICU, Dr. Bidari’s Ashwini Children Hospital, BLDEA’s Road, Vijayapura, Karnataka, India. **Senior Resident in Pediatrics, department of pediatrics, ***Pediatric Intensivist, ****Consultant Gastroenterologist, ***** Consultant in Pediatric surgery,******Gastrointestinal Surgeon, Aditya Birla Memorial Hospital,Chinchwad,Pune, India. Recived:22-Jun-17/Accepted:08-Aug-18/Published Online:30-Aug-18

ABSTRACT Triple A syndrome (All grove syndrome) is a rare autosomal recessive disorder characterized by the clinical triads of adrenal insufficiency, achalasia cardia and alacrimia with variable association of autonomic and neurological manifestations. Nearly100 cases have been reported all over world however in India, only 2 to 3 cases have reported. We present 13 years old boy with chronic recurrent sinusitis with failure to thrive without lacrimation since birth who had presented recurrent chronic sinusitis with pneumonia, septic shock, and acute meningoencephalitis with adrenal insufficiency. Catastrophic complications can be prevented with adequate cortisol and specific measures such as cardiac pneumatic dilatation or myotomy along with other supportive management. Key words: Triple “A” syndrome, child, Shock

months but acutely presented to us for fever for 2 days and altered sensorium with one episode of generalized tonic-clonic seizure for 1day. History of hyper nasal speech was present with no tears secretions by birth whenever he cries. He was wasted as well stunted. He was febrile with low sensorium, tachycardic with cold hypotensive septic shock with BP of 72/38 mmHg with mild respiratory distress. His investigations anemia with mild leukocytosis with high CRP levels (112 mg/dl). Chest X ray in figure 1 revealed right-sided pneumonia with parapneumonic effusion and X-ray PNS (Figure: 2) showed bilateral maxillary and frontal sinusitis. His CSF showed total cell count of 12 with lymphocytic predominance. Tuberculosis gene expert test of pleural fluid was negative. Immunological workup showed normal serum immunoglobulins levels and negative HIV antigen I and II. He was given appropriate treatment for 14 days and also underwent functional endoscopic sinus surgery (FESS) for his sinusitis and discharged home with reasonable recovery but got readmitted after 11 days with recurrent nonprojectile vomiting, multiple episodes in a day leading to hypovolemic shock with hypoglycemia in the emergency. His blood sugars by dextrostix were 38 mg, 62 mg and 87 mg at 0 hr, 1hr and 6hrs of 2nd admission respectively and he was

Introduction Triple “A” syndrome (All grove syndrome) is a rare autosomal recessive disorder characterized by the clinical triads of adrenal insufficiency, achalasia cardia, and alacrima. It was first described by Allgrove in 1978 (1) but in 1995, it was diagnosed as a syndrome with the variable association of autonomic and neurological manifestations. This disorder manifests in the early childhood with lifethreatening complications like severe hypoglycemia, shock, and recurrent infection. The syndrome usually presents during the first decade of life with dysphagia, while other signs may be delayed until adulthood. We present 13 years old boy with chronic recurrent sinusitis with failure to thrive without lacrimation since birth who has presented pneumonia, septic shock, and acute meningoencephalitis with adrenal insufficiency. Case report 13 years old boy had presented to us with recurrent vomiting and fever on/off for last 8 months with significant weight loss and failure to thrive for last 6 Correspondence: Dr.Ramaning Loni, MBBS, DCH, DNB (peds), IDPCCM, Dr.Bidari’s Ashwini Children Hospital, BLDEA’s Road, Vijayapura 586103, Karnataka, India. Phone: +919843685683, E-Mail : [email protected],


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Triple “A” syndrome presenting as recurrent chronic sinusitis

CASE REPORT

Figure 3 : Upper GI Endoscopy showing dilated more than lower half of esophagus Figure 1 : Chest X ray showing right sided lower lobar pneumonia and parapneumonic effusion

Figure 2 : X-ray PNS showing haziness in bilateral maxillary and frontal sinuses

Figure 4 : Upper GI series showing achalasia cardia

resuscitated for hypovolemic shock, hypoglycemia and stabilized. He underwent upper GI endoscopy (Figure 3) which showed narrowed LES with residual food. Upper GI series - Gastrograffin dye (Figure 4) showed prominent and dilated lower two-thirds esophagus with retained contrast with the very minimal flow of contrast in the stomach. His esophageal manometry showed LES pressure of 37 mmHg (high) with complete relaxation to wet swallows with the generalized failure of peristalsis: Achalasia type 2 and recurrent hypoglycemia workup showed lower serum cortisol level 4.55 nmol/l with normal fasting insulin and thyroid function test. He was started on IV hydrocortisone after endocrinologist’s opinion and continued till 4 days after surgery and later started on oral hydrocortisone supplementation as per Endocrinologist’s advice. He underwent laparoscopic cardiomyotomy with fundoplication on day 5thof readmission once child was stabilized after discussing pros and cons of both


ballondilatation and myotomy to the parents. His repeat Gastrograffin dye studies (upper GI series) showed resolution of achalasia cardia with the flow of dye into the stomach (Figure 5). His sugars normalized, tolerating oral diet well and his weight improved from 19 kg with BMI 14.4 to 27 kg with BMI 14.8 within 3 months on OPD follow up and his serum cortisol was within normal range with oral hydrocortisone 10mg in the morning and 5 mg in the evening. Discussion The description of Allgrove syndrome is limited to case reports/series and thus prevalence is unknown. Allgrove’s syndrome is considered a rare autosomal recessive disorder with variable presentations.1,2 Recent studies have identified a mutation in the AAA syndrome of a candidate gene on chromosome 12q13 in such patients.3,4 In our index case, the child has presented with dry eyes since birth with recurrent sinusitis, respiratory infections due to reflux regurgitation

57



CASE REPORT

to adrenal insufficiency. Adrenal insufficiency is also an early manifestation and manifests as severe hypoglycemic or hypotensive attacks during childhood which may lead to sudden death. So, the documentation of normal electrolytes indicated normal mineralocorticoid production although we have not measured plasma aldosterone levels. The only other cause of primary adrenal insufficiency with preservation of mineralocorticoid production is familial glucocorticoid deficiency. Although, most of the patients with Allgrove syndrome have preserved mineralocorticoid production, it may be impaired in 15% of patients.7 Dry eye with irritation was demonstrated by ophthalmological evaluation including Schirmer’s test. The child has undergone repeat upper GI studies(Gastrograffin study) after surgery which showed resolution of Achalasia and passage of dye into the stomach and small intestine. On follow up after 3 months, Child has gained weight and asymptomaticand having more than aevrage scholistic performance. Conclusion Allgrove’s syndrome is although a rare disorder. It’s catastrophic complications can be prevented with adequate cortisol and specific measures such as cardiac pneumatic dilatation or myotomy along with other supportive management. The prognosis for health and quality of life can be significantly improved by early diagnosis and treatment.

Figure 5 : upper GI series after surgery

leading to severe failure to thrive. Achalasia is most common presentation leading to failure to thrive, weight loss with recurrent sinopulmonary infections but alacrima was first to be noticed by parents in this case. Adrenal insufficiency and achalasia are usually manifested during the first decade of life. Achalasia of the cardia occurs in about 75% of cases so, in older children and adults it usually manifests as dysphagia especially for liquids. Symptoms of achalasia may appear in individuals as young as 5 months or as late as early adulthood.5 Based on clinical criteria, we have diagnosed the index case,however genetic work up is not done due to economic constraints with parental refusal. The child underwent esophagogastroduodenoscopy (EGD scopy), upper GI series, so as an assessment of esophageal motor function is essential in the diagnosis of achalasia. Barium esophagram and esophagogastroduodenoscopy (EGD) are complementary tests to manometry in the diagnosis and management of achalasia. However, neither EGD nor barium esophagram alone is sensitive enough to make the diagnosis of achalasia with certainty.6 The gold standard esophageal manometry which helped in the diagnosis of Achalasia cardia as LES pressure was 37 mmHg as resting pressure is required. In this case, the child had presented with hypoglycemic episodes with fluid refractory dopamine resistant shock due


Conflict of Interest : Nil Source of Funding : Nil References 1. Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978; 1:1284-6. 2. Grant DB, Barnes ND, Dumic M. Neurological and adrenal dysfunction in the adrenal insufficiency / alacrima / achalasia (3A) syndrome. Arch Dis Child 1993; 68:779–82. 3. Kinjo S, Takemoto M, Miyako K, Kohno H, Tanaka T, Katsumata N. Two cases of Allgrove syndrome with mutations in the AAAS gene. Endocr J 2004; 51:473-7. 4. Weber A, Wienker TF, Jung M, Easton D, Dean HJ, Heinrichs C, et al. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 1996; 5:2061-6. 5. Clark ALJ and Weber A. Adrenocorticotropin Insensitivity Syndromes. Endocr Rev 1998; 19 (6): 828-43.

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6. Howard PJ, Maher L, Pryde A et al. Five-year prospective study of the incidence, clinical features, and diagnosis of achalasia in Edinburgh. Gut 1992; 33: 1011 – 5.

7. Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, Milla PJ, von Petrykowski W, et al. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child 1993;68:779-82.

How to cite this article: Loni R, Agrawal P, Rajebhosale P,Panda M, Darveshi P, Valse P. Triple “A” syndrome presenting as recurrent chronic sinusitis with pneumonia, septic shock and meningoencephalitis in a child.J Pediatr Crit Care 2018;5(4):56-59. How to cite this URL: Loni R, Agrawal P, Rajebhosale P, Panda M, Darveshi P, Valse P. Triple “A” syndrome presenting as recurrent chronic sinusitis with pneumonia, septic shock and meningoencephalitis in a child.J Pediatr Crit Care 2018;5(4):56-59. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504009.html


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DOI-10.21304/2018.0504.00413

Clinical Update Oxygen Therapy Kundan Mittal*, Amit Jain**, Teena Bansal***, Prashant Kumar****, Anupama Mittal***** *Senior Professor, Incharge PICU & Respiratory Clinic, ***Associate Professor, Anaesthesia and Critical Care ****Professor, Anaesthesia and Critical Care, Pt. B D Sharma, PGIMS Rohtak,*****Deputy Civil Surgeon, Rohtak,Haryana,India. **Associate Professor, Pharmacology Guru Gobind Singh Medical College Faridkot,Haryana, India Received:28-Jul-18/ Accepted:06-Aug-18/Published Online:30-Aug-18

ABSTRACT Oxygen is life and falls in the category of essential drug. It is vital for cellular function. Oxygen therapy is the administration of oxygen in acute or chronic conditions above higher concentration than atmospheric air to prevent hypoxemia. The delivery of oxygen depends on various factors. Oxygen is full of advantage but injudicious use or hyperxaemia (FiO2>0.5) may be harmful to human body. Care should be taken while prescribing the oxygen. Hypoxemia should be avoided as such to prevent mortality. Key words: Oxygen, devices, FiO2, flow

Oxygen is colourless, odourless, and tasteless gasconstitutes approximately 20.94% of atmospheric air and transferred from environment to mitochondria from higher pressure of 21.2,19.9,13.4k Pa(concentration) to lower pressure of1.5kPa (concentration) of oxygen. The difference between PAO2 of 104 mmHg and PVO2 of 64 mmHg cause oxygen to diffuse in to pulmonary blood. Diffusion of oxygen into the cell is limited by the distance between the cell itself and the source of oxygen. A highly complex capillary network (microcirculation) exists to distribute the oxygen to cells and tissues. During exercise oxygen requirement increases 20 times from normal still no deficiency occurs because oxygen diffusion capacity increases four-fold. Also, blood remains three times as long as blood to cause full oxygenation, thus even during shortened time blood can be fully oxygenated. Normally 5mL of oxygen is transported to tissue by 100mL of blood and during exercise 15mL of oxygen is transported by 100mL of blood. Oxygen therapy is the administration of supplementary oxygen to achieve a higher inspiration of oxygen than is achieved when breathing room air. No oxygen no life. Oxygen should be used cautiously and judiciously. Hundred percent oxygen therapy is full of danger. Nitrogen in air stabilizes the alveoli. Oxygen should be prescribed safely like drug i.e. flow

L/min, device to be used, percentage of oxygen, high or low flow. Hypoxaemia is reduced oxygen concentration in arterial blood and hypoxia is oxygen deficiency in tissues. Any patient irrespective of age who is acutely illshould receive 100% oxygen. Various alternative methods to increase oxygen delivery are; protection of airway, maintain adequate cardiac output and tissue perfusion, correction of anemia, and avoiding respiratory depressants.1-3 Clinical indicators of oxygen deficiency a. Anxious look b. Increased work of breathing c. Perspiration d. Hyperventilation e. Decreased oxygen saturation f. Tachycardia g. Arrhythmias h. Altered level of consciousness i. Peripheral vasodilatation j. Hypotonia (decrease muscle tone) k. Cyanosis l. Hypotension m. Polycythaemia n. Coma

Correspondence: Dr. Kundan Mittal, Senior Professor Pediatrics, Pt B D Sharma, PGIMS, Rohtak Haryana, India, Phone-+919416514111, [email protected]


Etiology of Hypoxia a. Decrease in oxygen content (decrease

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Oxygen Therapy

CLINICAL UPDATE

Types of Oxygen Delivery Source • Oxygen Concentrators: These are primarily used at home and in primary health care settings. These devices use room air for oxygen using molecular sieve. They can deliver oxygen from 0.5L to 10L/ min depending on type of concentrator. Increasing flow rate will decrease oxygen concentration. Most of them need electricity for their operation. • Compressed gas cylinders: Portable compressed gas cylinders in different sizes are commonly used in hospitals and home. Usually available in two sizes i.e. 3.2kg and 2.1kg and last approximately 3.5 and 2.5hours at 2L/min. Duration can be increased if cylinder is made to deliver oxygen during inspiration only. There is increased risk of fire due to pasteurization. Devices are available which releases oxygen during inspiration only. • Central gas supply:Compressed or liquid gas is used in larger hospitals (at a pressure of 4bar, 400kPa) attached with flow meter, which is capable of delivering oxygen at 15L/min. • Liquid oxygen (LOX: vacuum insulated evaporator): Oxygen can be stored in liquid form at a temperature of -183C and can be in gas form at a temperature of -118.6C and above. The refill unit last longer compared to compressed cylinder. If not used the cylinder will evaporate in 2days time. • Hyperbaric oxygen (HBO): Oxygen constitute approximately 21% of air and air has atmospheric pressure of 760mmHg while oxygen (760 x 21/100) contributes 160mmHg. The concentration of gas in liquid is not only determined by pressure but also by solubility coefficient which is different for all gases and also varies for different fluids. Solubility coefficients of the important respiratory gases at body temperature are as follows: Oxygen: 0.024 mL O2/mL blood atm.PO2, CO2: 0.5 mLplasma/atm. PCO2, and Nitrogen: 0.067 mL/mL plasma/atm.PN2. HBO involves oxygen under pressure greater than found on earth surface at sea level.

haemoglobin level, SaO2, PaO2) b. Abnormal affinity of oxygen to haemoglobin (abnormal haemoglobin) c. Decreased cardiac output d. Inability of lung to oxygenate (gas exchange) e. Hypoventilation f. Low pressure (high altitude) g. Ventilation-Perfusion mismatch h. Intrapulmonary or cardiac shunts i. Local tissue oedema or ischaemia Assessing inadequacy of oxygen delivery: Oxygen delivery: Cardiac output (Hb x 1.34 x SaO2) + (PaO2 x 0.003) Various factors contribute in oxygen delivery to the tissues but we only measure PaO2. Inspite of normal PaO2child may be having less oxygen delivery to tissues. Types of hypoxemia: Acute: Rapid onset (90 days Generational: Cross-generational Hyperoxia: PaO2 ≥120-150mmHg Assessment of oxygenation using various variables • PaO2/FiO2 • SpO2/FiO2 • PAO2- PaO2 • PaO2/ PAO2 • Oxygen Index = MAP x FiO2/PaO2 Assessment of tissue oxygenation • CaO2 (arterial) = (Hb x 1.34 x SaO2) + (PaO2 x 0.003) • CvO2(venous) = (Hb x 1.34 x SvO2) + (PvO2 x 0.003) • Oxygen consumption = CO x (CaO2 – CvO2) x 10 • Oxygen Extraction Ratio = Oxygen consumption/ Oxygen delivery


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Calculation of life of cylinder in minutes

Expiratory time: 1.0sec Flow: 2000/60 = 33.4mL/second Filling time: 1/4th of expiratory time = 0.25sec Inspiratory time x flow/sec: 0.5 x 33.4 = 16.7mL Anatomical reservoir: 0.25x33.4 = 8.4mL Actual is 6.6mL Room air volume: TV – Anatomical reservoir = 60-16.7+6.6 = 36.7mL • Oxygen concentration of room air volume: 36.7 x 0.21 = • 16.7 + 6.6 + 7.7 = 31 • FiO2: 31/60 = 52% Heliox is a mixture of helium and oxygen. Because helium is lessdense than oxygen, it is used to carry oxygen past airway oobstruction. Because heliox is less dense than pure oxygen hence it has a faster flow. Multiply flow reading by A factor of 1.8 (if ratio is 80:20) and 1.6 (if it is 70:30) to get actualflow Normal body humidity is expressed as 44 mg/L or 47 mmHg. This means that at 98.6 F (37 C) gas is saturated with 47 mmHg or 44 mg/L of water vapor. Flow depends on minute ventilation and I:E ratio Flow = MV x (I+E) • • • • • • •

PSI (Cylinder) - Safe residual (200PSI) = ------------------------------------------------ x Cylinder Factor Flow rate in litre/minute Type of cylinder Capacity (appox.)

Bottle factor

Life of cylinder at flow rate 8L/min

D (steel)

350L

0.16

45

D (Alumunium)

414L

0.16

52

E

625L

0.28

78

G

5260L

2.41

660

M

3028L

1.56

378

H&K

6900L

3.14

864

Calculation of requirement of oxygen during transport Duration of journey in minutes x Flow in litre/minute No. Of = --------------------------------------------------------------cylinders Cylinder capacity Note: Always keep double the requirement.

Factors affecting amount of FiO2 delivered • Flow/min • Device: High or low flow, fixed or variable flow • Respiratory rate, depth of respiration, and pattern Example: TV 500mL, RR 20/min, I:E 1:2 (inspiratory time 1sec and expiratory time 2sec), Flow of oxygen 6L/min (100mL/sec) Dead Space 150mL (usually 1/3rd of TV: 2mL/kg), nasopharyngeal space is 1/3rd of dead space i.e. 50mL Usually no expiatory flow during last 1/4th time of expiratory time The filling of reservoir occurs during initial 1/4th of expiration time

A FiO2 Subtract 100-FiO2

20 or 21

B Note: FiO2 is ≥0.40 use 20 and 6L/min can cause nasal irritation and dryness. Flow is kept 35% should be humidified. Humidified oxygen delivered through venturi can decrease FiO2 since it will block the holes. Water should be sterile and changed after 24hour. Bottle can be changed as per manufacture instruction. OXYGEN DELIVERY DEVICES Oxygen delivery devices can be classified in to two categories: 1. Low flow devices:Variable performance (deliver variable fraction of oxygen concentration (FiO2) e.g. nasal canula, mustache and pendant reservoir canula, pulse-demand oxygen system, simple face mask, rebreathing mask (partial and nonrebreathing), trans-tracheal catheter 2. High flow devices: Air entrainment mask, oxygen hood, incubator, oxygen tents, oxygen blenders, ventilator a. Fixed performance devices b. Variable performance devices Points to remember: a. High and low flow rate is defined in relation to patient inspiratory flow rate. b. Low flow does not mean delivery of low FiO2. c. Dead space in children 1mL/Pound Low Flow devices: These devices deliver oxygen at flow rate less than the patient inspiratory flow rate/ demands. The FiO2 depends upon patient’s tidal volume, Inspiratory flow, minute volume, delivered oxygen flow, ventilatory pattern and size of oxygen reservoir. Low flow devices are useful in spontaneously breathing patients with fairly stable vitals.


Application of nasal cannula

2.

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Nasopharyngeal Catheters: a. Available in various sizes for bothchildren and adults (12-14F). b. Select size by comparing the external nostrils. c. Made of soft plastic having blind end with multiple holes on side near tip. d. Measure length from nostril to tragus of ear for nasal catheter.


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6. Partial rebreathing masks (NRM):

e. Put the catheter from external nostril to just behind the uvula. f. Fix the catheter with tape. g. Nasal cavity acts as reservoir. h. Risk of blockade of catheter is high. i. Delivers variable FiO2. j. Give humidified oxygen if flow rate is more than 2L/min and flow should not exceed >6L/ min. k. Useful in less severe cases.

and

Nonrebreathing

a. These are simple, transparent, disposable oxygen masks with reservoir. Nonrebreathing mask have two types of one-way valve (one present between reservoir bag and mask and second at exhalation port) so that higher FiO2 can be delivered. They are effective in spontaneously breathing patient for short period. b. Available in pediatric and adult size.

3. Simple oxygen masks: a. Simple, transparent, light weight mask and covers both mouth and nose. b. Easily to apply and available for both pediatric and adult population. c. Minimum flow rate to be kept is 4-6L/min. d. Delivers variable FiO2. e. Useful only in spontaneously breathing patients with respiratory distress.

c. Indicated in all types of seriously ill patients who are spontaneously breathing and require high concentration of oxygen. d. Keep the reservoir bag full i.e. flow of gas must be 6-8L/min to avoid rebreathing of carbon dioxide. Flow should be adequate to maintain the reservoir bag at least one-third to one-half full on inspiration. e. Application is similar to simple face mask. f.

Partial rebreathing mask delivers FiO2 0.4-0.6 at flow of 6-8L/min depending on ventilatory pattern

Simple face mask

4. Blow by oxygen: Children who can not tolerate device may be given oxygen by tubing or simple face mask (FiO20.3-0.4 at 10L/min) for short term use. 5. Pocket mask or resuscitation mask Pocket mask is available in paediatric and adult size and used to deliver rescue or manual breath during resuscitation.


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High flow oxygen delivery devices 1. Oxygen hood or head box: 1. Primarily used in children below one year of age or 4mmol/L) and also reflects metabolic adaptive response.

Q. What is albumin gap? Normal AG also depends on phosphate and albumin AG = 0.2 x Albumin(gm/L)+ 1.5 (phosphate) Albumin gap = 40-Albumin level/4 AG + Albumin gap= Actual anion gap ({4.4 - [observed serum albumin (g/dL)] × 0.25} + AG) - [serum lactate (mmol/L)] ([Na] + [K] - [Cl] - [HCO3]) -(2 x albumin g/dL + 0.5 x phosphate mg/dL) - [lactate mmol/L]] Q. Name few causes of high anion gap. Ans. GOLD MARK: Methanol, ethanol, lactate, cyanide, aspirin, ethylene glycol, ketones, oxyproline

Q. What is the etiology of increased lactate level in present case? Ans. Possible causes are extensive traumatic injury, hypoperfusion, renal injury, hypoperfusion, hypoxia, liver injury, linezolid.

Q. Treatment advised on the basis of ABG report Ans. Maintain tissue perfusion and manage acute kidney injury Q. Do you need to infuse sodium bicarbonate? Ans. No. There are limited indications to use sodium bicarbonate in intensive care settings.

Q What are the risk factors of acute kidney injury in present case? Ans. In present case acute renal injury may be as a result of direct trauma to kidney tissue, hypoperfusion and high CPK level. Child is on ventilator and high PEEP and sepsis may also contribute to renal injury. CPK elevations are frequently classified as mild, moderate, or severe [Mild less than 10 times the upper limit of normal (or 2,000 IU/L), Moderate 10 to 50 times the upper limit of normal (or 2,000 IU/L to 10,000 IU/L), and Severe greater than 50 times the upper limit of normal]. High level may be associated with acute kidney injury. Conflict of Interest : Nil Source of Funding : Nil

Q. What are the reasons for his conditions? Ans. Trauma, hypoperfusion, hypoxia, renal injury, liver injury, muscle trauma, inappropriate fluid therapy and possibly raised CPK level. Q. Tell us something about hyperlactatemia. Ans. Increased lactate level (normal lactate level 0.5-1.5 mmmol/L and half-life 10min; production exceeds consumption may be as result of hypoperfusion and microcirculatory dysfunction, hypoxia (global or localised), renal injury, associated gut injury, aerobic glycolysis, extensive trauma, severe sepsis, propofol, antiretroviral agents, acute

How to cite this article: Mittal K, Kumar P, Mishra R, Patki V. Postgraduate /Fellow Column-OSCE:Data Interpretation. J Pediatr Crit Care 2018;5(4):7982. How to cite this URL: Mittal K, Kumar P, Mishra R, Patki V. Postgraduate /Fellow Column-OSCE: Data Interpretation. J Pediatr Crit Care 2018;5(4):7982.. Available from: http://jpcc.in/userfiles/2018/0504-jpcc-jul-aug-2018/JPCC0504012.html


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DOI-10.21304/2018.0504.00416

Best Evidence Journal Scan - Sepsis Vinayak Patki*, Kundan Mittal**, H K Aggarwal***, Manish Munjal****, S Manazir Ali***** *Chief, Advanced Pediatric Critical Care Centre, Wanless Hospital, Miraj, Maharashtra, India. ** Senior Professor Pediatrics, ***Senior Professor, Department of Medicine and Nephrology, Pt B D Sharma, PGIMS, Rohtak, Haryana, India. ****Intensivist, Jaipur, Rajasthan, India, *****Professor, Dept. of Pediatric JLN Medical College, AMU, Aligarh, Uttar pradesh, India Received: 08-Aug-18/Accepted: 18-Aug-18/Published online: 30-Aug-18

1. Surviving Sepsis Campaign : Research Priorities for Sepsis and Septic Shock Craig M. Coopersmith, Daniel De Backer, Clifford S. Deutschman, Ricard Ferrer, Ishaq Lat, Flavia R. Machado, Greg S. Martin, Ignacio Martin-Loeches, Mark E. Nunnally, Massimo Antonelli, Laura E. Evans, Judith Hellman, JozefKesecioglu, Mitchell M. Levy, Andrew Rhodes. (Crit Care Med 2018; 46:1334–1356) DOI: 10.1097/ CCM.0000000000003225 Objective: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. Design: A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. Methods: Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (Supplemental Table 1, Supplemental Digital Content 2, http://links.lww. com/CCM/D636) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups : infection, fluids and vasoactive agents, adjunctive therapy, administration/ epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority

followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. Results: The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: 1) can targeted/ personalized / precision medicine approaches determine which therapies will work for which patients at which times?; 2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; 3) should rapid diagnostic tests be implemented in clinical practice?; 4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; 5) what are the predictors of sepsis long-term morbidity and mortality?; and 6) what information identifies organ dysfunction? Conclusions: While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock. Reviewer’s Comments: Sepsis is leading cause of morbidity and mortality globally although outcome has improved. It poses major economic burden to any country. Lot of research have been made in various areas of management of sepsis but still we are fighting for the best. No specific treatment is available till today. We all agree that prevention is better than cure but still we need lot of efforts to overcome the problems arising out due to sepsis. The committee focused on various issues and put forward certain research questions and priorities

Correspondence: Dr. Vinayak Patki, MB,DNB,FCCP,FIAP. Chief, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, 416410, Maharashtra, India. Phone: +919822119314, E-Mail- [email protected]


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in sepsis discussing what is already known and what can be done in future. Following areas need further research for better outcome. A. Infections a. Should empiric antibiotic combination therapy be used in sepsis or septic shock? b. Does optimization of antimicrobial pharmacokinetics and pharmacodynamics impact patient outcomes in sepsis? c. Should antiviral therapy be administered in the context of viral reactivation in patients with acquired immunosuppression? d. Should rapid diagnostic tests be implemented in clinical practice? B. Fluids and Vasopressors a. What are ideal endpoints for volume resuscitation and b. how should volume resuscitation be titrated? c. What is the optimal fluid for sepsis resuscitation? d. What is the optimal approach to selection, dose titration, e. and escalation of vasopressor therapy? C. Adjunctive Therapy a. Can targeted / personalized / precision medicine approaches determine which therapies will work for which patients at which times? b. Determine the efficacy of “blood purification” therapies such as endotoxin absorbers, cytokine absorbers and plasmapheresis. c. What is the ideal method of delivering nutrition support, including route, timing and composition of nutrition support, and whether this varies by hemodynamic status? d. What is the role of lung protective ventilation in septic patients without acute respiratory distress syndrome (ARDS)? D. Scoring/Identification a. What information identifies organ dysfunction? b. How can we screen for sepsis in varied settings? Vol. 5 - No.4 Jul-Aug 2018

c. How do we identify septic shock? d. What in-hospital clinical information is associated with important outcomes in septic patients? E. Administration/Epidemiology a. Which is the optimal model of delivering sepsis care? b. Which is the epidemiology of sepsis susceptibility and response to treatment? c. It is possible to stratify the risk of sepsis based on biomarker panels? F. Post-ICU a. What is the attributable long-term morbidity and mortality from sepsis? b. What are the predictors of sepsis long-term morbidity and mortality? c. Are there potential in-hospital interventions that can impact long term outcomes? d. Are there potential post-discharge interventions that can improve outcomes? G. Basic / Translational Science a. What mechanisms underlie sepsis-induced cellular and sub-cellular dysfunction? b. How does sepsis alter bio-energetics and/or metabolism (both enhancement and failure)? c. How does sepsis (and/or approaches used to manage sepsis) alter phenotypes and interactions in the host microbiome and do alterations in the microbiome effect outcomes? d. What mechanisms initiate, sustain and terminate recovery? Sepsis handling needs more solutions from causation, to early identification, diagnosis, management and prevention. Further sepsis is also associated with coagulopathy and endocrinopathy and need more research. Genetics plays key role in sepsis at different stage and needs further evaluation. Diagnostic criteria of sepsis are still not clear and this delays the early diagnosis of sepsis. We are still looking for perfect definition and marker of sepsis although more than 170 markers are available. Response to treatment assessment criteria are still qualitative to large extent

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and also some patient dies with same kind of spectrum of disease (host response) while others do not. Role of micronutrients and newer agents need more studies in sepsis management. 2. Platelet Transfusion Practices in Critically Ill Children Marianne E. Nellis, Oliver Karam, Elizabeth Mauer, Melissa M. Cushing,Peter J. Davis, Marie E. Steiner, Marisa Tucci, Simon J. Stanworth, DPhilPhilip C. Spinella. Crit Care Med. 2018 Aug;46(8):1309-1317. doi: 10.1097/CCM.0000000000003192 Objectives: Little is known about platelet transfusions in pediatric critical illness. We sought to describe the epidemiology, indications, and outcomes of platelet transfusions among critically ill children. Design: Prospective cohort study. Setting: Multicentre (82 PICUs), international (16 countries) from September 2016 to April 2017. Patients: Children ages 3 days to 16 years prescribed a platelet transfusion in the ICU during screening days. Interventions: None. Measurements and Main Results: Over 6 weeks, 16,934 patients were eligible, and 559 received at least one platelet transfusion (prevalence, 3.3%). The indications for transfusion included prophylaxis (67%), minor bleeding (21%), and major bleeding (12%). Thirty-four percent of prophylactic platelet transfusions were prescribed when the platelet count was greater than or equal to 50 × 109 cells/L. The median (interquartile range) change in platelet count post transfusion was 48 × 109 cells/L (17–82 × 109 cells/L) for major bleeding, 42 × 109 cells/L (16–80 × 109 cells/L) for prophylactic transfusions to meet a defined threshold, 38 × 109 cells/L (17–72 × 109 cells/L) for minor bleeding, and 25 × 109 cells/L (10–47 × 109 cells/L) for prophylaxis in patients at risk of bleeding from a device. Overall ICU mortality was 25% but varied from 18% to 35% based on indication for transfusion. Upon adjusted analysis, total administered platelet dose was independently associated with increased ICU mortality (odds ratio for each additional 1 mL/kg platelets transfused,


1.002; 95% CI, 1.001–1.003; p = 0.005). Conclusions: Most platelet transfusions are given as prophylaxis to non bleeding children, and significant variation in platelet thresholds exists. Studies are needed to clarify appropriate indications, with focus on prophylactic transfusions Reviewer’s comments : Evidence based guidelines are still missing regarding platelet transfusion in critically ill pediatric patients. According to present analysis in majority of children platelets were transfused prophylactically (67%) and data is still lacking when to transfuse in bleeding child. Most of them had platelet count 40x 109 cells/L. Platelets were mainly collected by apheresis (87%) and were leukoreduced (93%). In another study by Batool Alsheikh, Madhuradhar Chegondi, and Balagangadhar Totapally (2017) main indications for transfusion were haematological conditions and threshold was 29x109/L. There is insufficient evidence for platelet transfusion in specific conditions in pediatric population. For diagnostic purpose transfusion threshold may be higher in critically ill children. Even it traumatic coagulopathy use of massive transfusion protocol incorporating 1:1:1 ratio among RBCs, plasma, and single donor platelets is suggested. Tai-Tsung Chang in pediatar Neonatal 2008 published the guidelines for platelet transfusion in normal and diseased states and are helpful for reference. Further studies have shown that monitoring mean platelet volume is better than platelet count in intensive care in children. Although there is no validated tool for assessment in bleeding in children still the results in present study though descriptive in nature but still provide important preliminary data which identifies at risk population and facilitate for future study. 3. The Epidemiology of Hospital Death Following Pediatric Severe Sepsis: When, Why, and HowChildren With Sepsis Die ? Scott L. Weiss, Fran Balamuth, Josey Hensley, Julie C. Fitzgerald, Jenny Bush, Vinay M. Nadkarni, Neal J. Thomas, Mark Hall, Jennifer Muszynski Pediatr Crit Care Med 2017; 18:823–830. DOI: 10.1097/PCC.0000000000001222 Objective: The epidemiology of in-hospital death after pediatric sepsis has not been well characterized. They

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investigated the timing, cause, mode, and attribution of death in children with severesepsis, hypothesizing that refractory shock leading to early death is rare in the current era. Design: Retrospective observational study. Setting: Emergency departments and ICUs at two academic children’shospitals. Patients: Seventy-nine patients less than 18 years old treated for severe sepsis/septic shock in 2012–2013 who died prior to hospitaldischarge. Interventions: None. Measurements and Main Results: Time to death from sepsis recognition, cause and mode of death, and attribution of death to sepsis were determined from medical records. Organ dysfunction was assessedvia daily Pediatric Logistic Organ Dysfunction-2 scores for 7 days preceding death with an increase greater than or equal to 5 defined as worsening organ dysfunction. The median time to death was 8 days(interquartile range, 1–12 d) with 25%, 35%, and 49% of cumulative deaths within 1, 3, and 7 days of sepsis recognition, respectively. The most common cause of death was refractory shock (34%), then multipleorgan dysfunction syndrome after shock recovery (27%), neurologic injury (19%), single-organ respiratory failure (9%), and non-septic comorbidity (6%). Early deaths (≤ 3 d) were mostly due to refractory shock in young, previously healthy patients while multiple organ dysfunction syndrome predominated after 3 days. Mode of death was withdrawal in 72%, unsuccessful cardiopulmonary resuscitation in 22%, and irreversible loss of neurologic function in 6%. Ninety percent of deaths were attributable to acute or chronic manifestations of sepsis. Only 23% had a rise in Pediatric Logistic Organ Dysfunction-2 that indicated worsening organ dysfunction. Conclusions: Refractory shock remains a common cause of death inpediatric sepsis, especially for early deaths. Later deaths were mostly attributable to multiple organ dysfunction syndrome, neurologic and respiratory failure after life-sustaining therapies were limited. A pattern of persistent, rather than worsening, organ dysfunction preceded most deaths. Reviewer’s comments : Refractory shock was the most common cause of


death overall, though this cause was concentratedin early deaths while MODS, respiratory failure, and neurologic injury predominated after 3 days. Most deaths were attributed to sepsis, either to the primary infection or to an ensuing state of chronic critical illness after some clinical improvement. Patients more commonly exhibited a pattern of persistent, rather than worsening, organ dysfunction prior to death. Even after broad implementation of pediatric septic shock guidelines. It was very much surprising to find a high proportion of early deaths, with one quarter of deaths within 1 day and nearly half within 7 days of severe sepsis recognition. This data, therefore, support that timing of death following pediatric sepsis mirrors contemporary trends in overall PICU mortality. Most patients in this study died following withdrawal / withholding of lifesustaining therapies, particularly for deaths greater than 3 days from sepsis recognition. Major limitations of study were, data reflect the practices of only two sites, only one in five patients had available autopsy results and lack of information about end-of life decision-making, including the factors that led family and caregivers to limit life-sustaining therapies, nor were we able to differentiate between absence of organ dysfunction versus withdrawal/ withholding as the indication to not use in vasive mechanical ventilation, renal replacement therapy, or ECMO prior to death. Future research priorities in pediatric sepsis should include determining risk factors for early death and consider that life-saving interventions may need to be differentially targeted based on timing and cause of death. 4. Validation of the Vasoactive-Inotropic Score in Pediatric Sepsis Amanda M. McIntosh, SuhongTong, Sara J. Deakyne, Jesse A. Davidson, Halden F. Scott. Pediatr Crit Care Med ; 18:750–757 DOI: 10.1097/PCC.0000000000001191 Objectives : To assess the validity of VasoactiveInotropic Score (VIS) as a scoring system for cardiovascular support and surrogate outcome in pediatric sepsis. Design: Secondary retrospective analysis of a singlecenter sepsis registry.

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Setting: Free standing children’s hospital and tertiary referral center. Patients: Children greater than 60 days and less than 18 years with sepsis identified in the emergency department between January 2012 and June 2015 treated with at least one vasoactive medication within 48 hours of admission to the PICU. Interventions: None. Measurements and Main Results: VasoactiveInotropic Scorewas abstracted at 6, 12, 24, and 48 hours post ICU admission. Primary outcomes were ventilator days and ICU length of stay. The secondary outcome was a composite outcome of cardiac arrest / extracorporeal membrane oxygenation/ in-hospital mortality. One hundred thirty-eight patients met inclusion criteria. Most common infectious sources were pneumonia (32%) and bacteremia (23%). Thirty-three percent were intubated and mortality was 6%. Of the time points assessed, VasoactiveInotropic Score at 48 hours showed the strongest correlation with ICU length of stay (r = 0.53; p < 0.0001) and ventilator days (r = 0.52; p < 0.0001). On multivariable analysis, Vasoactive-Inotropic Score at 48 hours was a strong independent predictor of primary outcomes and intubation. For every unit increase in Vasoactive-Inotropic Score at 48 hours, there was a 13% increase in ICU length of stay (p < 0.001) and 8% increase inventilator days (p < 0.01). For every unit increase in Vasoactive-Inotropic Score at 12 hours, there was a 14% increase in odds of having the composite outcome (p < 0.01). Conclusions: Vasoactive-Inotropic Score in pediatric sepsis patients is independently associated with important clinically relevant outcomes including ICU length of stay, ventilator days, and cardiac arrest/ extra corporeal membrane oxygenation/mortality. Vasoactive-Inotropic Score may be a useful surrogate outcome inpediatric sepsis. Reviewer’s comments : VIS has been validated in pediatric cardiac surgery, and has been used in previous studies of pediatric patients with severe sepsis to describe the severity of illness and as a measure of hemodynamic support.Importantly, the association of VIS at 48 hours with these outcomes was independent of the


validated PIM3 score. Consistent with this concept, this study shows that persistent rather than early or maximal need for vasoactive and in otropic support in the first 48 hours is most strongly associated with duration of critical care support. Patients with a high VISat 48 hours demonstrate ongoing cardiovascular dysfunction and are inherently at highest risk of a poor outcome. This study shows that VIS is a reliable marker of cardiovascular support that is independently associated with important outcomes in pediatric sepsis and may complement existing acuity scores as an early prognostic indicator of the duration of critical care support in this population. There are limitations to this study, data was collected retrospectively, single centred study and it is possible that VIS values measured at discrete time points after ICU arrival in this study were affected by variations in the timing of a patient’s presentation to the ED and subsequent ICU admission. Also study was unable to assess the association of VIS with longer term mortality after hospitalization or functional outcomes. 5. Applying Artificial Intelligence to Identify Physiomarkers Predicting Severe Sepsis in the PICU Rishikesan Kamaleswaran, Oguz Akbilgic, Madhura A. Hallman, Alina N. West, Robert L. Davis, Samir H. Shah Pediatr Crit Care Med 2018; XX:00–009( Ahead of Print) DOI: 10.1097/PCC.0000000000001666 Objectives:They used artificial intelligence to develop a novel algorithmusing physiomarkers to predict the onset of severe sepsis (SS) incritically ill children. Design: Observational cohort study. Setting: PICU. Patients: Children age between 6 and 18 years old. Interventions: None. Measurements and Main Results: Continuous minute-by-minute physiologic data were available for a total of 493 critically ill children admitted to a tertiary care PICU over an 8-month period, 20 of whom developed severe sepsis. Using an alert time stamp generated by an electronic screening algorithm

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as a reference point. They studied up to 24 prior hours of continuous physiologic data.They identified physiomarkers, including sd of heart rate, systolic and diastolic blood pressure, and symbolic transitions probabilities of those variables that discriminated severe sepsis patient from controls (all other patients admitted to the PICU who did not meet severe sepsis criteria). They used logistic regression, random forests, and deep Convolutional Neural Network methods to derive models. Analysis was performed using data generated in two windows prior to the firing of the electronic screening algorithm, namely, 2–8 and 8–24 hours. When analyzing the physiomarkers present in the 2–8 hours analysis window, logistic regression performed with specificity of 87.4% and sensitivity of 55.0%, random forest performed with 79.6% specificity and 80.0% sensitivity, and the Convolutional Neural Network performed with 83.0% specificity and 75.0% sensitivity. When analyzing physiomarkers from the 8–24 hours window, logistic regression resulted in 77.1% specificity and 39.3% sensitivity, random forest performed with 82.3%specificity and 61.1% sensitivity, whereas the Convolutional Neural Network method achieved 81% specificity and 76% sensitivity. Conclusions: Artificial intelligence can be used to predict the onset of severe sepsis using physiomarkers in critically ill children. Further, it may detect severe sepsis as early as 8 hours prior toa realtime electronic severe sepsis screening algorithm. Reviewer’s comments : Using variables refined by iterative, virtual processes, author steam had previously designed a pediatric SS screening algorithm and tested it retrospectively on clinically validated gold standard cases. After implementing further modifications to the algorithm, including the application of appropriate filters, authors applied the electronic SS screening algorithm integrated within our electronic health record (EHR) in real time among hospitalized children between 6 and 18 years old. Our study found distinct quantifiable physiomarkers, such as sd of DBP, sd of HR, and PCA-PSPR of SBP and DBP, that uniquely identify critically ill children with SS well before they develop clinically recognizable characteristics. They further determined that this methods can also


predict SS in patientsup to 8 hours earlier than a currently implemented electronic SS surveillance algorithm. Their findings indicate a significant opportunity for bedside monitors to be integrated with artificial intelligence to enhance real-time monitoring of SS without reliance on asynchronous data entry within the EHR. Limitations to there results were limited sample size, they did not include children under the age of 6, due to the significant complexity in physiologic heterogeneity that exists withinthis age group. 6. Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis Bram Rochwerg, Simon J. Oczkowski, Reed A. C. Siemieniuk, Thomas Agoritsas, Emilie Belley-Cote, Frédérick D’Aragon, et al. Crit Care Med 2018; DOI: 10.1097/CCM.0000000000003262 Objective: This systematic review and meta-analysis addressesthe efficacy and safety of corticosteroids in critically ill patientswith sepsis. Data Sources: We updated a comprehensive search of MEDLINE, EMBASE, CENTRAL and LILACS, and unpublished sources for randomizedcontrolled trials that compared any corticosteroid to placeboor no corticosteroid in critically ill children and adults with sepsis. Study Selection: Reviewers conducted duplicate screening of citations, data abstraction and using a modified Cochrane risk of bias tool, individual study risk of bias assessment. Data Extraction: A parallel guideline committee provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. They assessed overall certainty in evidence using Grading of Recommendations Assessment, Development and Evaluation methodology and performed all analyses using random-effect models. For subgroup analyses, we performed metaregression and considered p valueless than 0.05 as significant. Data Synthesis: Forty-two randomized controlled trials including10, 194 patients proved eligible. Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying

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7. Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock. LisianePruinelli, Bonnie L. Westra,Pranjul Yadav, Alexander Hoff , Michael Steinbach, Vipin Kumar, Connie W. Delaney, Gyorgy Simon. Crit Care Med 2018; 46:500–505 DOI: 10.1097/CCM.0000000000002949 Objectives: To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality. Design: Retrospective cohort study. Setting: One health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015. Patients: All adult patients hospitalized with billing diagnosis of severe sepsis or septic shock. Interventions: Four 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystal loid fluid for hypotension (definedas “mean arterial pressure” < 65) or lactate (> 4). Measurements and Main Results: To determine the effect of t-minutes of delay in carrying out each intervention, propensityscore matching of “baseline” characteristics compensated for differences in health status. The average treatment effect inthe treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) hadinhospital mortality. Most patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes.

in the short-term (28–31 d) (relative risk, 0.93;95% CI, 0.84–1.03; 1.8% absolute risk reduction; 95% CI, 4.1%reduction to 0.8% increase), and possibly achieve a small effect onlong-term mortality (60 d to 1 yr) based on moderate certainty (relativerisk, 0.94; 95% CI, 0.89–1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Corticosteroids probably result in small reductions in length of stay in ICU (mean difference,–0.73 d; 95% CI, –1.78 to 0.31) and hospital (mean difference,–0.73 d; 95% CI, –2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, 1.12–1.42) and lower Sequential Organ Failure Assessment scores at day 7 (mean difference, –1.39; 95% CI,–1.88 to –0.89) (high certainty). Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32– 2.03) and hyperglycemia (relative risk, 1.16; 95% CI, 1.08–1.24) (moderatecertainty), may increase the risk of neuromuscular weakness (relativerisk, 1.21; 95% CI, 1.01–1.52) (low certainty), and appear to have no other adverse effects (low or very low certainty). Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest (p > 0.05 for all). Conclusions: In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness. Reviewer’s comments : This systematic review demonstrates that the use of corticosteroids in sepsis may result in a small absolute reduction inmortality of approximately 2%. Strengths of this review include a comprehensive literature search including unpublished sources, a published protocol. Limitations include significant clinical heterogeneity over studies conducted over a period of 60 years. All included studies enrolled patients based on previous sepsis diagnostic criteria. Based on the results of this review, their best estimates suggest a small absolute reduction in mortality with corticosteroids in sepsis based on low-to-moderate certainty evidence.


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showed that no delay is safe, although modest delays may not be harmful in a clinically meaningful way. There are several strengths in this study. The adopted methodology of sequential PSM in conjunction with bootstraps is novel and necessary to minimize the confounding that occursin observational studies. They were able to incorporate several covariates in their model, making the matched pairs very alike. Limitations exist in this study, includes that their data set only provided in-hospital mortality, and were not able to consider mortality that occurred outside the hospital or long-term outcomes. Based on these findings, future studies should also investigate the impact on long-term outcomes, including national or international dataset of clinical data.

Conclusions: The guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence forclinical practice and research. Reviewer’s comments : The effect of “delay” for each SSC 3-hour bundle recommendation on in-hospital mortality for patients with severe sepsis and septic shock was evaluated. They found that delays in administering all four guideline recommendations, even when they did not exceed 3 hours, were associated with a significant increase in in-hospital mortality. Overall, this study

How to cite this article: Patki V, Mittal K, Agarwal HK, Munjal M, Ali SM. Best Evidence: Journal scan-Sepsis. J Pediatr Crit Care 2018;5(4): 83-90. How to cite this URL: Patki V, Mittal K, Agarwal HK, Munjal M, Ali SM. Best Evidence: Journal scan-Sepsis. J Pediatr Crit Care 2018;5(4): 83-90. Available from: http://jpcc.in/userfiles/2018/0503-jpcc-jul-aug-2018/JPCC0504012.html


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DOI-10.21304/2018.0504.00417

Critical Thinking PICU QUIZ - Sepsis Vinayak Patki*, Kundan Mittal** *Chief Consultant, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, 416101, Maharashtra, India, **Senior Professor Pediatrics, Pt B D Sharma, PGIMS, Rohtak Haryana, India Received: 01-Aug-18/Accepted: 15-Aug-18/Published online: 30-Aug-18

Q.1 The clinical use of the term SIRS describes derangements in all of the following except A. respiratory rate, B. heart rate, C. Blood Pressure D. white blood cell count

C. Calcium channel dysfunction D. Sodium Potassium Transport dysfunction. Q.6 All of the following investigations are specific to diagnose Sepsis induced myocardial dysfunctionexcept ? A. Sr. Lactate B. Blood Troponin C. 2 D strain ECHO D. Pulmonary Artery Pressure

Q.2 In Sequential [Sepsis-Related] Organ Failure Assessment Scoring system which of the following is not considered while calculating the SOFA score? A. Sr. Bilirubin B. Platelet Count C. Sr. Lactate D. Sr. Creatinine

Q.7 A 13 old child presented with fever and feeling generally unwell. His mother reported he had Complained of shortness of breath and coughing up sputum the day before. He had no past medical history and was not taking any regular medication. He is School athlete. On examination his vital signs were as follows: Alert Temperature 38OC Respiratory rate 36/min Heart rate 120/min Blood pressure 90/60 mmHg Oxygen saturationson air 92% What is the expected mortality predication with qSOFA score for above Patient? A. Approximately5% B. Approximately10% C. Approximately15% D. Approximatel y 20%

Q.3 All of the following are acute phase reactants which are used as Biomarkers of sepsis except one: A. C-reactive protein (CRP) B. Osteoponitin C. ferritin D. procalcitonin Q. 4 All the following statements are true about CRP and Procalcitonin except one? A. C-reactive protein Begins to rise 12-24 hours and peaks Within 2-3 days B. Procalcitonin Detectable with 3-4 hours and peaks within 6-24hours C. CRP is more sensitive and specific for sepsis than Procalcitonin. D. Procalcitonin is valuable to monitor the clinical response to therapy for sepsis

Q.8 Which of the following immunologic test results is most strongly associated with the immunoparalyzed phenotype? A. Absolute lymphocyte count >1000 cells/uL B. Low plasma IL-6 level C. Markedly elevated ex vivo lipopolysaccharide (LPS)-induced TNF-α production capacity D. Monocyte HLA-DR expression of 20%

Q.5 Which of the following is not associated with Sepsis induced myocardial dysfunction? A. Global myocardial ischemia B. Direct myocardial depression Correspondence: Dr. Vinayak Patki, MB,DNB,FCCP,FIAP. Chief, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, 416410, Maharashtra, India. Phone: +919822119314, E-Mail- [email protected]


Q.9 Which statement best describes the dynamic inflammatory response in critical illness? A. marked and persistent CARS response is

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beneficial to the patient. B. Restoration of the SIRS/CARS balance can require immunostimulatory treatment. C. The CARS response affects the adaptive immune system more than the innate. D. The SIRS/CARS balance is easily quantified in the clinical laboratory

5. Central nervous [system Glasgow Coma Scale score] 6. Renal [Creatinine, mg/dLand Urine Output] Q.3 Answer B. Though Osteoponintin is A biomarkers of sepsis it is a cytokines and not a acute phase reactant. Amyloid,C-reactive protein (CRP), Erythrocycte sedimentation rate (ESR), ferritin, procalcitonin, ceruloplasmin ,pentraxin 3 and hepcidin are the acute phase reactants used as Biomarkers of Sepsis.

Q.10 Of the following, which does not describe a mechanism of peripheral T-cell tolerance? A. Antigen/MHC molecule recognition in the absence of costimulatory receptor binding B. Binding of the inhibitory T-cell costimulatory receptor, CTLA-4, to B7 molecules on antigen presenting cells C. Ingestion and destruction of self-reacting T cells by phagocytes D. Maintenance of a pool of CD4+ immunosuppressive regulatory T cells (Treg)

Q.4 Answer C. Studies have shown that sensitivity and specificity of CRP to diagnose serious bacterial infection in non hospitalized children is less than that of Procalcitonin.CRP cannot differentiate between an inflammatory process and infectious process.Procalcitonin, precursor of calcitonin hormone is normally secreted by neuroendocrine cells of the thyroid gland. During bacterial systemic infections it is believed to be secreted by neuroendocrine cells in the lungs and intestine. Its release is mediated by cytokines like TNF-α and IL-6.

Q.1 Answer C. As per1991 International Consensus Conference The clinical use of the term SIRS describes derangements in respiratory rate, heart rate, temperature, and white blood cell count. Meeting two of the four following criteria satisfies the requirement for SIRS: respiratory rate >20 breaths per min or a PaCo2 90 beats per minute, temperature >38 °C or 12,000/mm3 or 10% bandemia. And septic shock is defined as “acute circulatory failure characterized by persistent arterial hypotension [including systolic