RECENT APPROACH TO MANAGING SEPSIS IN CHILDREN.

Most recent updates(2024) to practical approach to diagnosing and evaluating sepsis in children especially in resource limited settings according to 2024 consensus guidelines

1. SEPSIS IN CHILDREN DR INNOCENT A. AGABA Department o f Paediatrics Modibbo Adama University Teaching Hospital Yola 14-08-24

2. OUTLINE Introduction Burden Aetiopathogenesis Clinical manifestation Diagnosing sepsis Investigations Management Prognosis Conclusion References

3. INTRODUCTION Sepsis in children is generally considered to comprise a spectrum of disorders that result from infection by bacteria, viruses, fungi,or parasites or the toxic products of these organisms. Although inflammation is an essential host response to infection, the onset and progression of sepsis centers upon a “ dysregulation ” of this normal response, initiating a chain of events that lead to tissue injury. It is this dysregulated host response rather than the primary infectious microorganism that is typically responsible for multiple organ failure and adverse outcomes. Tissues remote from the original insult display the cardinal signs of inflammation.

4. INTRODUCTION Early recognition is crucial in ensuring the best outcomes. In 1991 an international consensus meeting defined terms such as sepsis, Systemic Inflammatory Response Syndrome, severe sepsis, septic shock (Sepsis 1). In 2001, definitions were revised (Sepsis-2). In 2016, the third international consensus definitions for sepsis and septic shock (Sepsis - 3) redefined sepsis as life threatening organ dysfunction caused by dysregulated host response to infection, however this excluded children . In January 2024,the Society of Critical Care Medicine(SCCM ) convened a taskforce of 35 pediatric experts from 6 continents to develop a criteria for diagnosing sepsis in children .

5. BURDEN Sepsis is one of the most prevalent causes of mortality in intensive care Units(ICUs) and its incidence increased by more than double over the last 10 years. Respiratory infections and bloodstream infections are found in almost two-thirds of cases of severe sepsis worldwide. According to World Health Organization (WHO), almost half of all estimated sepsis cases worldwide occurred in children under 5 years of age. Mortality from pediatric sepsis ranges from 9% to 35%.

6. BURDEN While any individual can be affected, significant regional disparities in incidence and mortality exists with the highest rates in Lower-middle-income countries (LMICs). In Nigeria, there is no consensus national guideline for management of paediatric sepsis and there is a dearth of epidemiological data describing its prevalence. The emergence of increasingly antimicrobial resistant (AMR) bacteria as the cause of sepsis provides a growing challenge. A study amongst 7 LMICs in Asia showed significant resistance rates of gram-negative isolates (95% to Ampicillin , 83% to Cefotaxime and 80% to ceftriaxone ).

7. DEFINITION OF TERMS SYSTEMIC INFLAMMATORY RESPONSE SYNDROME  : SIRS is a widespread inflammatory response that may or may not be associated with infection. The presence of ≥2 of the following criteria (one of which must be abnormal temperature or leukocyte count) defines SIRS: ( i )Core temperature (measured by rectal, bladder, oral, or central probe) of >38.5°C or <36° (ii)Tachycardia, defined as a mean heart rate more than two standard deviations above normal for age, or for children younger than one year of age, bradycardia defined as a mean heart rate <10 th  percentile for age (iii)Mean respiratory rate more than two standard deviations above normal for age or mechanical ventilation for an acute pulmonary process (iv) Leukocyte count elevated or depressed for age, or >10 percent immature neutrophils

8. DEFINITION OF TERMS SEPSIS : P ediatric sepsis is identified by a Phoenix Sepsis Score of 2 points or higher in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurologic systems (Society of Critical Care Medicine task force recommendation, 2024). SEPTIC SHOCK : Sepsis with cardiovascular dysfunction that persists despite the administration of ≥40mls/kg of isotonic fluid in one hour. REFRACTORY SEPTIC SHOCK : ( i )Fluid refractory septic shock: Cardiovascular dysfunction persist despite at least 40-60mls/kg of fluid resuscitation (ii)Catecholamine-resistant septic shock: shock persists despite therapy with dopamine ≥ 10mcg/kg/min and/or direct catecholamine (epinephrine, Norepinephrine )

9. DEFINITION OF TERMS MULTIPLE ORGAN FAILURE : ≥ 2 or more organs with either of : Cardiovascular : ( i ) Hypotension, or (ii) reliance on a vasoactive drug to maintain BP, or (iii) 2 of the following : - metabolic acidosis, - elevated arterial lactate, - oliguria or - prolonged capillary refill Respiratory : ( i ) Arterial oxygen tension/fraction of inspired oxygen (PaO 2 /FiO 2 ) <300, (ii)arterial carbon dioxide tension (PaCO 2 ) >65 torr or 20 mmHg over baseline PaCO 2 , (iii) need for >50 % FiO 2  to maintain oxygen saturation ≥92% , or (iv) need for non elective mechanical ventilation.

10. Neurologic : ( i )GCS ≤11 or (ii) acute change in mental status. Renal: ( i ) Serum creatinine ≥ 2 times upper limit of normal for age (ii) 2 fold increase in baseline creatinine Hepatic: ( i ) Total Bilirubin ≥4mg/dl (excluding new borns ) (ii) ALT > 2 times upper limit of normalfor age

11. AETIOLOGY Sepsis can be caused by bacteria, viral , fungal, parasitic, and rickettsial infections . Viral pathogens can cause sepsis and be difficult to differentiate from bacterial pathogens. Viruses may cause the sepsis syndrome in isolation but the presence of bacterial co-infections, particularly methicillin -resistant  Staphylococcus aureus , should be suspected in patients with severe sepsis or septic shock. Between 30 - 75% of children with sepsis have no infectious etiology identified - Culture negative sepsis.

12. AETIOLOGY BACTERIA  The most common bacterial pathogens isolated from children with sepsis include: ● Staphylococcus aureus  including methicillin -resistant strains (MRSA) ● Coagulase -negative Staphylococcus especially in neonates or young infants with in-dwelling vascular catheters ●Streptococcus pneumoniae ●Streptococcus pyogenes ●Group B streptococcus in the neonate ● Pseudomonas aeruginosa  including carbapenem -resistant strains ● Escherichia coli , including those with extended spectrum beta- lactamase activity (ESBL) ● Klebsiella species, including those with ESBL activity

13. AETIOLOGY VIRUSES Influenza virus Severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] Parainfluenza virus. Adenovirus, Respiratory syncytial virus [RSV], Human metapneumovirus Dengue virus, a mosquito-borne pathogen that can cause Dengue shock syndrome.

14. AETIOLOGY FUNGI Fungal infections, especially Candida species, have been reported in 10% of pediatric patients with severe sepsis and septic shock. Fungal sepsis is more common in children with certain risk factors including: - Malignancy or other immunocompromising medical conditions - Indwelling vascular catheters - Prolonged neutropenia (>4 to 7 days) - Recent broad-spectrum antibiotic use

15. AETIOLOGY CULTURE NEGATIVE SEPSIS This "culture-negative" sepsis may indicate: ( i )host response to bacterial components (ii)antibiotic treatment prior to obtaining bacterial cultures. (iii)current diagnostic tests may not be sufficiently sensitive to detect the inciting pathogen in all cases.

16. RISK FACTORS Age younger than 1 month Serious injury (major trauma,burns or penetrating wounds ) Host immunosuppression Urinary tract abnormalities with frequent infection Non immunization Children with hemoglobin SS disease have a 400-fold increased risk of sepsis due to pneumococcus and Salmonella, among other pathogens Congenital heart disease is a risk factor for endocarditis and sepsis Infants and children with hematologic and solid-organ malignancies (before or during treatment) are at increased risk for sepsis from a considerable variety of organisms Neonates, infants, and children who are hospitalized (particularly in the intensive care unit [ICU]) are at increased risk for SIRS Those with indwelling devices or prosthetic material and other breaches in barrier protective function are also at increased risk for SIRS

17. PATHOPHYSIOLOGY OF SEPSIS Normal host response Transition to sepsis Systemic effects Organ specific effects

18. NORMAL HOST RESPONSE

19. NORMAL HOST RESPONSE 1 . The host response to an infection is initiated when innate immune cells, particularly macrophages, recognize and bind to microbial components: - Pathogen releases pathogen-associated molecular patterns (PAMPs). - Pattern recognition receptors (PRRs) on the surface of host immune cells may recognize and bind to microbial PAMPs e.g TLRs. - PRRs can also recognize endogenous danger signals, so-called alarmins or danger-associated molecular patterns (DAMPs) that are released during the inflammatory insult. E.g Heat shock proteins. - Microparticles from circulating and vascular cells also participate in the deleterious effects of sepsis- induced intravascular inflammation.

20. NORMAL HOST RESPONSE 2. The binding of immune cell surface receptors to microbial components has multiple effects: The engagement of TLRs elicits a signaling cascade intracellularly that culminates in the production of ( i ) pro- inflammatory cytokines i.e IL -1, TNF α (ii) Chemokines i.e ICAM – 1,V- CAM 1,NO2 (iii) Coagualtion and complement activation – a prothrombotic state Polymorphonuclear leukocytes (PMNs) become activated and express adhesion molecules that cause their aggregation and margination to the vascular endothelium.  The release of mediators by PMNs at the site of infection is responsible for the cardinal signs of local inflammation

21. NORMAL HOST RESPONSE 3. This process is regulated by a mixture of pro- inflammatory and anti-inflammatory mediators secreted by macrophages: The balance of pro-inflammatory (IL -1, TNF α ) and anti-inflammatory (IL-10, IL-6) mediators regulates the inflammatory processes. Phagocytes can switch into an anti-inflammatory phenotype. Activation of regulatory immune cells Neuro -inflammatory system results in acetylcholine release which inhibits inflammation. If the mediators balance each other and the initial infectious insult is overcome, homeostasis will be restored. The end result will be tissue repair and healing . Multiple studies have documented reduced responsiveness of blood leukocytes to pathogens in patients with sepsis. Suggesting a state of “ immunoparalysis ”

22. TRANSITION TO SEPSIS “Malignant intravascular inflammation” Sepsis occurs when the release of pro-inflammatory mediators in response to an infection exceeds the boundaries of the local environment, leading to a more generalized response . Why do immune responses that usually remain localized sometimes spread beyond the local environment causing sepsis? - effect of invading micro- organsim & their toxic products - release of large quantitites of pro-inflammatory mediators -complement activation -some individuals are genetically susceptible

23. SYSTEMIC EFFECTS Generalized immune response leads to widespread cellular injury. Cellular injury results from: ( i ) Tissue ischaemia i.e reduced red cell deformability, hypotension (ii) Cytopathic injury (mitochondrial dysfunction, oxidative stress) (iii) Cell death i.e Apoptosis, Necrosis, Autophagy (iv) immunosuppression (v)Activation of coagulation system & vascular endothelium Cellular injury is the precursor to organ dysfunction

24. ORGAN SPECIFIC EFFECTS No organ system is protected from the consequences of Sepsis CARDIOVASCULAR SYSTEM - Hypotension resulting from ( i ) an unintended consequence of the release of vasoactive mediators (ii) may also be due to redistribution of intravascular fluid - Decreased systolic and diastolic ventricular performance due to the release of myocardial depressant substances is an early manifestation of sepsis. Vascular hypo responsiveness (i.e., inability to appropriately vasoconstrict ) leads to an inability to appropriately distribute systemic blood flow among organ systems . - Decrease in the number of functional capillaries which causes an inability to extract oxygen maximally

25. ORGAN SPECIFIC EFFECTS LUNGS Endothelial injury in the pulmonary vasculature during sepsis disturbs capillary blood flow and enhances microvascular permeability, resulting in interstitial and alveolar pulmonary edema - Acute respiratory distress syndrome is a manifestation of these effects. GASTROINTESTINAL TRACT The circulatory abnormalities typical of sepsis may depress the gut's normal barrier function, allowing translocation of bacteria and endotoxin into the systemic circulation and extending the septic response. Gut ischaemia

26. LIVER -   Liver dysfunction can prevent the elimination of enteric-derived endotoxin and bacteria-derived products which permits direct spillover of these potentially injurious products into the systemic circulation E. KIDNEY - Acute tubular necrosis due to hypoperfusion and/or hypoxemia is one mechanism. - Microcirculatory dysfunction, inflammatory response induced by pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) and bio-energetic adaptation response including tubular cell cycle arrest machinery.

27. CENTRAL NERVOUS SYSTEM The most common CNS complications are an altered sensorium (encephalopathy ). - Dysfunction of the blood brain barrier probably contributes, allowing increased leukocyte infiltration, exposure to toxic mediators, and active transport of cytokines across the barrier.

28. CLINICAL MANIFESTATIONS The clinical manifestations of sepsis are highly variable, depending on the initial site of infection, the causative organism, the pattern of acute organ dysfunction, the underlying health status of the patient, and the interval before initiation of treatment 1. The primary infection 2. SIRS 3. Septic shock 4. Multi-organ dysfunction

29. CLINICAL MANIFESTATIONS THE PRIMARY INFECTION: Upper respiratory tract: Catarrhal symptoms, Pharyngeal exudates +/- swelling, lymmphadenopathy Ear : Ear turging +/- ear discharge Lower Respiratory tract : cough, pleuritic chest pain, consolidative auscultatory findings Urinary tract : Dysuria , loin pain CNS : Convulsions, altered sensorium , meningism Catheters : redness or drainaige at insertion sites Bone & Joints : Pain, swelling, reduced movement Skin : rashes, swellings erythema , ulcers, abscesses

30. CLINICAL MANIFESTATIONS SIRS

31. CLINICAL MANIFESTATIONS SEPTIC SHOCK : Clinical signs of abnormal perfusion indicate septic shock and include one or more of the following: ●Altered mental status ●Warm or cold extremities ●Decreased urine output ●Bounding or thready /absent peripheral pulses ●Abnormal capillary refill (either "flash" or >2 seconds)

32. DIAGNOSING SEPSIS Society of Critical Care Medicine(SCCM) recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection.

33. PHOENIX SEPSIS SCORING

34. PHOENIX SEPSIS SCORING

35. INVESTIGATIONS Gram stain Culture of blood, stool, urine, CSF, swab from body sites Nucleic Acid Amplification tests (NAATs) Other investigations Rapid blood glucose Arterial blood gas or venous blood gas and pulse oximetry Complete blood count with differential (including platelet count) Blood lactate EUCR Serum Calcium Clotting profile, Fibrinogen and D- Dimer C-reactive protein, pro calcitonin Imaging

36. MANAGEMENT The management of Sepsis in Children should be in line with the guidelines set out by the Surviving Sepsis Campaign 2020 Initial management & resuscitation (2) Definitive care (3) Further in-hospital Management

37. Initial management and resuscitation RED FLAGS. ●Presence of fever (core temperature >38.3°C for patients three months of age and older or >38°C for infants younger than three months of age) ●Hypothermia (core temperature <36°C [96.8°F]) ●Tachycardia, Tachypnea ●Abnormal pulse (diminished, weak, or bounding) ●Abnormal capillary refill (central refill ≥3 seconds or flash refill [<1 second]) ● Hypotensive ●Abnormal mental status: ● Purpura anywhere on the body or petechiae below the nipple line ●Macular erythema  and with mucosal changes ( eg , strawberry tongue and conjunctival injection suggestive of toxic shock syndrome

38. Initial Management & resuscitation Each hour of delay in initiation of appropriate resuscitation or persistence of hemodynamic abnormalities is associated with a clinically significant increased risk of death . Patients should undergo rapid clinical assessment within 15 minutes by a physician, physician assistant, or advanced practice nurse to confirm findings of sepsis, or septic shock. Clinicians must appreciate that hypotension is a late sign of cardiovascular dysfunction and shock in pediatric patients and is  not  necessary to diagnose septic shock

39. Initial management & Resuscitation Each institution should develop a multidisciplinary approach to the resuscitation of pediatric patients with sepsis or septic shock that codifies the time-limited stabilization tasks recommended within the first few hours of treatment by the Surviving Sepsis Campaign. Principles of resuscitation are: - Recognition of children at risk for sepsis and septic shock - Vascular access and rapid fluid resuscitation - Empiric antimicrobial therapy - Initiation of vasoactive agents to patients not responding sufficiently to fluid resuscitation  Timing is determined by whether the child has septic shock or sepsis

40. Resuscitation – when to start  IN CHILDREN FOR WHOM SEPTIC SHOCK IS RECOGNISED, THE FOLLOWING SHOULD BE DONE WITHIN THE FIRST 1 HOUR: •Obtain intravenous (IV)/ intraosseous (IO) access. •Collect blood culture (before antibiotics are administered whenever possible). •Start broad-spectrum, empiric antimicrobial therapy. •Measure blood lactate. •Administer a fluid bolus of 10 to 20 mL /kg if shock is present and provide further fluid resuscitation depending upon patient condition and response. •Start vasoactive agents if shock persists after 40 to 60 mL /kg (or sooner if signs of fluid overload develop or myocardial dysfunction is present). • Children whose circulatory, metabolic and respiratory derangements are not rapidly corrected should be cared for in the an intensive setting. IN CHILDREN FOR WHOM SEPSIS IS PRESENT WITHOUT THE SIGNS OF SHOCK, THE ABOVE OUTLINED INTERVENTIONS SHOULD BE DONE WITHIN THE FIRST 3 HOURS

41. Resuscitation – when to stop RESTORATION OF TISSUE PERFUSION AND REVERSAL OF SHOCK IS IDENTIFIED BY THE FOLLOWING THERAPEUTIC ENDPOINTS : ●Quality of central and peripheral pulses (strong, distal pulses equal to central pulses) ●Skin perfusion (warm, with capillary refill <2 seconds) ●Mental status (normal mental status) ●Urine output (≥1 mL /kg/hour, up to 40 mL /hour, once effective circulating volume is restored) ●Blood pressure ●Normal serum lactate ( eg , <2 mmol /L) ●Central venous oxygen saturation (ScvO 2 ) ≥70 percent, if available and appropriate (invasive monitoring may not be needed in patients who rapidly respond to initial resuscitation); this target is  not  applicable to children with congenital heart disease characterized by mixing lesions.

42. Resuscitation – what to do AIRWAY & BREATHING : -Commence supplemental oxygen -Monitor via pulse oximetry -Aim for spo2 92 – 97%. -Endotracheal intubation using rapid sequence intubation (RSI) is frequently necessary in children with fluid-refractory, catecholamine-resistant septic shock to protect the airway, assist with ventilation, and/or promote oxygenation

43. Resuscitation – What to do CIRCULATION IV access (preferably two sites and of the largest caliber that can be reliably inserted) should be established within five minutes in patients with septic shock . If a peripheral IV cannot be obtained in this time, placement of an IO needle is indicated Treat hypoglycemia, hypocalcaemia Fluid resuscitation Monitoring

44. Fluid resuscitation Give rapid infusion of IVF Ringers Lactate 10 – 20mls/kg (or Normal saline) over 5 – 10 minutes. Examine child for fluid overload or signs of shock. If fluid overload is present and shock persists, start Iv vasoactive therapy. If fluid overload is present but shock has resolved, stop fluid resuscitation.

45. If fluid overload is absent but shock persists,repeat rapid infusion of IVF 10 – 20mls/kg. Reassess after each bolus until 40 – 60mls/kg has been given. If fluid overload is absent and shock is resolved, stop rapid IVF resuscitation and commence maintenance. If fluid overload is absent but shock persists despite 40 – 60mls/kg IVF treat Fluid- refractory shock with: -Iv epinephrine/ Norepinephrine (If BP low) -Low dose epinephrine (If BP normal) If shock persists despite catecholamines , manage as catecholamine resistant shock with - Iv Hydrocortisone -Evaluate for unrecognised morbidities

46. EMPIRIC ANTIBIOTIC THERAPY Prompt identification and treatment of the site(s) of infection are the primary therapeutic interventions for septic shock, with most other interventions being purely supportive. For children with septic shock, broad-spectrum IV antibiotic therapy should begin within one hour of presentation, preferably after obtaining appropriate cultures. A ntifungal and antiviral agents should be included as part of the initial regimen for susceptible patients. While antibiotics should be administered as soon as possible after sepsis recognition, it is reasonable to first perform a diagnostic investigation when clinical signs of shock are not present, and the diagnosis of sepsis is uncertain.

47. EMPIRIC ANTIBIOTIC THERAPY GENERAL PRINCIPLES: Maximize the antimicrobial dose by using dosing recommended for severe infection for each administered drug. Antimicrobials that cover against the same organism should not be routinely administered to immunocompetent patients. Multidrug therapy is recommended in immunocompromised patients or immunocompetent patients at high risk for multi drug-resistant pathogens. 4. Children with septic shock at risk for methicillin -resistant Staphylococcus aureus (MRSA) due to either high community prevalence or personal/family history of MRSA should receive empiric vancomycin or an alternative agent. 6. Coverage for enteric organisms should be added whenever clinical features suggest genitourinary and/or gastrointestinal sources ( eg , perforated appendicitis or bacterial overgrowth in a child with short gut syndrome ).

48. 7. Treatment for Pseudomonas species should be included for children who are immunosuppressed , have a history of Pseudomonas sp infection, or at risk for infection with these organisms ( ie , neutropenic patient). Listeria monocytogenes and herpes simplex virus (HSV) are important pathogens in infants ≤28 days of age. When treating empirically, antibiotics that can be given by rapid IV bolus ( eg , beta-lactam agents or cephalosporins ) should be administered first, followed by infusions of antibiotics, such as vancomycin , which must be delivered more slowly. Ongoing antimicrobial therapy should be modified based upon culture results, including antimicrobial susceptibility and the patient's clinical course.

49. EMPIRICAL ANTIMICROBIAL REGIMENS Children >28 days of age who are normal hosts: • Cefotaxime or ceftriaxone . • Add vancomycin if risk factors for MRSA are present • For patients with a possible genitourinary source, add an aminoglycoside ( eg , gentamicin ). • For possible gastrointestinal source, add piperacillin with tazobactam , clindamycin , or metronidazole . It is best to avoid piperacillin-tazobactam if vancomycin is being administered because of the risk of renal injury when these two antibiotics are co-administered. • In the presence of septic shock in settings with resistant organisms or in at-risk patients, add combination therapy (using at least two antibiotics of different antimicrobial classes) aimed at covering resistant organisms

50. EMPIRICAL ANTIBIOITIC REGIMENS Children >28 days who are immunosuppressed or at risk for infection with Pseudomonas species : •Cefepime or carbapenem (eg, imipenem, meropenem) in settings where - bacterial organisms with extended-spectrum beta-lactamase (ESBL) resistance are prevalent or - for patients who have been recently (within two weeks) treated with broad-spectrum antibiotics - or were known to be infected or colonized with a multidrug resistant Gram-negative organism within the past 6 to 12 months . •Add vancomycin if risk factors for MRSA are present. • If concerned about resistance to cefepime/ceftazidime/carbapenem, add an aminoglycoside (eg, gentamicin , amikacin).

51. EMPIRICAL ANTIBIOTIC REGIMEN Children who cannot receive penicillin or who have recently received broad-spectrum antibiotics: • Meropenem . • Add vancomycin if risk factors for MRSA are present. •Aztreonam or ciprofloxacin PLUS clindamycin may be used instead of meropenem.

52. Patients at increased risk of fungal infection (eg, identified fungal source, immunocompromised with persistent fever on broad-spectrum antibiotics): • Add liposomal amphotericin B or an echinocandin (eg, caspofungin, micafungin) to the antimicrobial regimen [48]. If candidemia is suspected, an echinocandin is the agent of choice. Patients with risk factors for rickettsial infection (eg, travel to or reside in an endemic region) : • Add a tetracycline antibiotic (eg, doxycycline) to the antimicrobial regimen. Patients at risk for adrenal insufficiency should be treated with stress-dose hydrocortisone early in the course of resuscitation (IV hydrocortisone 50 to 100 mg/m2/day or approximately 2 to 4 mg/kg/day , intermittent or continuous infusion, maximum dose 200 mg/day)

53. Duration of Antibiotics Therapy Determined by ultimate source of infection; 7-10d is typically sufficient . Above regimens may be empiric therapy for 48-72h, until cultures and sensitivities are known, so as to accurately tailor treatment . If culture-negative sepsis, antibiotic choice and duration determined by severity of presentation and most likely pathogen . Infectious disease consultation may be necessary

54. Definitive care & further mgt Priorities for continued management of children with septic shock include: ● Manage the infection by identifying the optimal choice of antimicrobial therapy based upon culture results and by ensuring that the source of infection is controlled. ● Monitor respiratory status, assess for pediatric acute respiratory distress syndrome (PARDS), and provide optimal respiratory support. ● Monitor tissue perfusion (capillary refill time, heart rate, pulses, urine output, and mental status), blood pressure , and cardiac function. ● Avoid hypoglycemia and correct electrolyte and metabolic derangements ( eg , hypocalcemia ). ● Monitor blood lactate levels; patients with persistently elevated and/ or worsening blood lactate are at increased risk of mortality and may warrant escalation of support [3,4 ]. ● Generally, Children with sepsis should not be fed until gut hypoxia and hypoperfusion have been excluded.

55. C hildren with fluid-refractory septic shock requiring continued vasopressor support, additional priorities include : ●Placement of invasive monitoring devices to accurately assess blood pressure and response to treatment and to deliver vasopressor infusions safely. ● Continued fluid resuscitation and vasopressor delivery targeted to measured cardiac function, lactate , and central venous oxygen saturation (ScvO2). ●Administration of blood products, when needed, to treat severe anemia or bleeding. ● Treatment of adrenal insufficiency and evaluation of other potential underlying causes ( eg , hypothyroidism). ●Provision of advanced extracorporeal therapies in patients who do not respond to conventional therapy

56. FURTHER MGT & CONSIDERATIONS Management of organ dysfunction and failure Stress Ulcer prophylaxis DVT prophylaxis IVIG in selected patients Novel therapeutics i.e Immunostimulatory therapy Mitochondrial dysfunction inhibitors

57. PROGNOSIS Different insults are associated with different outcomes . Host immune status is important in determining outcome . Aggressive fluid resuscitation early in the course of SIRS results in decreased mortality

58. CONCLUSION The onset and progression of sepsis centers upon a “ dysregulation ” of normal host inflammatory response to infection, initiating a chain of events that lead to tissue injury. The most recent criteria for diagnosis sepsis is a phoenix sepsis score ≥ 2 in the presence of a suspected infection. Prompt identification and treatment of the site(s) of infection are the primary therapeutic interventions for septic shock, with most other interventions being purely supportive . Each pediatric institution should develop a multidisciplinary protocol/guideline to improve early identification and treatment. One of the great disappointments during the past 30 years has been the failure to convert advances in our understanding of the underlying biologic features of sepsis into effective new therapies.

59. REFERENCES Schlapbach LJ, Watson RS, Sorce LR, et al. International Consensus Criteria for Pediatric Sepsis and Septic Shock. JAMA 2024; 331:665. Pomerantz Wendy, “Children with early and life-threatening sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)”. UpToDate , June 13,2024. Shankar Santhanam , “ Paediatric sepsis”. Medscape , May 17, 2024