Sepsis and Septic Shock

Etiology and Pathophysiology

Etiology

• May be community- or hospital-acquired
• Source of infection:
  • Identified in ⅓ of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 
  • Most commonly pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, followed by intra-abdominal and genitourinary infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Cultures:
  • Blood cultures: positive in ⅓ of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Negative cultures from all sites are common
• Most common gram-positive Gram-Positive Penicillins pathogens:
  • Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess
  • Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
• Most common gram-negative pathogens:
  • Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli
  • Klebsiella Klebsiella Klebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species. Klebsiella spp.
  • Pseudomonas aeruginosa Pseudomonas aeruginosa A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. Aeruginosa is a major agent of nosocomial infection. Pseudomonas
• Fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology: reported in about 20% of cases
• Viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology: reported in only 1% of cases

Pathophysiology

Pathogen load and virulence Virulence The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenic capacity of an organism is determined by its virulence factors. Proteus + host genetic composition and comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus result in a complex, exaggerated, and prolonged host response to infection that evolves over time.

1. Recognition of pathogen-associated molecular patterns (PAMPs) by pathogen recognition receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on innate immune cells → inflammatory response (e.g., release of tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor) →  tissue damage and necrotic cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death → release of damage-associated molecular patterns (DAMPs) → further activation of leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology → microvascular changes (endothelial cell dysfunction + coagulation and complement activation Complement Activation The sequential activation of serum complement proteins to create the complement membrane attack complex. Factors initiating complement activation include antigen-antibody complexes, microbial antigens, or cell surface polysaccharides. Systemic Lupus Erythematosus)
2. Macrovascular changes: vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs and hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension 
3. Microvascular changes + macrovascular changes → vascular leak, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, intravascular volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration → impaired tissue oxygenation, cellular alterations such as greater glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis (lactate production), mitochondrial injury, and release of oxygen species → increasing organ damage

Clinical Presentation

• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and peripheral pulses:
  • Early septic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock with low volume status Volume Status ACES and RUSH: Resuscitation Ultrasound Protocols: cold extremities and narrow pulse pressure reflecting increased systemic vascular resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing (SVR) and reduced cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics (CO)
  • With progression of shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock: relatively warm extremities and widening of pulse pressure reflecting reduced SVR and increased CO
• Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure:
  • Symptoms of acute respiratory distress syndrome Acute Respiratory Distress Syndrome Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome (ARDS) (ARDS) including:
    • Tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination
    • Shallow breathing
    • Use of accessory muscles
    • Respiratory fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia with paradoxical abdominal movement
    • Bilateral rales Rales Respiratory Syncytial Virus (crackles)
    • Hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage
    • Bilateral pulmonary infiltrates not explained by heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) 
• Cardiac failure Cardiac failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Heart Failure:
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
  • Tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination
  • Pulmonary rales Rales Respiratory Syncytial Virus subsequent to pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
• Acute kidney injury Acute Kidney Injury Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury ( AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury):
  • Decreased urinary output ( oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation)
  • Azotemia Azotemia A biochemical abnormality referring to an elevation of blood urea nitrogen and creatinine. Azotemia can be produced by kidney diseases or other extrarenal disorders. When azotemia becomes associated with a constellation of clinical signs, it is termed uremia. Acute Kidney Injury/ uremia Uremia A clinical syndrome associated with the retention of renal waste products or uremic toxins in the blood. It is usually the result of renal insufficiency. Most uremic toxins are end products of protein or nitrogen catabolism, such as urea or creatinine. Severe uremia can lead to multiple organ dysfunctions with a constellation of symptoms. Acute Kidney Injury
• Neurologic presentation and complications: 
  • Altered mental status Altered Mental Status Sepsis in Children:
    • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • No focal lesions on imaging
  • Global encephalopathy Encephalopathy Hyper-IgM Syndrome on electroencephalography Electroencephalography Seizures
  • Critical-illness polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy and myopathy Myopathy Dermatomyositis if especially prolonged intensive care unit ( ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus) stay
  • Chronic moderate-to-severe cognitive impairment
• Other clinical/laboratory features and complications:
  • Ileus Ileus A condition caused by the lack of intestinal peristalsis or intestinal motility without any mechanical obstruction. This interference of the flow of intestinal contents often leads to intestinal obstruction. Ileus may be classified into postoperative, inflammatory, metabolic, neurogenic, and drug-induced. Small Bowel Obstruction
  • Elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation
  • Adrenal failure
  • Sick euthyroid Euthyroid Thyroiditis syndrome

Diagnosis

General approach

1. Suspect sepsis in any individual presenting with any of the following:
   • Infection without apparent organ dysfunction 
   • New-onset and unexplained organ dysfunction without apparent infection
   • Abnormal vital signs such as fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination, tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, or low blood pressure
   • Altered mental status Altered Mental Status Sepsis in Children
2. Administer screening Screening Preoperative Care tools: serve as early identification Identification Defense Mechanisms tools and/or risk stratification tools:
   • NEWS: National Early Warning Score
     • Strongest level of evidence exists for the NEWS score
     • Sensitive ED screening Screening Preoperative Care tool, predicts sepsis-related outcomes
     • Score is based on rapid bedside assessment of respiration Respiration The act of breathing with the lungs, consisting of inhalation, or the taking into the lungs of the ambient air, and of exhalation, or the expelling of the modified air which contains more carbon dioxide than the air taken in. Nose Anatomy (External & Internal) rate, O₂ saturation, need for supplemental O₂, temperature, systolic blood pressure, heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology, and level of consciousness.
   • MEWS: Modified Early Warning Score is similar to NEWS, but supplemental O₂ use is not factored into scoring.
   • SOFA: Sequential Organ Failure Assessment Sequential Organ Failure Assessment Sepsis in Children
     • Predicts mortality Mortality All deaths reported in a given population. Measures of Health Status risk in individuals with sepsis
     • Designed to evaluate mortality Mortality All deaths reported in a given population. Measures of Health Status in populations, but not as useful in determining individual risk
   • qSOFA qSOFA Presence of 2 of the following 3 criteria indicates a worse outcome in a patient suspected of having sepsis and triggers an immediate diagnostic workup and treatment as appropriate. Sbp < 100 mm hg, respiratory rate > 22/min, altered mental status. Types of Shock: quick Sequential Organ Failure Assessment Sequential Organ Failure Assessment Sepsis in Children
     • No longer recommended as a solitary screening Screening Preoperative Care tool for sepsis
     • Useful in predicting poor outcomes (prolonged ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus course and death)
   • SIRS: Systemic Inflammatory Response Syndrome criteria
     • No longer recommended as a solitary screening Screening Preoperative Care tool for sepsis
     • Relies on laboratory results, which delays diagnosis (unsuitable for triage)
     • Criteria may be met MET Preoperative Care in conditions unrelated to infection
3. Sepsis standard operating procedures: Initiate early interventions in individuals at moderate-to-high risk of sepsis based on screening Screening Preoperative Care tools (formerly known as early goal directed therapy) 
4. Initiate hour-1 bundle (see “Management”): Closely monitor for response to interventions and criteria of septic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock.

Diagnostic criteria

• Criteria for sepsis: 
  • Suspected (or documented) infection
  • Increase in ≥ 2 SOFA points 
• Criteria for septic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock:
  • Suspected (or documented) infection
  • Vasopressor Vasopressor Acute Cholangitis therapy necessary to maintain mean arterial pressure Mean Arterial Pressure Mean arterial pressure (MAP) is the average systemic arterial pressure and is directly related to cardiac output (CO) and systemic vascular resistance (SVR). The SVR and MAP are affected by the vascular anatomy as well as a number of local and neurohumoral factors. Vascular Resistance, Flow, and Mean Arterial Pressure (MAP) ≥ 65 mm Hg despite adequate IV crystalloid Crystalloid Isotonic solutions of mineral salts, such as ringer’s lactate and sodium chloride (saline solution), used in fluid therapy to rehydrate blood volume. Intravenous Fluids administration
  • Serum lactate > 2.0 mmol/L despite adequate IV crystalloid Crystalloid Isotonic solutions of mineral salts, such as ringer’s lactate and sodium chloride (saline solution), used in fluid therapy to rehydrate blood volume. Intravenous Fluids administration
• qSOFA qSOFA Presence of 2 of the following 3 criteria indicates a worse outcome in a patient suspected of having sepsis and triggers an immediate diagnostic workup and treatment as appropriate. Sbp < 100 mm hg, respiratory rate > 22/min, altered mental status. Types of Shock: 
  • A simple bedside tool for use outside the ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus and in the preclinical setting:
    • In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with suspected infection: having ≥ 2 of the following 3 criteria indicates poor outcomes (prolonged ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus course and death) and triggers further investigation, frequent monitoring, escalation of treatment, and ICU ICU Hospital units providing continuous surveillance and care to acutely ill patients. West Nile Virus admission, as appropriate
    • In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship without previous suspicion of infection: triggers consideration of infection
  • Criteria:
    • Systolic blood pressure < 100 mm Hg 
    • Respiratory rate Respiratory rate The number of times an organism breathes with the lungs (respiration) per unit time, usually per minute. Pulmonary Examination ≥ 22/min
    • Altered mentation 
• Systemic inflammatory response syndrome Systemic Inflammatory Response Syndrome Sepsis in Children (SIRS): no longer used for the diagnosis of sepsis

Management

Sepsis and septic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock are medical emergencies!

Respiratory support

• Indications for endotracheal intubation Intubation Peritonsillar Abscess and mechanical ventilatory support:
  • Significant hypoxemia Hypoxemia Neonatal Respiratory Distress Syndrome (PaO₂ < 60 mm Hg or oxygen saturation Oxygen Saturation Basic Procedures < 90%)
  • Hypoventilation (rising PCO₂) 
  • Significantly altered level of consciousness Altered Level of Consciousness Intracerebral Hemorrhage 
  • Inability to protect airways with risk of aspiration 
  • Persistent metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis with pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 7.20
• Goal: arterial oxygen saturation Oxygen Saturation Basic Procedures of 92%–95%

Hour-1 bundle

The hour-1 bundle encourages physicians Physicians Individuals licensed to practice medicine. Clinician–Patient Relationship to act as quickly as possible. Ideally, the following steps should begin within the 1st hour after the diagnosis of sepsis. 

1. Monitor serum lactate level (remeasure  if > 2 mmol/L).
2. Obtain blood cultures (positive in only 30% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with presumed sepsis) before initiating antibiotics.
3. Initiate broad-spectrum Broad-Spectrum Fluoroquinolones antibiotics.
4. Intravenous (IV) crystalloids: Rapidly administer (30 mL/kg) if hypotensive ( mean arterial pressure Mean Arterial Pressure Mean arterial pressure (MAP) is the average systemic arterial pressure and is directly related to cardiac output (CO) and systemic vascular resistance (SVR). The SVR and MAP are affected by the vascular anatomy as well as a number of local and neurohumoral factors. Vascular Resistance, Flow, and Mean Arterial Pressure < 65 mm Hg) and/or lactate ≥ 4 mmol/L.
5. Vasopressors Vasopressors Sepsis in Children:
   • Administer if hypotensive during or after resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome with IV crystalloids.
   • 1st choice: norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS, plus vasopressin to increase mean arterial pressure Mean Arterial Pressure Mean arterial pressure (MAP) is the average systemic arterial pressure and is directly related to cardiac output (CO) and systemic vascular resistance (SVR). The SVR and MAP are affected by the vascular anatomy as well as a number of local and neurohumoral factors. Vascular Resistance, Flow, and Mean Arterial Pressure and reduce norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS use

Monitoring

• Arterial pulse contour analysis
• Focused echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA) ( cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics, beat-to-beat stroke volume Stroke volume The amount of blood pumped out of the heart per beat, not to be confused with cardiac output (volume/time). It is calculated as the difference between the end-diastolic volume and the end-systolic volume. Cardiac Cycle, and pulse pressure variation)
• Passive leg-raise maneuver
• Inferior vena cava Inferior vena cava The venous trunk which receives blood from the lower extremities and from the pelvic and abdominal organs. Mediastinum and Great Vessels: Anatomy collapsibility on ultrasound

Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids

• Should not be used routinely
• Dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics has been shown to reduce mortality Mortality All deaths reported in a given population. Measures of Health Status in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with coronavirus disease 2019 Coronavirus disease 2019 Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the respiratory system but can also cause damage to other body systems (cardiovascular, gastrointestinal, renal, and central nervous systems). ( COVID-19 COVID-19 Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the respiratory system but can also cause damage to other body systems (cardiovascular, gastrointestinal, renal, and central nervous systems). ) who are receiving respiratory support.
• Weak recommendation: Initiate IV hydrocortisone Hydrocortisone The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. Immunosuppressants if septic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock does not respond to fluids and vasopressors Vasopressors Sepsis in Children. 
• Wean steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors if vasopressors Vasopressors Sepsis in Children are no longer needed.

Additional measures

• Red blood cell transfusion: only recommended if hemoglobin is < 7 g/dL
• Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin therapy: A blood glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance target of 140–180 mg/dL (7.7 to 10 mmol/L) is recommended. 
• Prophylaxis Prophylaxis Cephalosporins for deep venous thrombosis Venous thrombosis The formation or presence of a blood clot (thrombus) within a vein. Budd-Chiari Syndrome: low-dose unfractionated heparin Unfractionated heparin A highly acidic mucopolysaccharide formed of equal parts of sulfated d-glucosamine and d-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc. , of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. Anticoagulants or low-molecular-weight heparin (LMWH) if no contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation exist, such as active bleeding or significant thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia 
• Close monitoring and treatment of electrolyte abnormalities
• Nutritional support: Enteral route is preferred.
• Effectively communicate sepsis status during hand-offs.