Critical - Sepsis

• Sepsis and septic shock are major healthcare issues, impacting millions globally each year.
• Mortality rates range from 1 in 3 to 1 in 6 affected individuals with some countries still experiencing septic shock mortality rates of approximately 50%
• Over the last 30 years faster recognition and treatment have come about through improved research and clinical processes
• In 2016, the definition of sepsis was refined to emphasize organ dysfunction in the context of infection.

Evolution of Sepsis Definitions

• Circa 750 a.c, Sepsis was described as "putrefaction" or the "decay of organic matter."
• 1800's Germ Theory posited sepsis originated from harmful microorganisms
• 1913, proposed patients die from the body's reaction to the infection, not the infection itself.
• 1914, focus was on infection-induced inflammation and invasion of the bloodstream causing symptoms
• 1992, introduced SIRS criteria to define sepsis, which was later expanded upon at a conference in 2001
• 2016, sepsis as a life-threatening organ dysfunction resulting from infection

Sepsis 1 Definition (1991)

• SIRS: Systemic Inflammatory Response Syndrome
  • Temperature: > 38°C or < 36°C
  • Heart Rate: > 90 beats/min
  • Respiratory Rate: > 20 breaths/min OR PaCO2 < 32mmHg
  • White Blood Cells: > 12,000/cu mm, or < 4000/cu mm, or > 10% immature forms
• Sepsis defined as a systemic response to infection manifested by ≥ 2 SIRS criteria plus infection
• Sepsis is considered severe when associated with organ dysfunction or hypoperfusion.
• Septic shock occurs when sepsis-induced hypotension persists despite fluid resuscitation.

Sepsis 2 Definition (2001)

• Documented or suspected infection
• PLUS:
• General Parameters:
  • Fever > 38.3°C or hypothermia, HR > 90 beats, Respiratory rate > 30/m, altered mental status significant edema, or hyperglycemia
• Inflammatory Parameters:
  • Leukocytosis, Leukopenia, or normal WBC count with > 10% immature forms, or increased Plasma C reactive protein & procalcitonin.
• Hemodynamic Parameters:
  • Arterial hypotension mixed venous oxygen saturation > 70%, or Cardiac index > 3.5 L/ min /m².
• Organ Dysfunction Parameters:
  • Hypoxemia, acute oliguria, coagulation abnormalities, thrombocytopenia, or hyperbilirubinemia.
• SIRS signs alone are insufficient to identify patients at risk of organ dysfunction.
• The overlap includes SIRS, Infection, and Sepsis.

Sepsis 3 Definitions (2016)

• Life-threatening organ dysfunction caused by a dysregulated host response to infection.
• Sepsis is suspected or documented infection with an acute increase of ≥ 2 SOFA points.
• Septic shock is sepsis coupled with persisting hypotension requiring vasopressor therapy to maintain MAP ≥ 65 mmHg and Lactate > 2 mmol/L (18 mg/dL) after adequate fluid resuscitation.

Etiology of Sepsis

• Sepsis can be community-acquired (80%) or hospital-acquired.
• Lung infections are the most common while infections in the abdomen, bloodstream, and renal/genitourinary tracts are also likely
• Most Common Gram-Positive Bacteria Pathogens:
  • Staphylococcus aureus
  • Coagulase-negative Staphylococcus.
• Gram-Negative Bacteria Pathogens:
  • Escherichia coli
  • Klebsiella pneumoniae
• Neutropenic patients are at risk from Invasive candidiasis and uncommon pathogens
• Antimicrobial-resistant bacteria:
  • MRSA
  • Vancomycin-resistant Enterococci

Diagnosis and Screening

• SIRS criteria alone are insufficient for identifying at-risk patients
• Septicemia, which refers to sepsis with positive blood cultures is rarely used now
• Blood cultures are not commonly positive.

Clinical Manifestations of Septic Shock

• Cardiovascular System: Hypotension, altered microcirculation, altered echocardiography variables, and elevated Lactate levels
• Hepatic System: Elevated Bilirubin and liver enzymes
• Renal System: Oliguria, increased Serum creatinine, increased Blood urea nitrogen, and increased Biomarkers
• Neurological System: Altered mentation, confusion, disorientation
• Respiratory System: Hypoxemia and reduced PaO2:FiO₂ ratio
• Haematological System: Low platelet count and Disseminated intravascular coagulation with Petechiae

Sepsis Screening

• Screening is done using:
  • SIRS Criteria (considered positive if ≥ 2 criteria are fulfilled), these have low specificity
  • Quick Sequential Organ Failure Assessment (qSOFA) criteria
  • Sequential Organ Failure Assessment (SOFA) criteria
  • National Early Warning Score (NEWS)
  • Modified Early Warning Score (MEWS

Quick SOFA Score (qSOFA)

• Can predict poor outcomes, and not recommended as a sole screening tool for sepsis.
• qSOFA is considered positive if ≥ 2 of the following are present:
  • Hypotension: Systolic blood pressure ≤ 100 mm Hg
  • Altered mental status
  • Tachypnea: Respiratory rate ≥ 22/min

qSOFA Score - Quick Sequential Organ Failure Assessment Score

• Identifies patients at higher risk for adverse outcomes.
• Measures include: Respiratory Rate > 22 breaths / min, Systolic BP < 100 mmHg, and Altered Mental Status of GCS < 14.
• qSOFA Scores of ≥2 have a 3 to 14-fold increase in In-hospital mortality.

SOFA Score

• The SOFA score is determined upon admission to the ICU
• Measures Respiratory, Coagulation, Liver, Cardio-vascular, CNS and Renal function

SOFA Score Interpretation

• SOFA scores related to mortality are:
  • 0-6, <10%
  • 7-9, 15-20%
  • 10-12, 40-50%
  • 13-14, 50-60%
  • 15, >80%
  • 15-24, >90%

Diagnostic Algorithm for Sepsis

• If infection is suspected, assess qSOFA, then SOFA followed by evaluating for organ dysfunction and administering antibiotics as needed.
• In sepsis, vasopressors may be required to maintain MAP ≥65 mm Hg and serum lactate level >2 mmol/L?

Sepsis Bundles

• Prior to 2001, there were no guidelines for early sepsis management
• In 2001, the critical "golden hours" spurred the beginning of early goal-directed therapy (EGDT)
• Before 2001, EGDT included:
  • Central venous pressure (CVP) of 8–12 mmHg
  • Mean arterial pressure (MAP) of 65 mmHg
  • Urine output of 0.5 ml/kg/h
  • Superior vena cava oxygen saturation (ScvO2) or mixed venous saturation of 70% or 65% Respectively
• The Surviving Sepsis Campaign (SSC) launched in 2004 aimed to improve management and survival from sepsis via diagnosis
• SSC incorporated two sepsis care bundles in 2008 including:
  • Resuscitation bundle to be achieved in 6-h
  • Management bundle to be completed within 24-h
• In 2012 the 6-h resuscitation bundle was modified into a 3-h resuscitation bundle and a 6-h septic shock bundle
• By 2018, the 3h- & 6h bundles were combined into a 1-h bundle
• The Hour 1 bundle has five essential elements:
  • Obtain serum lactate
  • Draw blood cultures prior to antibiotic administration
  • Begin rapid IV fluid bolus if MAP < 65 mm Hg or lactate ≥ 4 mmol/L
  • Use vasopressors to keep MAP ≥ 65 mm Hg
  • Administer broad-spectrum antibiotics.

Hour-1 Bundle for Initial Resuscitation for Sepsis and Septic Shock Includes

• Measure initial serum lactate; remeasure if elevated (> 2 mmol/L)
• Obtain blood cultures prior to administering antibiotics
• Administer broad-spectrum antibiotics
• Begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥ 4 mmol/L
• Apply vasopressors to maintain MAP ≥ 65 mm Hg if hypotensive during or after fluid resuscitation

Treatment of Sepsis and Septic Shock

• Should be undertaken as a medical emergency with a focus on source removal.
• 2021 SSC Guidelines:
  • Screening and early treatment
  • Initial Resuscitation
  • Mean arterial pressure
  • Admission to ICU
  • Infection
  • Source control
  • Fluid management
  • Vasoactive agents
  • Inotropes
  • Monitoring and IV access
  • Ventilation
  • Additional therapies

Screening and Early Treatment

• SSC recommends against using qSOFA compared to SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock.
• Studies show qSOFA is more specific but less sensitive than 2 of 4 SIRS criteria for early identification.
• Of infected patients, 24% had a qSOFA score 2 or 3 accounting for 70% of poor outcomes.

Initial Resuscitation

• Sepsis is an emergency, begin resuscitation immediately.
• 30 mL/kg of intravenous (IV) crystalloid fluid within 3 hours.
• Correct hypovolemia by increasing cardiac output and increasing oxygen delivery.
• Use dynamic measures to guide fluid resuscitation, rather than physical examination or static parameters alone
• Dyanmic measures include:
  • Passive leg raising combined with cardiac output (CO) measurement
  • Fluid challenges against stroke volume (SV)
  • Systolic pressure or pulse pressure
• These have demonstrated better diagnostic accuracy at predicting fluid responsiveness compared with static techniques
• Guide resuscitation and decrease serum lactate in patients with elevated lactate levels
• Use capillary refill time to guide resuscitation as an adjunct to other measures of perfusion

Mean Arterial Pressure (MAP)

• Initial (MAP) should be 65 mm Hg better than higher MAP targets.
• RCT in septic shock found targeting a MAP of 65-70 resulted in no difference in mortality
• Higher MAP with vasopressors was associated with a higher risk of atrial fibrillation.

Admission to Intensive Care

• Admit patients to the ICU within 6hr
• Assessment and evaluation should not be delayed

Infection Control

• Re-evaluate and search continuously for alternative diagnoses and discontinue empiric antimicrobials if the cause is determined or strongly suspected.
• There is no "gold standard” test to diagnose sepsis.
• A third or more of patients initially diagnosed with sepsis turn out to have non-infectious conditions.
• Obtain Appropriate routine microbiologic cultures before starting antimicrobial therapy within < 45 min

Antimicrobial Choice

• If a patient is a high risk, use an antibiotic that covers MDR/MRSA organisms

MRSA coverage

• In adults with sepsis or septic shock, use empiric antimicrobials when high risk for patients of MRSA infection.

Patient-related risk factors for MRSA

• Prior history of MRSA infection/colonization
• Recent IV antibiotics
• History of recurrent skin infections or chronic wounds
• Presence of invasive devices
• Haemodialysis
• Recent hospital admissions
• Severity of illness

MDR coverage

• In adults with sepsis or septic shock, use 2 antimicrobials with gram negative coverage over 1 gram negative agent for high risk patients of MDR organisms

Risk factors for MDR

• Proven infection or colonization with antibiotic-resistant organisms within preceding year
• Local prevalence of antibiotic-resistant organisms
• Hospital acquired (versus community acquired infection)
• Broad-spectrum antibiotic use within the preceding 90 days.
• Concurrent use selective digestive decontamination (SDD)

Fungal coverage

• For adults with sepsis or septic shock, use empiric antifungals when high risk for patients of fungal infection

Risk factors for Candida sepsis

• Candida colonisation at multiple sites
• Surrogate markers such as Serum Beta-D-Glucan assay
• Neutropenia
• Immunosuppression
• Severity of illness (High APACHE score)
• Longer ICU length of stay
• Central venous catheters and other intravascular devices
• Persons who inject drugs
• Total parenteral nutrition
• Broad spectrum antibiotics
• Gastrointestinal tract perforations and anastomotic leaks
• Emergency gastrointestinal or hepatobiliary surgery
• Acute renal failure and haemodialysis
• Severe thermal injury

Risk factors for endemic yeast

• These include cryptococcus, histoplasma, blastomyces, coccidioidomycosis
  • Antigen markers
  • HIV infection
  • Solid organ transplantation
  • High dose corticosteroid therapy
  • Haematopoietic stem cell transplantation
  • Certain biologic response modifiers
  • Diabetes mellitus
• Restricting antimicrobial therapy to the shortest course associated with better outcomes is an important part of antimicrobial stewardship

Duration VS De-escalation

• Suggested Daily assessment for de-escalation of antimicrobials over using fixed durations of therapy
• For patients with adequate source control, use shorter duration of antimicrobial therapy
• If unclear, use procalcitonin AND clinical evaluation over clinical evaluation alone

Source Control

• Rapidly identify and correct infections where possible.
• Promptly remove any devices that are a cause.

Fluid Management

• Use balanced crystalloids instead of normal saline for resuscitation
• Adverse effects for normal saline include, Hyperchloremic metabolic acidosis, Renal vasoconstriction, Increased cytokine secretion, and Concern about acute kidney injury (AKI)
• In patients who received large crystalloids use albumin
• Avoid starches and gelatin for resuscitation

Vasoactive Agents

• First Line: Norepinephrine over other vasopressors
• Second Line: Add Vasopressin instead of escalating the dose of norepinephrine if inadequate MAP levels persist
• Third Line: Add Epinephrine if inadequate MAP levels persist
• Terlipressin is not recommended for adults with septic shock
• Exercise caution when using dopamine and epinephrine due to risk for arrhythmias
• If norepinephrine is unavailable, epinephrine can be used as an alternative

Inotropes

• In adults with septic shock and cardiac dysfunction with persistent hypoperfusion despite adequate volume status and arterial blood pressure:
  • add dobutamine to norepinephrine or, epinephrine alone

Monitoring & Intravenous Access

• Invasive arterial blood pressure monitoring recommended
• If no central venous access is available, vasopressors peripherally to restore mean arterial pressure rather than delaying initiation, until central access is secured.

Additional Therapies

• Septic shock patients who need vasopressors may need IV hydrocortisone
  • The typical corticosteroid used IV hydrocortisone
  • Dose of 200 mg/day, given as 50 mg intravenously every 6 h or as a continuous infusion.
  • It is suggested to be started at a dose of norepinephrine or epinephrine ≥ 0.25 mcg/kg/min at least 4 h after initiation
• Use a restrictive better than liberal transfusion strategy with haemoglobin
• However, RBC transfusion should not be guided by haemoglobin concentration alone
• Assess the patient & note considerations such as Acute myocardial ischaemia, Severe hypoxemia, or Acute haemorrhage
• Administer Pharmacologic venous thromboembolism (VTE) prophylaxis, Low molecular weight is better than unfractioned heparin
• Do not use just mechanical VTE prophylaxis, in addition to pharmacological prophylaxis alone
• Start insulin therapy when glucose is ≥180 mg/dL (10 mmol/L)
  • Typical target blood glucose range is 144–180 mg/dl (8–10 mmol/L).
• Do not use Sodium Bicarbonate unless patients have severe metabolic acidemia
• Stress Ulcer Prophylaxis should be done for patients at risk of gastrointestinal bleeding.
• IV Vitamin C is not recommended