History, Definitions, and Terminology

• In 1991, SIRS criteria were introduced as a way to identify sepsis and patients at high risk of sepsis-related death. Sepsis was defined as the presence of 2/4 SIRS criteria with evidence of infection. Severe sepsis was sepsis with organ dysfunction, and septic shock was if there was hypotension unresponsive to fluids. 
• In 2001, Sepsis-2 expanded and clarified these definitions without a complete overhaul. However, the broad nature of SIRS commonly led to misclassifications, necessitating further revision.
• Between 2014-2016, the Sepsis-3 conference elected to eliminate SIRS and severe sepsis, instead introducing SOFA and qSOFA to identify sepsis in the absence of SIRS and to focus more on organ dysfunction which narrows the spectrum of sepsis
• Now, sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection
• Septic Shock is defined as sepsis PLUS pressor need and lactate >2 without hypovolemia (after being resuscitated)

Etiology, Pathophysiology, and Clinical Complications

• Pneumonia is the most common cause of sepsis; gram-positive bacteria are more common in the U.S. but gram-negative sepsis tends to make patients sicker faster
• Gram positives have exotoxins and superantigens, GNRs have lipopolysaccharide (LPS)
• Pathophysiology - immune response to inflammation → vessel dilation → capillary leak → edema and intravascular hypovolemia → extrinsic coagulation cascade and DIC → microvascular thrombosis → tissue ischemia → organ dysfunction and acidosis
• Good urine output is reassuring, but low urine output is nonspecific
• Significant clinical complications of sepsis to be on the lookout for include vasodilation, ARDS, cholestasis, AKI, hepatic dysfunction, DIC
• Risk factors for fungemia include neutropenia, chemo, transplant, and indwelling lines

Laboratory Values in Sepsis

• Lactate elevation is most commonly attributed to hypoperfusion and is viewed as something that needs to be rapidly corrected. However, lactate may be more appropriately thought of as a reflection of endogenous epinephrine production and persistent or worsening elevation may prompt you to rethink the source of infection, your antibiotic selection, or if there is another diagnosis.
• The differential for lactatemia includes Type A (Tissue Hypoxia) caused by hypovolemia, shock, localized ischemia (mesenteric, limb), decreased oxygenation, anemia, and increased metabolic demand (seizure, rigors, exercise). Type B (No tissue hypoxia) can be caused by increased adrenergic state (albuterol, cocaine, epinephrine, pheo), decreased Krebs (thiamine deficiency, alcohol use, cyanide), liver dysfunction (decreased gluconeogenesis, reduced clearance)
• The Neutrophil/Lymphocyte Ratio (NLR) can help identify patients with early physiologic stress (endogenous cortisol and catecholamines mobilize neutrophils and kill lymphocytes) - If the ratio is 6-10+ it may suggest clinically relevant stress warranting closer monitoring
• Procalcitonin is a measure of inflammation that is sensitive to bacterial pathogens, most notably gram negatives. It has been investigated for the purpose of identifying patients unlikely to have a bacterial infection and de-escalating antibiotics in the ICU setting; however it can reasonably be used in patients already started on abx with normal immune systems who have a presentation equivocal for sepsis - if the procalcitonin is <0.5, it is less likely to be sepsis/septic shock, noting that it can take a day to become elevated

Initial Resuscitation and Fluid Management

• Some suggest the goals of resuscitation are to clear lactate, return the cap refill to <3 seconds, and improve hemodynamics and UOP. However, be wary of misinterpreting the etiology of lactate elevation and assuming poor UOP is due to prerenal AKI instead of intrinsic ATN from sepsis as it may lead to inappropriately overloading a patient. The focus should be on ensuring tissue perfusion.
• Hypovolemia is NOT the core problem in sepsis. Rather, it is vasodilation and poor perfusion from poor distribution of blood to vital organs. However, many patients with sepsis will present with hypovolemia and benefit from fluid resuscitation to achieve euvolemia. 
• A great deal of administered fluid may likely leak out of the vessels in sepsis - unless there is a compelling clinical reason to suspect otherwise, giving more than 2-3 liters of fluid is unlikely to help, and may even cause harm via overload and pulm edema
• In general, MAP is the most reliable parameter for assessing response to therapy; the primary concern with low MAP is renal injury
• A fluid challenge (250-500cc bolus) can be utilized to see if further fluid may be beneficial, however common ways we measure fluid responsiveness should be taken with a grain of salt
• Passive Leg Raise can be done rather than bolusing - raise legs to a 45-degree angle for 1 minute while lying supine and watch CVP - this is the equivalent of giving ~250-350cc
• Some prior work suggests that an adequate fluid challenge is if CVP increases >2 
• IVC diameter collapsibility <50% with inspiration suggests CVP is elevated
• Pulse Pressure Variation - validated in mechanically ventilated patients 

Vasopressor Selection and Use

• Start with Norepinephrine (Levophed) as the initial pressor; norepinephrine can be administered peripherally, but prolonged use can lead to increased risk of extravasation leading to necrosis 
• Consider adding Vasopressin when the Levophed dose reaches 5-15mcg/min or in patients who are tachycardic or at risk for arrhythmia.  Vasopressin is usually considered either on or off. It should not be used peripherally. 
• Epinephrine is typically the third agent introduced, especially when Levophed exceeds 25mcg/min; may be beneficial in patients with reduced EG, inappropriately low/normal heart rate; epinephrine infusions will increase lactate
• Phenylephrine (Neo) is chosen for increasing afterload, particularly when Levophed causes side effects like arrhythmias or in cases of AFib with RVR and hypotension, provided cardiac output is satisfactory
• Dopamine is not commonly used but can be considered for patients with bradycardia who are at low risk for arrhythmias.
• Methylene blue is a rare choice, reserved for suspected vasoplegia.

Acidosis Management

• In cases of severe acidemia (pH <7.1), which can lead to myocardial depression, decreased pressor efficacy, and increased arrhythmias, consider using bicarbonate. This is especially true if there's significant AKI.
• Bicarbonate can be administered as a 50mEq/50mL ampule or as an infusion with 150mEq in 1L D5W.
• Note: Administering bicarbonate increases pCO2 levels, which the patient must ventilate. Ensure the patient has a strong respiratory drive or be prepared for potential intubation.
• Early dialysis initiation hasn't shown consistent benefits unless there's an urgent need, remembered by the acronym AEIOU.

Steroid Use in Sepsis

• The use of steroids in sepsis remains a topic of debate. However, for septic shock, in patients refractory to low-medium doses of pressor may benefit from IV hydrocortisone at doses of 50mg every 6 hours or 100mg every 8 hours. This treatment typically lasts 5-7 days, followed by a taper based on the patient's response.
• Fludrocortisone is unlikely to add any additional benefit
• The body naturally increases cortisol production during stress, including severe infections like sepsis, as a defense mechanism against inflammation and to maintain cardiovascular stability.
• Some septic patients might experience "relative adrenal insufficiency" or "critical illness-related corticosteroid insufficiency (CIRCI)", where the adrenal glands don't produce adequate cortisol.
• Contraindications may include immunocompromise, fungal infection, poorly controlled diabetes

Fluid Management in Critically Ill Patients

• SMART Trial (NEJM, 2018): Compared balanced crystalloids to saline in critically ill adults. Found 14.3% vs. 15.4% adverse kidney events; 10.3% vs. 11.1% for in-hospital mortality at 30 days.
• Will This Hemodynamically Unstable Patient Respond to a Bolus of IV Fluids (JAMA, 2016): A study focusing on the response of hemodynamically unstable patients to IV fluid boluses.

Vasopressor Selection and Use

• SOAP II Trial (NEJM, 2010): Compared dopamine to norepinephrine in shock. Found similar 28-day mortality rates, but dopamine had an increased risk of arrhythmia.

Renal Replacement Therapy (RRT) in Septic Shock

• IDEAL-ICU Trial (NEJM, 2018): Compared early vs. delayed RRT in septic shock. For those without an urgent need for dialysis, there was no difference in 90-day mortality, and the delayed group had overall lower RRT use.

Blood Transfusion Guidelines in Sepsis

• TRISS Trial (NEJM, 2014): Compared transfusion guidelines in sepsis for patients with Hgb <7 vs. <9 goal. Found similar 90-day mortality rates, but the lower threshold used 50% fewer blood units.

Early Goal-Directed Therapy (EGDT)

• EGDT is a structured approach to treating sepsis and septic shock in the early stages, particularly during the first six hours after recognition. The concept of EGDT was introduced to optimize the management of sepsis by targeting specific physiological goals including CVP, MAP, ScvO2, UOP, and lactate.
• The approach was initially popularized by a landmark study (NEJM 2001), which suggested that EGDT could significantly reduce mortality in septic patients. 
• However, subsequent large-scale trials including ARISE (NEJM, 2014), ProCESS (NEJM, 2014), and ProMISe (NEJM, 2015) did not show a mortality benefit of EGDT over usual care, leading to some changes in sepsis management guidelines.

Adjunctive Therapies in Sepsis

• CORTICUS Trial (NEJM, 2008): Investigated the use of hydrocortisone in septic shock. Found that hydrocortisone did not significantly reduce mortality but did speed up shock reversal.
• Meta-Analysis of Corticosteroids in Treatment of Sepsis (NNT): Suggested corticosteroids might reduce the risk of short-term 28-day mortality, but likely not long-term at 90 days.
• Vitamin C, Thiamine, and Hydrocortisone in Severe Sepsis (Chest, 2017): A small trial that showed positive outcomes but hasn't become routine practice.

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