URMC- Adult Non-Invasive Sepsis Resuscitation Protocol Overview

URMC – Adult Non-Invasive Sepsis Resuscitation Protocol For use with Adult* patients where goals of care are curative Patient has 2 or more of the following criteria: Temp <36 or >38 RR >20 HR>90 WBC <4 or > 12 or > 10% bands Acute Mental Status Change N Does not meet sepsis criteria, continue supportive care SIRS Y START SEPSIS CLOCK HOUR 0 Identify reasons for SIRS criteria N Patient has known or suspected infection? Consider VS q4hrs x3 Y Source Control ? Infected Catheter ? Operative Intervention ?Drainable pus Notify provider for orders Obtain Blood Cultures** Broad spectrum antibiotics after cultures** STAT Lactate** SEPSIS Y Supplemental Oxygen to maintain SpO2 >92% Continue supportive care Monitor for s/sx of hypoperfusion Acute mental status change ↓ urinary output Cool/clammy skin Delayed capillary refill Cyanosis Recheck lactate in 2-4 hours If lactate ↑ or SBP <90 restart protocol SBP <90 or Lactate ≥ 4*** N Y SEVERE SEPSIS RRT CONSULT - ADMITTED PATIENTS Crystalloid Bolus – 30mL/kg** (bolus as rapidly as possible) HOUR 1 RAPID RESPONSE TEAM CONSULT - ADMITTED PATIENTS SBP <90 Lactate ≥ 4 ***or <20% lactate clearance N ***Lactate ≥ 2 and <4 Consider VS q2hrs x2 then q4 x3 Y SEPTIC SHOCK N Review goals of care with patient/family. Goals of care remain curative? Comfort oriented care HOUR 3 Y ICU CONSULT – ALL PATIENTS Crystalloid Bolus – 30mL/kg** (bolus as rapidly as possible) ICU CONSULT - ALL PATIENTS Continue rapid fluid resuscitation Goal: MAP >65, Normal Serum Lactate (Most pts with severe sepsis/septic shock require ≥ 5L in the first 6 hrs) Obtain consent and establish central venous access Initiate Septic Shock Management Protocol * - refer to attached guidelines ** - provider order required © University of Rochester Medical Center Guidelines are intended to be flexible. They serve as reference points or recommendations, not rigid criteria. Guidelines should be followed in most cases, but there is an understanding that, depending on the patient, the setting, the circumstances, or other factors, guidelines can and should be tailored to fit individual needs.

URMC – Adult Septic Shock Management Protocol For use with Adult* patients where goals of care are curative Ensure Sepsis Resuscitation Protocol Initiated Consider the following therapies for continued management of septic shock CVP < 8 (CVP <12 if intubated) MAP <65 ScvO2 < 70 (only after CVP & MAP goals met) NS 500mL boluses q 30 min until goal Initiate Vasopressor (see below) Consider PRBC transfusion for HCT < 30 Maintenance IVF once target CVP met ≥8 (≥ 12 if intubated) Titrate to MAP ≥ 65 Consider Dobutamine 2.5-20 mcg/kg/min Recheck CVP after each bolus until goal and then in 4 hours Obtain ScvO2 (central venous oxygen saturation) Recheck ScvO2 q 2 hours until ≥70 Check lactate q 2 hours until > 20 % lactate clearance and then in 4 hours Goal – normalization of lactate Vasopressors: Norepinephrine as the first choice vasopressor. (usual range 1-80 mcg/min ) Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. (usual range 0.01- 1 mcg/kg/min) Vasopressin can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage in the setting of refractory hypotension. (usual range 0.01-0.04 units/min) Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). (usual range 1-20 mcg/kg/min) Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. (usual range 20-200 mcg/min) Inotropic Therapy: A trial of dobutamine infusion may be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP (usual range 2.5-20 mcg/kg/min) * - refer to attached guidelines © University of Rochester Medical Center Guidelines are intended to be flexible. They serve as reference points or recommendations, not rigid criteria. Guidelines should be followed in most cases, but there is an understanding that, depending on the patient, the setting, the circumstances, or other factors, guidelines can and should be tailored to fit individual needs.

Sepsis: Epidemiology 750,000 cases per year 200,000 deaths per year Increased incidence and mortality with age and co-morbidity 2/3 occur in hospitalized patients Incidence increasing in the North America Angus et.al., CCM 2001:291303-1310

Systemic Inflammatory Response Syndrome (SIRS) A complex systemic response which includes two or more of the following manifestations: Fever or hypothermia (>38oc or < 36oc) Tachycardia (> 90 beats/min) Tachypnea (> 20 breaths/min) WBC count of > 12,000 or <4,000 cells/mm3 or > 10% immature neutrophils CCM 20:864-874, 1992

Assess if the patient has 2 more of the following criteria Elderly patients have a blunted immune response – late signs Increased systemic vascular resistance “clamped down” – poorer outcomes Assess if the patient has 2 more of the following criteria Temp <36 or >38 RR>20 HR>90 WBC <4 or >12 or >10% bands Acute Mental Status Change Additional findings SBP <90 Lactate > or = to 4 Lactate clearance <20% Correction for Acidosis Compensation for hypotension – intravascular shifts Immature cells… we have exhausted frontline defenses Decrease in cerebral profusion pressure, end organ hypoperfusion, elevated C02 Fluid leaking into tissue By product of anaerobic metabolism

Nursing Interventions Blood cultures x 2 – add Lactate Culture from lines as well (HD/CVC/PICC/IVAD/PD cath) Fungal culture? Immunosuppressed? – Isolator tubes Urine analysis with culture (Urosepsis?) Strict I/O – “is the tank full?” watch UO with IVF – UO is the “poor mans CVP” – if we give IVF and have adequate UO (30 cc/hr) we have “a full tank” think next steps…vasopressors (next slide) Hemodynamic monitoring CVP (normal= 5-10) – CVC port for reading Arterial line Obtain ABG (Lactic acidosis  Metabolic acidosis) Fluid resuscitation is crucial… patients may receive 5 and 6 liters of NS Fluid overload? Maintain ventilation

Vasoactive Medications Norepinephrine as the first choice vasopressor. (usual range 1-80 mcg/min ) Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure. (usual range 0.01- 1 mcg/kg/min) Vasopressin can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage in the setting of refractory hypotension. (usual range 0.01-0.04 units/min) Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). (usual range 1-20 mcg/kg/min) Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target. (usual range 20-200 mcg/min)

ICU Sepsis information CVP < 8 (CVP <12 if intubated) MAP <65 ScvO2 < 70 (only after CVP & MAP goals met) NS 500mL boluses q 30 min until goal Initiate Vasopressor (see below) Consider PRBC transfusion for HCT < 30 Maintenance IVF once target CVP met ≥8 (≥ 12 if intubated) Titrate to MAP ≥ 65 Consider Dobutamine 2.5-20 mcg/kg/min Recheck CVP after each bolus until goal and then in 4 hours Obtain ScvO2 (central venous oxygen saturation) Recheck ScvO2 q 2 hours until ≥70

Confirmed or suspected infection, plus > 2 SIRS criteria Sepsis Severe Sepsis Confirmed or suspected infection, plus > 2 SIRS criteria Sepsis plus > 1 organ dysfunction CCM 20:864-874, 1992

Septic Shock Sepsis with hypotension (SBP < 90 mm Hg or a reduction of > 40 mm Hg from baseline) despite adequate fluid resuscitation along with perfusion abnormalities: Lactic acidosis Oliguria Altered mental status CCM 20:864-874, 1992

Sepsis: Etiology 1/2 culture positive cases are gram negative organisms 1/2 gram positive organisms 2 - 5% fungi or mixed infections Mycobacteria, rickettsiae, viruses and protozoans may cause sepsis 1/3 of cases culture negative

Sepsis Defined “Sepsis is a clinical syndrome characterized by systemic inflammation due to infection… Even with optimal treatment, mortality due to severe sepsis or septic shock is approximately 40 percent and can exceed 50 percent in the sickest patients” “Sepsis results when the response to infection becomes generalized and involves normal tissues remote from the site of injury or infection” “Significant derangement in metabolic autoregulation, the process that matches oxygen availability to changing tissue oxygen needs, is typical of sepsis. In addition, microcirculatory and endothelial lesions frequently develop during sepsis. These lesions reduce the cross-sectional area available for tissue oxygen exchange, disrupting tissue oxygenation and causing tissue ischemia and cellular injury” UpToDate2013 SIRS Overview from the Cleveland Clinic This slide has the Slide Design template “content” applied. The first level bullet has been set up with a “null” character to make it appear unbulleted and still allow automatic bullets for subsequent levels. The second through fifth levels have bullets: from the left margin, tab once (or click the “increase indent” button) and the second level bullet will appear; further tabbing increases the indent and produces the corresponding bullet.

Sepsis: A Network of Cascading Events INFLAMMATION PROINFLAMMATORY MEDIATORS Activated Protein C T TM ANTI-INFLAMMATORY MEDIATORS PAI-1 T-PA TAF-1 INFECTION ENDOTHELIAL INJURY TF Severe sepsis is associated with three integrated components: Infection with the systemic activation of inflammation. During progression of sepsis, a wide variety of proinflammatory cytokines is released. Endotoxin induces rapid increases in the levels of tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) in experimental models of sepsis. These proinflammatory cytokines are linked to the development of the clinical signs of sepsis. Release of proinflammatory cytokines is associated with endothelial injury and vascular bed-specific changes in the thrombogenicity of the endothelium.These can include increased tissue factor (TF) expression in a subset of endothelial cells and release of plasminogen activator inhibitor-1 (PAI-1). Activation of coagulation. Inflammatory changes trigger the extrinsic pathway of coagulation. Activation of coagulation in patients with sepsis is not always disseminated intravascular coagulation. Instead, in most patients, it is a subclinical activation of the hemostatic system as indicated by changes in commonly measured hemostatic parameters. Experimentally, there are increases in thrombin-antithrombin (TAT) complexes. Clinical laboratory findings include significant increases in D-dimer, a marker of coagulation and associated fibrinolysis. Impairment of fibrinolysis. In patients with sepsis, plasminogen levels fall rapidly while antiplasmin levels remain normal. This decreases the normal fibrinolytic response. Fibrinolysis is further impaired by release of PAI-1 and the generation of increased amounts of thrombin-activatable fibrinolysis inhibitor (TAFI). Although plasminogen/antiplasmin ratio and PAI-1 levels remain abnormal in nonsurviving patients, they tend to normalize in survivors. Kidokoro A, Iba T, Fukunaga M, et al. Alterations in coagulation and fibrinolysis during sepsis. Shock. 1996;5:223-28. Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest. 1997;27:3-9. Lorente JA, Garcia-Frade LJ, Landin L, et al. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103:1536-42. van Deventer SJH, Buller HR, ten Cate JW, et al. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990;76:2520-6. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost. 1998;24:33-44. COAGULATION FIBRINOLYSIS Copyright © 2001, Eli Lilly and Company. All rights reserved.

Circulation Hypotension is related to the process where at a cellular vasodilators are released in a effort to match the oxygen demand or organs and tissue. The result is systemic vasodilation which further impairs profusion. There is also a decrease in ADH (vasopressin levels) which can also affect blood pressure In the heart an large blood vessels there is decreased systolic and diastolic performance. Cardiac output can be maintained via Frank Starlings mechanism but not all patients can compensate. In small vessels leading to and from organs there is impaired vasoconstriction which leads to hypoperfusion In the capillaries the cells lose the ability to extract oxygen maximally In the endothelium cellular changes result in coagulopathies and increased membrane permeability which leads to tissue edema.

Lungs/Nervous system Endothelial injury affect capillary blood flow which enhances microvascular permeability which leads to alveolar pulmonary edema. There is a ventilation-perfusion mismatch that leads to hypoxemia. Can result in ARDS. The most common sign is encephalopathy. Changes in metabolism and alterations in cell signaling are due to inflammatory mediators.

GI tract/Liver/Kidneys The gut’s normal barrier function is impaired which leads to bacterial movement and a worsened septic response. The liver normally acts as the first line defense in clearing bacteria but dysfunction can lead to spillover of these bacteria into the systemic circulation. Patients with sepsis often suffer from acute renal failure where hypoperfusion and hypoxia lead to renal injury. Patients may require dialysis and can improve survival rates.