• Shyam Murali

The Surviving Sepsis Campaign Guidelines 2016


Sepsis is a dysregulated inflammatory response to infection that can lead to severe consequences, such as organ dysfunction and death. It had a global incidence of 437 per 100,000 person-years between the years 1995 and 2015 and its rates have only increased, likely due to advancing age, immunosuppression, and multi-drug resistant infection. Fortunately for us, the Surviving Sepsis Campaign has put together a list of easy to follow guidelines and recommendations that help us treat our patients in an evidence-based method.


In this post, I am hoping to save you the hours and hours it takes to read their document by summarizing it here in an easy-to-read format. Of note, these guidelines were published in 2017, and there has been new research published in the field since then. There is also significant contention over many of these topics; feel free to have those discussions in the comments below in a collegial manner.


Some of the guidelines have a "strong" recommendation, while others are designated as "weak" recommendations. The guidelines also include "Best Practice Statements" (statements where the benefit or harm is unequivocal, but the evidence is hard to summarize or assess using their methodology). I have included those designations as (S), (W), or (BPS), respectively, in this recap.


Strap yourself in, because this is gonna be a long ride...


Initial Resuscitation

  • Treat sepsis immediately (BPS)

  • 30mL/kg IV fluid bolus of crystalloid within the first three hours for patients with sepsis-induced hypoperfusion (S)

  • Following initial bolus, give additional fluids as guided by frequent reassessment of hemodynamic (HD) status (BPS)

  • Use further HD assessment (eg. echocardiography) to determine the type of shock (BPS)

  • Use dynamic over static variables (W) - Passive leg raises - Fluid challenges against stroke volume measurements - Variations in systolic pressure, pulse pressure, or stroke volume to changes in intrathoracic pressure induced by mechanical ventilation. > Pulse pressure variation has a sensitivity of 72% and a specificity of 91% for fluid responsiveness

  • Target an initial Mean Arterial Pressure (MAP) of 65mmHg in septic shock requiring vasopressors (S) - Targeting higher MAP improves cardiac index but does not improve other variables (renal function, arterial lactate levels, oxygen delivery and consumption, or MORTALITY AT 28 DAYS OR 90 DAYS). MAPs of 85 had higher risk of arrhythmias. Subgroup with chronic hypertension had reduced need for RRT at MAP 85.

  • Normalize lactate if elevated (W) - Serum lactate level may represent tissue hypoxia, accelerated aerobic glycolysis driven by excess beta-adrenergic stimulation, or other causes (e.g., liver failure) - Reduction in mortality with lactate-guided resuscitation - Remeasure lactate if initial value is elevated >2mmol/L - This method of resuscitation has no impact on ICU Length of Stay (LOS) - Counterpoint: A recent trial, the Andromeda Shock trial, had findings that does not necessarily support lactate-guided resuscitation. Check out these posts about the trial: RebelEM, EM Nerd on EMCrit, EM Lit of Note, St. Emlyn's, and The Bottom Line


Screening and Performance Improvement

  • Have performance improvement programs via formal screening efforts and improved management of patients once they are identified as being septic (BPS)

  • Consider implementation of the core set of recommendations into a “bundle”

  • Performance improvement programs increase compliance with SSC bundles and reduce mortality


Diagnosis

  • Obtain blood cultures (aerobic and anaerobic) prior to starting antimicrobial therapy, if no substantial delay (SSC recommends less than 45 minutes; sterilization due to antibiotics occurs within minutes to hours after first dose) (BPS)

  • Risk/benefit ratio favors rapid administration of antimicrobials if it is not logistically possible to obtain cultures promptly

  • Do not “pan culture” unless the source is not clinically apparent


Antimicrobial Therapy

  • Administer IV antibiotics ASAP, within 1 hour of recognition (S) - Delays have adverse effects on mortality, LOS, acute kidney injury (AKI), acute lung injury (ALI), and organ injury - Assess causes of delays to accelerate appropriate antimicrobial delivery

  • Use empiric broad-spectrum therapy with one or more antibiotics to cover all likely pathogens (S) - Choice is dependent on patient’s history, clinical status, and local epidemiologic factors: > Anatomic site of infection with respect to typical pathogens at the site and ability of antimicrobials to penetrate that site > Prevalent pathogens within the community, hospital, and even hospital ward > Resistance and susceptibility patterns of those prevalent pathogens > Presence of specific immune defects (neutropenia, splenectomy, poorly controlled HIV infection, and acquired/congenital immunoglobulin defects, complement, or leukocyte function/production) > Age and patient comorbidities (chronic illness, chronic organ dysfunction, presence of invasive devices, recent infections or colonization) - Consider potential drug intolerances and toxicity - Err on the side of over-inclusiveness - Majority of patients with severe sepsis/septic shock have some form of immunocompromise, so initial regimen should be broad enough to cover most pathogens isolated in healthcare-associated infections: carbapenem, extended-range penicillin/β-lactamase inhibitor - Additional anti-gram-negative antibiotic for critical ill patients - Vancomycin, teicoplanin, or other anti-MRSA antibiotic, if risk factors present - Macrolide or fluoroquinolone, if significant risk of Legionella infection - Consider antifungals (echinocandin, if severely ill) for immunocompromised, prolonged invasive vascular devices, TPN, necrotizing pancreatitis, recent major surgery, prolonged broad-spectrum antibiotics, prolonged hospital/ICU admission, recent fungal infection, and multisite colonization - Use your local antibiogram

  • Empiric therapy to be narrowed once pathogen and sensitivities identified (BPS) - Approximately 1/3 of patients with sepsis do not have a causative pathogen identified - Thoughtfully de-escalate antibiotics based on adequate clinical improvement even if cultures are negative

  • Do not use sustained systemic antibiotic prophylaxis in severe inflammatory states of noninfectious origin (burns, pancreatitis, etc) (BPS) - Brief prophylaxis for specific invasive procedures may be appropriate

  • Optimize dosing strategies by accepted pharmacokinetic/pharmacodynamic principles and other drug properties (BPS) - Initial fluid resuscitation increases the volume of distribution for antimicrobials and causes suboptimal drug levels in patients with sepsis and septic shock - Aminoglycosides: once daily dosing of 5-7mg/kg gentamicin equivalents; if mild renal function impairment, same dose but decreased frequency. Trough concentrations should be sufficiently low to minimize potential for renal toxicity. - Fluoroquinolones: optimize dose within a nontoxic range (Cipro 600mg q12hrs, Levo 750mg q24hrs, assuming preserved renal function) - β-lactam: increased frequency of dosing; consider continuous/extended infusion - Vancomycin: use 25-30mg/kg loading dose for sepsis/septic shock, trough target of 15-20mg/L

  • Use empiric combination therapy (with at least two antibiotics of different classes) aimed at most likely pathogen(s) for septic shock (W)

  • No combination therapy for non-shock sepsis, including bacteremia (W) - Except to broaden coverage

  • No combination therapy for routine treatment of neutropenic sepsis/bacteremia (S) - Except to broaden coverage

  • If combination therapy is used for septic shock, de-escalate to discontinuation of combination therapy within the first few days if there is evidence of clinical improvement or infection resolution (BPS)

  • Duration of antibiotics - 7-10 days is adequate for most serious infections with sepsis and septic shock (W) - Longer courses appropriate in patient who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus, some fungal and viral infections, or immunologic deficiencies, including neutropenia (W) - Shorter courses if rapid resolution following effective source control of intra-abd or urinary sepsis and those with anatomically uncomplicated pyelo (W) - Perform daily assessment for de-escalation of antimicrobial therapy w/sepsis and septic shock (BPS) - Treatment of 3-5 days was as effective as treatment of up to 10 days for intra-abdominal sepsis; <7 days as effective as longer for acute pyelo w/ or w/o bacteremia, uncomplicated cellulitis, and SBP - Prolong antimicrobial therapy if there is slow clinical response, undrainable foci of infection, bacteremia with S. aureus (14 days if uncomplicated, 6 weeks if complicated [endocarditis, implanted prosthesis, positive follow-up blood cultures, continued fever, metastatic infection]), candidemia, some viral infections, and immunologic deficiencies (W)

  • Measure procalcitonin to support shortening duration of antibiotics (W)

  • Procalcitonin can be used to support discontinuation (W) - Procalcitonin-based algorithms can speed safe antimicrobial de-escalation without adverse effect on mortality


Source Control

  • Rapidly control anatomic sources of infection in sepsis/septic shock as soon as medically and logistically practical (BPS)

  • Promptly remove intravascular access devices that are possible sources after other vascular access is established (BPS)


Fluid Therapy

  • Fluid challenge techniques should be applied where fluid administration is continued as long as HD factors improve (BPS)

  • Crystalloids for initial resuscitation and subsequent intravascular volume replacement - Balanced vs Normal Saline – no recommendations in SSC - Avoid hyperchloremia

  • Either balanced or saline (W)

  • Albumin in addition to crystalloids when patients require substantial amounts of fluids (W) - There may be some improved mortality, especially in septic shock patients or those requiring high volumes of IV fluids

  • No hydroxyethyl starches for intravascular volume replacement (S)

  • Use crystalloids over gelatins when resuscitating patients (W) - Low quality studies and high cost of gelatin


Vasoactive Medications

  • Norepinephrine as first choice (S) - Increases MAP due to vasoconstrictive effects with little effect on heart rate and stroke volume - Lower mortality and risk of arrhythmias when compared to dopamine

  • Add Vasopressin (0.03U/min) or epinephrine if needed (W) - Epinephrine > clinical trials do not demonstrate worsening of clinical outcomes > no difference in mortality, but increase in adverse drug-related events with epi compared to norepi > May increase aerobic lactate production via stimulation of skeletal muscle β2-adrenergic receptor - Vasopressin (0.03U/min) > Levels in septic shock are lower than anticipated for shock state > Higher doses are associated with cardiac, digital, and splanchnic ischemia, should be reserved for situations in which alternative vasopressors have failed - Phenylephrine > Pure α-agonist > Splanchnic vasoconstriction > Use should be limited until more research is available

  • Use dopamine as alternate to norepi in highly selected patients (low risk of tachyarrhythmias and absolute or relative bradycardia) (W) - No low-dose dopamine for renal protection

  • Dobutamine for patients with evidence of persistent hypoperfusion despite adequate fluid loading and vasopressors (W) - Can be first-choice inotrope for patients with measured or suspected low cardiac output in the presence of adequate LV filling pressure (or adequate fluid resuscitation) and adequate MAP. - Other inotropes > PDE inhibitors (milrinone, levosimendan): increase intracellular cAMP -> inotropic effects independent of β adrenergic receptors > Levosimendan: not better than dobutamine and has higher risk of SVT than placebo

  • Patients requiring vasopressors should have an arterial catheter placed as soon as practical (W) - Remove as soon as it is not necessary Here's my favorite post on arterial lines from PulmCrit on EMCrit.


Corticosteroids

  • Do not use IV hydrocortisone to treat septic shock if adequate fluid resuscitation and vasopressors restore hemodynamic stability (W) - Use IV hydrocortisone at 200mg per day if fluids and vasopressors do not work (W) - Improved mortality, increased proportion of shock reversal by day 7 and day 28

  • Etomidate will suppress HPA axis; increased mortality when etomidate is used before application of low-dose steroids

  • Make sure to taper the dose


Are you still with me...?

Blood Products

  • RBC transfusion only for Hgb<7.0 in the absence of MI, severe hypoxemia, or acute hemorrhage (S) - TRISS trial: compared transfusion threshold of 7.0 vs 9.0 in septic shock: similar 90 day mortality, ischemic events, and use of life support - Similar result from ProCESS trial

  • Do not use erythropoietin for anemia associated with sepsis (S)

  • Do not use FFP to correct clotting abnormalities in the absence of bleeding or planned invasive procedures (W) - No RCTs exist related to prophylactic FFP transfusion - Can give FFP if there is a documented deficiency of coagulation factors AND active bleeding or before surgical/invasive procedures

  • Give platelet transfusion when (W) - platelets <10,000/mm3 in the absence of bleeding - platelets <20,000 if significant risk of bleeding - platelets >50,000 with active bleeding, surgery, or invasive procedures


Immunoglobulins

  • Do not use IV immunoglobulins in patients with sepsis and septic shock (W)


Blood Purification

  • No recommendations

  • Trials are small, unblinded, and have high risk of bias


Anticoagulation

  • Do not use antithrombin (S) - Decrease in antithrombin at onset of sepsis correlates with DIC and lethal outcome - Phase III clinical trial of high-dose antithrombin for sepsis/septic shock and systematic reviews of antithrombin for critically ill patients did not demonstrate any beneficial effect on overall mortality - Increases risk of bleeding

  • No recommendation about thrombomodulin or heparin


Mechanical Ventilation

  • Use Tidal Volume of 6mL/kg PBW for sepsis-induced Acute Respiratory Distress Syndrome (ARDS) (S)

  • Upper limit plateau pressures 30cmH2O for sepsis-induced ARDS (S)

  • No single mode of ventilation has consistently been shown to be advantageous when compared to any other

  • Higher PEEP over lower PEEP in adults with sepsis induced moderate to severe ARDS (W) - Opens up lung units to participate in gas exchange; increases lung compliance - Prevents atelectrauma - Methods of deciding how much PEEP to use: > Minimizing driving pressure (plateau pressure minus PEEP) --> favorable balance of lung recruitment and overdistension > Titrate PEEP upward on 6mL/kg PBW until plateau pressure is 28cmH2O > Use PEEP/FiO2 titration table

  • Use recruitment maneuvers with severe ARDS (W). Options include: - Temporarily raise transpulmonary pressure to open atelectatic alveoli - Apply sustained CPAP: improves survival, reduces occurrence of severe hypoxia requiring rescue therapy - Monitor closely during recruitment maneuvers

  • Prone over supine for sepsis induced ARDS with P/F ratio<150 (S) - Prone within 36 hours of intubation, >16 hours/day --> improved survival - Reduced mortality, improved oxygenation, improved compliance - Increase in pressure sores

  • For refractory hypoxia, consider APRV and ECMO

  • Do not use high-frequency oscillatory ventilation for sepsis induced ARDS (S) - Higher mortality, increased duration of mechanical ventilation, increase in barotrauma

  • No recommendations about noninvasive ventilation for sepsis-induced ARDS

  • HFNC may have a role

  • Use neuromuscular blocking agent for less than 48hrs in patients with sepsis induced ARDS and P/F ratio <150 (W) - Improve chest wall compliance, prevent respiratory dyssynchrony, and reduce peak airway pressures and barotrauma - Decreased oxygen consumption - Improves survival and more organ failure-free days without increased risk of ICU-acquired weakness - Mechanisms by which NMBAs produce or contribute to myopathies and neuropathies are unknown

  • Conservative fluid strategy for patients with established sepsis induced ARDS without evidence of tissue hypoperfusion (S)

  • Do not use β2-agonist for sepsis-induced ARDS without bronchospasm (S) - Reduce survival to hospital discharge in ARDS patients and reduce ventilator-free days - Cause arrhythmias and tachycardia - Use them for bronchospasm and hyperkalemia

  • Do not use routine PA catheter for sepsis induced ARDS (S)

  • Use lower TV over higher TV in patients with sepsis-induced respiratory failure without ARDS (W)

  • HOB 30-45 degrees to minimize aspiration and VAP (S)

  • SBTs for patients who are ready for weaning (S)

  • Use standardized protocol for weaning (S)


Sedation and Analgesia

  • Minimize continuous or intermittent sedation in mechanically ventilated sepsis patients; target specific titration end points (BPS) - Reduces duration of mechanical ventilation and LOS and allows earlier mobilization - Propofol and precedex are more shorter acting and result in better outcomes than benzodiazepines


Glucose Control

  • Use a protocolized approach to glucose management in sepsis (S)

  • Commence insulin dosing when two consecutive glucose levels >180mg/dL - Target <180mg/dL as derived from the NICE-SUGAR trial

  • Monitor every 1-2 hours until values and infusion rates are stable, then every 4 hours if patient is receiving insulin infusion (BPS)

  • Use arterial line blood rather than capillary blood for glucose testing (W) - Capillary blood sugar may be inaccurate


Renal Replacement Therapy

  • Use continuous or intermittent RRT in patients with sepsis and AKI (W) - Can be used to facilitate management of fluid balance in hemodynamically unstable septic patients (W) - Do not use for increase in creatinine or oliguria without other definitive indications for dialysis (W)


Bicarbonate Therapy

  • Do not use sodium bicarbonate to improve hemodynamics or to reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH greater than 7.15 (W) Learn about the BICAR-ICU Trial from the Wiki Journal Club post.


Venous Thromboembolism Prophylaxis (ppx)

  • Use UFH or LMWH in the absence of contraindications (S)

  • LMWH > UFH (S) - Overall decrease in costs of care - Reduction in rates of PE and HIT

  • Combination pharmacologic and mechanical ppx (W)

  • Use mechanical ppx when pharmacologic ppx is contraindicated (W)


Stress Ulcer Prophylaxis

  • Give stress ulcer ppx only to patients with sepsis/septic shock who have risk factors for GI bleeding (S) - Mechanical ventilation for >48 hours - Coagulopathy - Preexisting liver disease - Need for RRT - Higher organ failure scores

  • PPIs or H2 antagonists (W)


Nutrition

  • Do not use early parenteral nutrition alone or in combination with enteral feedings in septic patients who can be fed enterally (S)

  • Use IV glucose and advance enteral feeds as tolerated instead of administering parenteral nutrition over the first 7 days if enteral feeding is not feasible (S) - Increased risk of infection if parenteral nutrition started early

  • Use enteral feeding early rather than fasting the patient or using IV glucose (W) - Physiologic advantages: maintenance of gut integrity and prevention of intestinal permeability, dampening of the inflammatory response, and modulation of metabolic responses that may reduce insulin resistance - Early enteral feeding reduced death and pneumonia

  • Consider early trophic/hypocaloric or full enteral feeding (W) - Trophic/hypocaloric: goal feeds remained at less than 70% of standard caloric targets for at least a 48hr period before they were titrated toward goal - No differences in outcomes between trophic/hypocaloric vs early full enteral feeding - Insufficient evidence for use in malnourished patients

  • Do not use omega-3 fatty acids as an immune supplement (S) - Increased mortality and fewer ventilator-free and ICU-free days in ALI patients - Uncertainty of benefit, potential for harm, and the excess cost and varied availability

  • Do not routinely monitor gastric residual volumes; measure in patients with feeding intolerance or those who are considered to be high risk of aspiration (W) - Relationship between measurement of GRVs and outcomes of vomiting, aspiration, or pneumonia has not been consistently confirmed - Strategy of not monitoring was non-inferior compared to monitoring q6hrs with regard to VAP, death at 28 and 90 days - Measure if patient has demonstrated feeding intolerance: vomiting, reflux of feeds into the oral cavity - Post-surgical patients excluded from the studies

  • Use prokinetic agents (metoclopramide, domperidone, and erythromycin) in critically ill patients with sepsis/septic shock and feeding intolerance (vomiting, aspiration of gastric contents, or high GRVs) (W) - These meds prolong QT interval and ventricular arrhythmias, increase risk for sudden cardiac death. Monitor QT regularly. - Assess need daily and stop when not needed

  • Place post-pyloric feeding tubes in septic patients with feeding intolerance or those at high risk of aspiration (W) - Not always easily available and easily placed - Small reduction in pneumonia risk, no effect on death, aspiration, or vomiting

  • Do not use IV selenium, arginine, or glutamine (S) - Arginine lead to reduced nitric oxide synthesis, loss of microcirculatory regulation, and enhanced production of superoxide and peroxynitrite > could lead to unwanted vasodilation and hypotension - Glutamine can improve gut mucosal atrophy and permeability, possibly leading to reduced bacterial translocation; enhance immune cell function, decrease proinflammatory cytokine production, and increase glutathione and antioxidative capacity - No consistent reduction in mortality

  • No recommendation about carnitine


Setting Goals of Care

  • Discuss goals of care and prognosis with patients and families (BPS) - Establish realistic ICU treatment goals - Use proactive family care conferences to identify advance directives and treatment goals - Promotes communication and understanding between the patient’s family and the treating team; improves family satisfaction; decreases stress, anxiety, and depression in surviving relatives; facilitates end-of-life decision-making; and shortens ICU LOS for patients who die in the ICU

  • Incorporate goals of care into treatment and end-of-life care planning (S)

  • Utilize palliative principles where appropriate (S) - enhances the ability to recognize pain and distress; establishes the patient’s wishes, beliefs, and values, and their impact on decision-making; develops flexible communication strategies; conducts family meetings and establish goals of care; provides family support during the dying process; helps resolve team conflicts; and establishes reasonable goals for life support and resuscitation

  • Address as early as feasible, but no later than within 72 hours of ICU admission (W)



Phew...this summary was long, but trust me, the original article was much longer. Fortunately, it was jam packed with a ton of evidence-based recommendations.


Use the comments box below to post your thoughts about the manuscript.

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