Update: What are the 2021 pharmacotherapy updates to the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock?

Background

Sepsis is defined as a severe condition characterized by life-threatening organ dysfunction due to a dysregulated host response to infection.¹ Septic shock, a subset of sepsis, is characterized by profound circulatory, cellular, and metabolic abnormalities that are associated with a higher rate of mortality than sepsis alone. It is estimated that nearly 1.7 million American adults will develop sepsis annually, leading to deaths in 270,000 patients.² In the majority of sepsis cases, infections that lead to sepsis typically begin outside of the hospital.

New Guideline

The Society of Critical Care Medicine (SCCM) published an updated guideline on the diagnosis and management of adult patients with sepsis and septic shock in December 2021,³ updating their previous 2016 guidelines.⁴ Since the 2016 guideline, new literature has been published on sepsis and sepsis care. The guideline addresses screening tools for the diagnosis of sepsis, as well as resuscitative measures, vasopressors, antimicrobial selection, and other treatment modalities. The following summary of the 2021 SCCM guidelines aims to focus on pharmacotherapy updates since the 2016 guidelines. Best Practice Statements from SCCM focused on pharmacotherapy recommendations are listed in Table 1.

Screening for Sepsis & Septic Shock

The 2021 SCCM Guidelines recommend performance improvement programs in hospitals and healthcare systems that include sepsis screening tools for acute patients, as well as standard operating procedures (SOPs) for treatment (strong recommendation, very-low quality evidence for SOPs).³ This has been changed to a recommendation in the 2021 guidelines³ from a Best Practice Statement in 2016.⁴ Standard operating procedures in hospitals and health care systems have evolved to include ‘usual care’ regimens for the treatment of sepsis, which include early identification, laboratory results, cultures, antibiotic therapy, and fluids.³ A study of 509 hospitals in the U.S. that had successfully implemented SOPs based on state-specified sepsis regulations found that hospitals with protocol-driven care were associated with significant decreases in 30-day mortality in adult patients compared to hospitals with unregulated sepsis protocols.⁵ Protocolized care was also associated with a shorter length of stay, decreases in Clostridium dificile infections, and increased central venous catheter (CVC) use.

Initial Resuscitation

For septic hypoperfusion or septic shock, it is suggested to administer at least 30 mL/kg of intravenous (IV) crystalloids within the first 3 hours of initial resuscitative efforts (weak recommendation, low quality of evidence).³ This has been downgraded from a recommendation based on strong, low-quality evidence in the 2016 SCCM guidelines.⁴ If fluid therapy beyond the initial 30 mL/kg is required, use of stroke volume (SV) and/or cardiac output (CO) can be used to guide the administration of repeat, smaller boluses.³

Mean Arterial Pressure

For adults on vasopressor therapy, an initial target mean arterial pressure (MAP) of 65 mm Hg is recommended over higher MAP targets (strong recommendation, moderate-quality of evidence). Previous SCCM guidelines recommended higher initial MAP targets⁴; however, this updated recommendation is based on the lack of benefit seen with higher MAP targets above 65 mm Hg, as well as a lack of harm noted in elderly patients with MAP targets of 60 to 65 mm Hg. Mean arterial pressures below 60 mm Hg have been associated with decreased organ perfusion.³

Antimicrobial Timing

For those with suspected septic shock or a high likelihood of sepsis, antimicrobial therapy is recommended to be given immediately, or within the first hour of recognition (strong recommendation, low quality of evidence for septic shock; strong recommendation, very-low quality evidence for sepsis). This recommendation has been updated from the 2016 SCCM guidelines that recommended antibiotics be administered as soon as possible, and within 1 hour for sepsis and septic shock.⁴ This updated recommendation is a result of observational studies that found a mortality benefit with each hour of early antimicrobial administration in patients with septic shock.^3,6-8  The data is less clear for patients with suspected sepsis without shock, which is reflected in the SCCM 2021 recommendation to administer antimicrobials within the first 3 hours of recognition after rapid clinical assessment of the underlying etiology (weak recommendation, very low quality of evidence). Additionally, in adults with a low probability of sepsis without shock, the SCCM recommends deferring antimicrobials while continuing to closely monitor the patient (weak recommendation, very low quality of evidence). These more specific recommendations are an update from the more generalized 2016 SCCM guidelines, which recommended administration of antimicrobials as soon as possible, or within 1 hour, in possible sepsis with or without shock, and in adults with a low likelihood of infection.⁴

Antimicrobial Selection

For patients at low risk for a MRSA infection, it is suggested to not include MRSA coverage in the empiric regimen (weak recommendation, low quality of evidence).³ This risk is assessed based on a variety of patient factors, such as history of MRSA infection, recent IV antibiotic therapy, hemodialysis, and recent hospital admission. Additionally, for empiric coverage in patients with sepsis or septic shock or at high risk for multidrug resistant (MDR) organisms it is suggested to include 2 antimicrobials with gram-negative coverage (weak recommendation, very low quality of evidence). For patients at low risk for MDR organisms with sepsis or septic shock, the use of only 1 gram-negative agent is suggested (weak recommendation, very low quality of evidence). Once the pathogen is identified and susceptibilities are known in septic or septic shock patients, it is suggested against using double gram-negative coverage (weak recommendation, very low quality of evidence). These updates in the 2021 guidelines outline more specific recommendations for the timing and treatment of antibiotic therapy in patients with sepsis or septic shock, since the 2016 SCCM guidelines included more generalized statements regarding empiric therapy, however, are weak recommendations based on low-quality evidence.⁴ Unaddressed in 2016 SCCM guidance, for adults with sepsis or septic shock, prolonged infusions of beta-lactam antibiotics are now suggested for maintenance therapy over conventional bolus infusions (weak, moderate quality evidence).³

Furthermore, with antimicrobial therapy in patients with sepsis and septic shock, it is suggested to monitor and assess daily for opportunities to de-escalate therapy (weak recommendation, very low quality of evidence). Shorter durations of antimicrobial therapy are also suggested over longer durations in patients with adequate source control (weak recommendation, very low quality of evidence). In patients with adequate source control where the duration of therapy is unclear, it is suggested to combine procalcitonin levels and clinical evaluation to determine when to discontinue antimicrobials (weak recommendation, low quality of evidence). Procalcitonin levels, however, are suggested against in combination with clinical evaluation versus clinical evaluation alone when deciding when to initiate antimicrobials (weak recommendation, very-low quality evidence). The aforementioned recommendations are all considered new to the 2021 SCCM guidelines and are not addressed in 2016 guidance.^3,4

Antifungal Therapy

In adults with sepsis or septic shock with a high risk of fungal infection, empiric antifungal coverage is suggested (weak recommendation, low quality of evidence).³ Empiric antifungal therapy is suggested against in patients at a low risk for fungal infection (weak recommendation, low quality of evidence). Risk factors for fungal infection include immunosuppression, use of total parenteral nutrition (TPN), use of broad-spectrum antibiotics, and extended ICU stays, among others. The 2021 SCCM guidance regarding the coverage of fungal infections are more specific in nature compared to previous guidance, as antifungal therapy recommendations are now stratified based on high-and low risk status.

Antiviral Therapy

In the 2021 SCCM guidance, no recommendations were made on the use of antiviral agents.

Hemodynamic Management

In adults with sepsis or septic shock, crystalloids are recommended as first-line fluids for resuscitation (strong recommendation, moderate-quality evidence). Balanced crystalloids are suggested over normal saline for resuscitation (weak recommendation, low quality evidence), a change from the 2016 SCCM guidance for either balanced crystalloids or saline solution, with no preference.^3,4 The use of crystalloids prevents adverse events such as hyperchloremic metabolic acidosis, increased cytokine secretion as well as acute kidney injury (AKI). Balanced crystalloids, when compared to normal saline, have been associated with no differences in mortality, or lower mortality across several studies.^9-12  The lack of benefit and elevated cost of albumin also supports the recommendation for crystalloids as first-line fluids for resuscitation.³ In adults with sepsis or septic shock, it is suggested to reserve albumin for patients who receive large volumes of crystalloids (weak recommendation, moderate quality of evidence).

There are several agents that should be avoided during resuscitation in patients with sepsis or septic shock. The 2021 SCCM guidelines recommend against using starches for resuscitation (strong recommendation, high-quality of evidence), which has not changed from 2016 guidance.^3,4 The use of hydroxyethyl starch (HES) is associated with an increased use of renal replacement therapy (RRT) and increases in mortality.^13,14 In addition, gelatins are suggested against in resuscitation (weak recommendation, moderate quality of evidence), due to a lack of mortality benefit, an association with a greater risk of anaphylaxis compared to crystalloids, and an increased risk of RRT compared to normal saline.^14-17 This recommendation is based on upgraded evidence since 2016, which suggested crystalloids over gelatins based on low-quality evidence.⁴

Furthermore, there is insufficient evidence on the use of restrictive versus liberal fluid administration strategies in the presence of persistent hypoperfusion during the first 24 hours after the initial resuscitative period (no recommendation).³ From the 2016 SCCM guidelines, balanced crystalloids or saline were recommended for fluid resuscitation, with no guidance on the volume of administration.⁴

Vasoactive and Inotrope Therapies

For treatment of hypoperfusion with sufficient volume status, norepinephrine is recommended as a first-line agent over other vasopressors (strong recommendation).³ Norepinephrine is more potent than dopamine, and has been associated with lower risk of arrhythmias and mortality versus dopamine in a systematic review (SR) and meta-analysis (MA) of 11 randomized controlled trials (RCTs).¹⁸ The SCCM 2021 guidance also states that if norepinephrine is not available, then epinephrine or dopamine can be used, however, in patients with an increased risk for arrhythmia, the use of these agents should be carefully monitored.³ If hypoperfusion persists, the SCCM suggests adding vasopressin instead of increasing the dose of norepinephrine (weak recommendation, moderate quality of evidence). The addition of vasopressin has shown a lower risk of atrial fibrillation, and improved survival in patients with less severe shock compared to norepinephrine alone.^19,20 The SCCM also states that in their SR of 10 RCTs, vasopressin with norepinephrine was associated with decreased mortality, but did not reduce the need for RRT, and did not decrease the risks of digital ischemia or arrhythmias compared to norepinephrine therapy alone.³ If vasopressin add-on therapy to norepinephrine does not provide adequate MAP levels, it is suggested to add epinephrine (weak recommendation, low quality of evidence). The use of epinephrine may not provide additional benefit based on the saturation of the alpha-1 receptors by norepinephrine use, however, the SCCM states that epinephrine may be useful in refractory septic shock in patients with cardiac dysfunction. Dobutamine is also suggested as add-on therapy to norepinephrine for patients with cardiac dysfunction, or epinephrine can be used alone (weak recommendation, low quality of evidence). Dobutamine can increase cardiac output and oxygen transport but can also result in severe vasodilation. Based on an indirect comparison MA, dobutamine with epinephrine resulted in no mortality benefit when compared to using no ionotropic agents.²¹ The SCCM states that no evidence currently supports the superiority of dobutamine over epinephrine.³

Several agents are suggested against to achieve adequate MAP. Terlipressin is suggested against due to increases in adverse events observed in studies (weak recommendation, low quality of evidence). Increases rates of digital ischemia and also diarrhea have been observed with terlipressin when compared to norepinephrine.²² Furthermore, 2021 guidance from the SCCM states that levosimendan is suggested against based on no mortality benefit in comparison to dobutamine (weak recommendation, very low quality of evidence).³ Levosimendan has also been associated with an elevated risk of supraventricular tachyarrhythmia and less successful weaning from mechanical ventilation when compared to no inotropic agent use.²³

Monitoring and IV Access

The SCCM suggests starting vasopressors peripherally to restore MAP in the absence of central venous access so as not to delay treatment (weak recommendation, very low quality of evidence), however, this is only recommended for a short period of time (< 6 hours).³ A major concern for this route of administration is the risk for extravasation; however, in a SR of 7 studies, extravasation only occurred in 3.4% of patients.²⁴ Extravasation is least likely to occur when a well-placed peripheral catheter is proximal to the antecubital fossa.²⁵ This recommendation is new in the 2021 SCCM guidance, and was not addressed in the 2016 guidelines.^3,4

Use of Neuromuscular Blocking Agents

In adults with moderate to severe sepsis-induced acute respiratory distress syndrome (ARDS), the use of intermittent boluses of neuromuscular blocking agents (NMBA) is suggested over continuous infusions of NMBA (weak recommendation, moderate quality of recommendation).³ In the 2016 guidelines, the SCCM gave a weak recommendation for using an NMBA infusion for 48 hours.⁴ The SCCM states that this updated guidance is based on recent data that illustrates the unclear effects of the infusion versus bolus method on outcomes such as ventilator-free days, duration of ventilation, and ICU-acquired weakness.³

Additional Therapies

For patients in septic shock and receiving norepinephrine or epinephrine at a dose of ≥0.25 mcg/kg/min for at least 4 hours, it is suggested to administer IV corticosteroids (weak recommendation, moderate quality of evidence). The SCCM states that an updated MA found that IV corticosteroid use accelerated the resolution of shock and increased the number of vasopressor-free days, however, an increase in neuromuscular weakness was observed.³ This recommendation was upgraded from a weak recommendation with low quality of evidence in the 2016 SCCM guidelines which suggested against hydrocortisone use unless the patient was hemodynamically unstable.⁴

Although patients with septic shock or sepsis may experience hyper-inflammation and immunosuppression, the 2021 SCCM guidelines suggest against the use of IV immunoglobulins (IVIG) (weak recommendation, low quality of evidence).³ The SCCM states that the lack of high-quality evidence, and the cost of the treatment make this a weak recommendation. Previous guidance from 2016 was also a weak recommendation against its use.⁴

For adults with sepsis or septic shock with a high risk of gastrointestinal (GI) bleeding, stress ulcer prophylaxis is suggested (weak recommendation, moderate quality of evidence).³ Recent evidence has shown no mortality benefit, and a reduction in GI hemorrhage.^3,26 The SCCM also states that a recent MA has also shown an increased risk of C. dificile infection with proton pump inhibitor (PPI) use.³

For adults with sepsis or septic shock, venous thromboembolism (VTE) prophylaxis is recommended unless contraindicated (strong recommendation, moderate quality of evidence). Low molecular weight heparin (LMWH) is also recommended over unfractionated heparin (UFH) for VTE prophylaxis (strong recommendation, moderate quality of evidence). Patients with sepsis or septic shock are at an increased risk for developing VTE or pulmonary embolism (PE). The 2016 guidance found that the use of LMWH had shown lower rates of deep vein thrombosis (DVT) development compared to UFH with no significant differences in bleeding, incidence of PE, or mortality.⁴ Furthermore, the utility of LMWH as a once-daily injection makes it a more feasible option. The SCCM states that mechanical VTE prophylaxis is suggested against in addition to pharmacologic prophylaxis, over pharmacologic prophylaxis alone (weak recommendation, low quality of evidence). From the 2016 SCCM guidelines, mechanical VTE prophylaxis was recommended to use in addition to pharmacologic prophylaxis whenever feasible.⁴ However, due to cost-effectiveness and lack of evidence to support add-on therapy, it is not recommended to use dual prophylaxis.³ In patients with sepsis or septic shock for whom pharmacologic prophylaxis is contraindicated, the use of mechanical prophylaxis may be warranted.

Patients with sepsis or septic shock with AKI requiring RRT are suggested to receive either continuous or intermittent RRT (weak recommendation, low quality of evidence).  The SCCM states that additional meta-analyses assessing the 2 methods of RRT have shown no differences in mortality or treatment effects.^3,27,28 The SCCM states that because of higher rates of central venous access device (CVAD) infection with earlier initiation of RRT, as well as the risk versus benefits of delayed versus early treatment, RRT without a definitive treatment indication (e.g. uremic complications, refractory acidemia, refractory fluid overload, hyperkalemia) is suggested against (weak recommendation, low quality of evidence).³

Insulin therapy is recommended in adults with sepsis or septic shock with glucose levels of ≥ 180 mg/dL (strong recommendation, moderate quality of evidence). This is primarily based on the 2018 American Diabetes Association (ADA) recommendations for glycemic control in critically ill patients, which recommends the initiation of insulin therapy in patients with persistent glucose readings > 180 mg/dL, with a target glucose range of 140-180 mg/dL.²⁹

For adults with sepsis or septic shock, the use of IV ascorbic acid is suggested against (weak recommendation, low quality of evidence).³ Ascorbic acid, used in combination with hydrocortisone and thiamine, was thought to be beneficial based on anti-inflammatory properties, but the overall effects of treatment are judged as small with a low quality of evidence.

Unchanged from the 2016 SCCM guidelines, sodium bicarbonate therapy is suggested against for hypoperfusion-induced lactic academia to improve hemodynamics or reduce vasopressor requirements (weak recommendation, low quality of evidence). The use of sodium bicarbonate is suggested, however, in septic shock with concurrent severe metabolic academia (pH ≤ 7.2) and AKI (Acute Kidney Injury Network [AKIN] score 2 or 3; weak recommendation, low quality of evidence).

Transitions of Care

For adults with sepsis or septic shock, it is suggested that a handoff process of critical information occur during transitions of care, versus no handoff process (weak recommendation, very low quality of evidence), though there is insufficient evidence for a specific structured handoff tool.

Conclusion

The 2021 SCCM guideline provides new and updated recommendations regarding the management of adult patients with sepsis or septic shock. Additional information on the management of sepsis and septic shock not pertaining to pharmacotherapy, including tools for sepsis scoring, ventilator recommendations, nutritive care recommendations, as well as others, can be found in the 2021 SCCM Surviving Sepsis guideline, and the reader is directed to the guideline for further information.

References

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25. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30(3):653.e659-617. doi:10.1016/j.jcrc.2015.01.014
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28. Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis. 2002;40(5):875-885. doi:10.1053/ajkd.2002.36318
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Prepared by:
Cydnee Harris
PharmD Candidate Class of 2022
University of Illinois at Chicago, College of Pharmacy

Christie Denton, PharmD
Clinical Assistant Professor, Drug Information Group
University of Illinois at Chicago, College of Pharmacy

March 2022

The information presented is current as of February 18, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.