Sepsis Management in Adults: Pharmacotherapy Focus

Full update November 2021

The chart below summarizes select pharmacotherapeutic interventions in sepsis/septic shock in adults. This information is mostly based on the Surviving Sepsis Campaign guidelines, available at https://pubmed.ncbi.nlm.nih.gov/34605781/. Quick identification and treatment of sepsis saves lives.1 To this end, the certain interventions are grouped into “bundles” or interventions intended to be started within a certain timeframe (one, three, or six hours) of recognition of sepsis or septic shock.1-3 Bundles have evolved from years of data from quality improvement initiatives and other studies.2 The Hour-1 components are denoted in the chart below (footnote “a”). Resources pertaining to the Hour-1 bundle can be found at https://www.sccm.org/SurvivingSepsisCampaign/Guidelines/Adult-Patients. Sepsis is a CMS quality measure.

Intervention/Indication

Associated Testing or Monitoring

Comments

Fluids

For hypotension or shock, or lactate
≥4 mmol/L [36 mg/dL].1,2,a

At least 30 mL/kg of IV crystalloid is suggested within the first three hours.1,a

Balanced crystalloids (e.g., LR, Normosol-R, Plasma-Lyte A) are suggested over NS to potentially decrease risk of hyperchloremic metabolic acidosis, acute kidney injury, or mortality (in a prespecified subgroup of critically ill patients with sepsis) [Evidence level B-2].1,13

After initial fluid resuscitation, additional fluid boluses can be given (e.g., 4 mL/kg) per volume status monitoring.1

Albumin is suggested for patients who have received large volumes of crystalloids (but confers no mortality benefit).1

It is recommended that starches (e.g., hetastarch) not be used in resuscitation, and gelatin is suggested against.1

Serum lactate.1,a

Dynamic measures (e.g., passive leg raises with CO measurement, fluid challenge against stroke volume measurement) are suggested over physical exam, or static measures such as CVP alone.1

Capillary refill: adjunct to other perfusion measures.1

The fixed bolus is based on usual practice and volumes used in the ProCESS, ARISE, and ProMISe studies.1 There are no studies comparing different volumes.1

Some experts suggest bolusing in 500 mL increments per response.9

The best weight to use in obese patients (IBW, adjusted, or actual) is unclear. CMS allows use of IBW for BMI >30 kg/m2 if documented.12

CMS allows less fluid for documented advanced heart failure or advanced kidney disease.12

In a study suggesting benefit of balanced crystalloids over NS, only ~15% of total patients had sepsis.13

If CO or SV cannot be measured, a passive leg raise test with pulse pressure measurement can be used.1

CVP has limited utility to predict a response to a fluid challenge within the range of 8 to 12 mmHg (“normal”).3

Antimicrobials

For patients with septic shock, started within one hour.1,a

MRSA coverage is recommended for patients at high risk of MRSA (e.g., MRSA history; recent IV antibiotics or hospitalization; chronic wound; dialysis).1

Double gram-negative coverage is suggested for patients at high risk of MDR gram-negatives.1

An antifungal is suggested for patients at high risk of fungal infection (e.g., febrile neutropenia despite ≥4 days of antibiotics; immunocompromise).1

Optimize dosing based on pharmacodynamics and pharmacokinetics (e.g., for beta-lactams, after a bolus, use prolonged infusion for maintenance).1

Blood cultures: draw before starting antimicrobials if it will not cause treatment delay (e.g., >45 min).1,a

Procalcitonin: utility is limited for antimicrobial initiation decisions, but suggested for use with clinical evaluation to make treatment duration decisions.1

Rapid diagnostic techniques: use to facilitate de-escalation.1

Mortality benefit of quick initiation is clearest for shock1. For possible sepsis (without shock), consider a short (≤3 hours) investigation for infection before starting.1 For patients with a low likelihood of infection (without shock), consider postponing antimicrobials and monitoring closely.1

De-escalate when possible (e.g., look for alternative diagnoses if infection is unconfirmed; switch from double to single gram-negative coverage once the organism is identified).1

For most common infections, five to seven days of antibiotic treatment is as effective as longer durations.1

CMS no longer specifies which antibiotics are appropriate.12

Vasopressors

For MAP of <65 mmHg during or after fluid resuscitation, started peripherally if central access is not already in place.1,2

Norepinephrine is first-line.1 (If norepinephrine is not available, consider epinephrine or dopamine.1)

Consider vasopressin 0.03 units/min if response is inadequate to norepinephrine or epinephrine
0.25 to 0.5 mcg/kg/min.1

Epinephrine: also used as add-on.1

Target MAP of 65 mmHg, using invasive monitoring if available.1

Also monitor perfusion and cardiac output.1

Epinephrine and dopamine pose risk of arrhythmias.1

Epinephrine can increase lactate production, making it hard to use lactate as a monitoring parameter.1

Dobutamine can reduce MAP.1

Angiotensin II could be used as an adjunct to increase MAP (e.g., in refractory shock or to limit norepinephrine dose).1,11

Starting norepinephrine before or during fluid resuscitation may limit the amount of fluid needed and does not seem to be harmful [Evidence level B-3].10

Inotropic agents

For persistent hypoperfusion despite

adequate volume and MAP.1

Epinephrine is suggestedin place of norepinephrine.1

Dobutamine can be added to norepinephrine.1

VTE Prophylaxis

For patients with sepsis or septic shock.1

LMWH (preferred) or UFH is recommended, unless contraindicated.1

Use mechanical prophylaxis if pharmacologic prophylaxis is contraindicated.1

NA

Dalteparin (Fragmin) or UFH is preferred if CrCl <30 mL/min.3

There is no clear benefit of combining pharmacologic with nonpharmacologic prophylaxis.1

Insulin

Glucose level ≥180 mg/dL.1,6

Use an insulin infusion in critically ill patients.1

Target glucose 144 to 180 mg/dL.1

Glucose targets were chosen to minimize the risk of hypoglycemia.1

Sodium bicarbonate

Suggested for septic shock, blood pH ≤7.2, and AKIN score 2 or 3.1

Consider sodium bicarbonate 4.2%, 125 to 250 mL over 30 min. Max 1,000 mL within 24 hours.4

Target arterial pH >7.3.4

Guidelines suggest against use for lactic acidemia due to hypoperfusion, to improve hemodynamics or to reduce vasopressor needs.1

Stress Ulcer Prophylaxis

Suggested for patients with risk factors for GI bleed.1

Proton pump inhibitors or H2-blockers.3

NA

Proton pump inhibitors pose risk of Clostridioides difficile colitis.1

Corticosteroids

Suggested for septic shock with continuing vasopressor need (norepinephrine or epinephrine
≥0.25 mcg/kg/min at least four hours after starting) to maintain MAP.1

Usual corticosteroid is hydrocortisone 50 mg IV every six hours or 200 mg/day as a continuous infusion.1

In recent RCTs (VANISH, ADRENAL, APROCCHSS), duration was ~7 days.1

Cortisol and ACTH are not useful to help determine which septic patients will respond to steroids.3

Meta-analyses have found that corticosteroids reduced duration of shock, vasopressor use, mechanical ventilation, and ICU stay.1,7

Continuous infusion preferred over boluses to minimize hyperglycemia.3

Blood

Transfuse when hemoglobin <7 g/dL (or higher in extenuating circumstances [e.g., ACS, hemorrhage, etc]).1

NA

Hemoglobin

Recommendation based on the TRISS, TRICC, and TRICOP studies.1

Vitamin C

Suggested against in current guidelines.1

50 mg/kg in 50 mL D5W every six hours for 96 hours has been used.5

NA

No effect on mortality.1

Might reduce vasopressor use.5

  1. Hour-1 bundle component.2
  2. Screening: Suspect sepsis in acutely ill, high-risk patients.1 Tools include SIRS criteria, NEWS, or MEWS.1 NEWS may be the most sensitive [Evidence level B-3].8 qSOFA should not be used alone due to poor sensitivity.1 A blood lactate level is also suggested.1,a Repeat if >2 mmol/L.2

Abbreviations: ACTH = adrenocorticotrophic hormone; ACS = acute coronary syndrome; AKIN = Acute Kidney Injury Network; ASAP = as soon as possible; BMI = body mass index; CMS = Centers for Medicare and Medicaid Services; CO = cardiac output; CVP = central venous pressure; GI = gastrointestinal; IBW = ideal body weight; ICU = intensive care unit; LMWH = low-molecular-weight heparin; IV = intravenous; LR = Lactated Ringer’s; MAP = mean arterial pressure; MDR = multidrug resistant; MEWS = Modified Early Warning Score; MRSA = methicillin-resistant Staphylococcus aureus; NEWS = National Early Warning Score; NS = normal saline; SIRS = systemic inflammatory response syndrome; qSOFA = quick Sequential Organ Failure Assessment; UFH = unfractionated heparin; VTE = venous thromboembolism

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

References

  1. Evans L, Rhodes A, Alhazzani W. et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med 2021;49:e1063-143.
  2. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med 2018;44:925-8.
  3. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017;45:486-552.
  4. Jaber S, Paugam C, Futier E, et al. BICAR-ICU Study Group: sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a mulicentre, open-label, randomised controlled, phase 3 trial. Lancet 2018;392:31-40 [abstract]. [Erratum in Lancet 392:2440].
  5. Fowler AA 3rd, Truwit JD, Hite RD, et al: Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial. JAMA 2019; 322:1261-70. [erratum in JAMA 2020;323:379.].
  6. The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-97.
  7. Rygard SL, Butler E, Granholm A, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2018;44:1003-16 [abstract].
  8. Liu VX, Lu Y, Carey KA, et al. Comparison of early warning scoring systems for hospitalized patients with and without infection at risk for in-hospital mortality and transfer to the intensive care unit. JAMA Network Open 2020;3:e205191.
  9. Marik PE, Byrne L, van Haren F. Fluid resuscitation in sepsis: the great 30 mL per kg hoax. J Thorac Dis 2020;12(Suppl):S37-47.
  10. Ospina-Tascon GA, Hernandez G, Alvarez I, et al. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care 2020;24:52. https//doi.org/10.1186/s13054-020-2756-3.
  11. Shi R, Hamzaoui O, DeVita N, et al. Vasopressors in septic shock: which, when, and how much. Ann Transl Med 2020;8:794. http://dx.doi.org/10.21037/atm.2020.04.24.
  12. Albritton N, Witt J. CMS Hospital Inpatient Quality Reporting (IQR) Program. Severe sepsis and septic shock: management bundle (composite measure) v.10 measure updates. Questions and answers. June 30, 2021. https://www.qualityreportingcenter.com/globalassets/iqr2021events/iqr63021/6_30-sepsis-webinar-qa-document_vfinal508.pdf. (Accessed October 12, 2021).
  13. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378:829-39.

Cite this document as follows: Clinical Resource, Sepsis Management in Adults: Pharmacotherapy Focus. Hospital Pharmacist’s Letter/Pharmacy Technician’s Letter. November 2021. [371119]

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