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Current sepsis research

What nurses need to know

Seckel, Maureen A. MSN, RN, APRN, ACNS-BC, CCNS, CCRN, FCCM, FCNS

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doi: 10.1097/01.CCN.0000654796.79252.dc
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Figure
Figure

Sepsis is a major cause of mortality in the US, with a reported one out of three inpatient hospital deaths due to sepsis.1 Despite recently published definitions and guidelines that provide a framework for the care of patients with sepsis, there is no strong consensus among healthcare providers and in the literature on all aspects of recognition and management of this deadly disease.2,3 In addition, no one screening tool or test that is specific and sensitive to sepsis is yet available.

In order to fill the research gaps and increase the strength of evidence-based practice, an abundance of sepsis literature is published annually. It is overwhelmingly time-consuming for nurses practicing at the bedside to keep up with the rapid pace of sepsis literature, distill the research, and discern whether any given recommendation is appropriate to incorporate into practice. Although not inclusive of all sepsis literature recently published, this article highlights some of the recent significant research and discusses implications for nursing practice.

Sepsis recognition

The Sequential Organ Failure Assessment (SOFA) score is a tool used as an objective measure of organ dysfunction in critical illness, including sepsis.4 A SOFA score of 2 or more points from the patient's baseline is abnormal and indicates an increased mortality risk.2,4 The CDC has published an electronic SOFA tool (eSOFA) that can be used as part of a hospital toolkit for sepsis surveillance.5 (See SOFA vs. eSOFA.)

Rhee and colleagues conducted a retrospective cohort study of adult patients in a large database of 111 hospitals. They compared SOFA scores with eSOFA scores in patients diagnosed with sepsis and validated in a four-hospital health system.6 The results showed that the eSOFA tool had high internal consistency or correlation with the SOFA score (Cronbach's alpha, 0.81).6 Mortality was higher in patients with eSOFA at 17.1% versus 14.4% with statistical significance (P < .001) along with better discrimination for mortality.6

Take-home points from this study: Neither eSOFA nor SOFA were designed to identify patients with sepsis. The eSOFA tool was designed to be a retrospective surveillance tool to track sepsis incidence and outcome monitoring for quality improvement, while SOFA is useful for predicting already-identified patients with sepsis who are at risk for higher mortality by scoring organ dysfunction. Both tools are useful to retrospectively track patients with sepsis, and eSOFA data may be easier to obtain from the electronic health record. This study showed that eSOFA scores compare favorably with SOFA scores in assessing mortality risk and may be useful to use for facility or system performance improvement opportunities.5,6

Table
Table:
SOFA vs. eSOFA

Treatment

Researchers continue to investigate drugs and other treatment strategies in a search for more effective therapies for patients with sepsis. Here is a discussion of some recent studies and their implications for clinical practice.

Vasopressors. Angiotensin II, a vasoactive peptide hormone, is a potent vasoconstrictor produced in the kidneys as part of the renin-angiotensin system.7 In a multicenter, randomized control trial with a placebo arm, Khanna and colleagues enrolled adults with vasodilatory (distributive shock) on high-dose vasopressors after a minimum of 25 mL/kg of volume resuscitation.8 Vasodilatory shock is the most common type of shock and is characterized by peripheral vasodilation and hypotension despite preserved cardiac output, with sepsis being the most common cause.9 Over 80% of the patients enrolled in this study had septic shock. Patients received either an infusion of angiotensin II (n = 163) or a placebo (n = 158).8 Results showed that patients in the angiotensin II group had statistically significant improvements in mean arterial pressure (MAP) during the first 3 hours (initiation phase) (69.9% versus 23.4% in the placebo group, P < .001).8 Additionally, a significantly greater increase of 12.5 mm Hg in MAP was found for patients in the angiotensin II group versus 2.9 mm Hg in the placebo group (P < .001).8 During the first 48 hours, the angiotensin II group also had statistically significantly decreased dosing of other vasopressors, with the mean change in norepinephrine dosing (mcg/kg/min) of -0.03 ± 0.10 versus 0.03 ± 0.23, P < .001.8 There was no change in mortality at day 7 or day 28 between the angiotensin II and placebo groups. Thromboembolic events were the most common adverse reaction in the angiotensin II group (12.9% versus 5%).8

Take-home points for this study: Angiotensin II increased BP in patients already on a high-dose vasopressor who had vasodilatory shock, but it did not change mortality.8 The study was sufficiently powered to show superiority in the angiotensin II group in increasing MAP and decreasing the doses of other vasopressors.8

As an addendum, the study was published in 2017, angiotensin II received FDA approval in late 2017, and it became available on the market in 2018.10 This is the first new vasopressor available to critical care practitioners in many years and is very specific to patients with septic shock. In the next few years, expect to see case series and other published data from centers that have added angiotensin II to their formulary.

Vitamin C, hydrocortisone, and thiamine. This combination has been suggested as synergistic adjunctive therapy for patients with sepsis and septic shock to treat decreased organ perfusion and impaired oxygen delivery and to reduce mortality.11 In a retrospective, before/after case series at one hospital, Marik and colleagues compared 47 sepsis patients who were treated with vitamin C, hydrocortisone, and thiamine with 47 sepsis patients who were not.12 They found no significant differences in the two patient populations regarding illness severity, meaning that they were comparable.12 The treatment group had a statistically significant improvement in hospital mortality (8.5% versus 40.4%, P < .001), decreased duration of vasopressor administration (18.3 ± 9.8 versus 54.9 ± 28.4, P < .001), and less renal replacement therapy for acute kidney injury of 10% versus 33%, P = .02.12

Take-home points for this study: The combination of vitamin C, hydrocortisone, and thiamine may prove effective in treating patients with sepsis, but additional stronger experimental studies such as a randomized control study need to take place. While the results were positive for this one facility, what is not known is whether the results are replicable and whether they are solely due to the combination of vitamin C, hydrocortisone, and thiamine. To investigate further, a multicenter, double-blind, placebo-controlled, randomized control trial, Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS), has been registered and is in progress.13 Data from this study should help answer the question of whether this combination of these drugs is efficacious and determine whether this combination therapy should be used to treat patients with sepsis.

Thiamine deficiency has been shown to be prevalent in patients with septic shock, but why is unknown.14 A recent pilot study showed that thiamine administration in patients with septic shock was associated with both reduced serum lactate levels at 24 hours and possibly a mortality benefit, although not statistically significant.15

Woolum and colleagues studied the effect of thiamine administration alone in a larger group of patients with septic shock in a retrospective, single-center, matched cohort study.16 Patients identified for inclusion in this study had septic shock by diagnosis coding, met The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria, and had thiamine administered intravenously within 24 hours of admission.16 A matched cohort of patients with septic shock and Sepsis-3 criteria without thiamine administration was also identified.16 The results showed a nonstatistically significant association with improved lactate clearance and 28-day mortality in patients who received thiamine.16

Take-home points for this study: Although the results are interesting, there was no statistical significance and, once again, stronger experimental studies need to take place before routine administration thiamine is implemented to treat patients with septic shock.3

Prehospital antibiotics. Early antibiotic administration as soon as possible or within 1 hour of sepsis, and septic shock recognition is a strong recommendation from the recent sepsis guidelines.3 It appears logical that giving antibiotics even earlier—for example, prehospital in the ambulance—may have a positive effect on outcomes. But what does the evidence show?

Alan and colleagues conducted a randomized controlled, open-label, multicenter trial involving adult patients with varying severity of sepsis.17 Patients were randomized to the intervention group (1,548 patients) and a usual care control group (1,150 patients). A prehospital blood culture was obtained in the intervention group and ceftriaxone administered, along with usual care regarding fluids and oxygen.17 Patients with a known allergy to ceftriaxone or other beta-lactam antibiotics, known pregnancy, or suspected prosthetic joint infections were excluded.17 Results showed no statistically significant difference in mortality (28-day or 90-day), ICU admissions, or hospital length of stay between the two groups.17

Take-home points for this study: No statistically significant benefit was found for administering an antibiotic prehospital.17 However, the healthcare providers involved in the study did note a benefit of improved sepsis recognition and response times in general.17

Based on this study, giving antibiotics prehospital in the ambulance cannot be recommended.

Steroids. Many studies have been conducted to evaluate the use of steroids in patients with sepsis, with conflicting results. Based on weak evidence, the most recent sepsis guidelines recommended against routinely using I.V. glucocorticoid therapy as part of initial therapy. Glucocorticoid therapy may be considered in select patients with refractory septic shock (systolic BP less than 90 mm Hg) for more than 1 hour following both adequate fluid resuscitation and vasopressor administration.3

One recent study found that continuous infusions of hydrocortisone in patients with septic shock requiring mechanical ventilation did not improve 90-day mortality.18 However, another study showed a decrease in 90-day mortality in ICU patients with septic shock who received both intermittent hydrocortisone and fludrocortisone.19

In a systematic review and meta-analysis, Fang and colleagues looked at whether corticosteroids were associated with a decrease in 28-day mortality in adult patients with sepsis, severe sepsis, or septic shock. The review included 37 randomized control studies with 9,564 patients meeting inclusion criteria.20 The results showed an association between improved 28-day mortality and corticosteroid use with a relative risk, 0.90; 95% CI, 0.82-0.98.20 However, no statistically significant improvement was found in 90-day mortality (relative risk, 0.94; 95% CI, 0.85-1.03).20 In other words, corticosteroids were associated with significant benefit for both ICU and in-hospital 28-day mortality. Other findings that may be associated with corticosteroid use include shock reversal and vasopressor-free days, decreased ICU length of stay, time to resolution of shock, and SOFA score.20

Take-home points for this study: Corticosteroids were associated with a reduced 28-day mortality in adults with sepsis, severe sepsis, and septic shock.20 There is some suggestion from this analysis that low-dose corticosteroids and a longer course of therapy may be better.20 What we still do not know is the optimal strategy for administering corticosteroids, including optimal dosing for patients with sepsis. Additional research is needed to find the correct risk-benefit ratio.

Fluids. There is tremendous debate about whether resuscitation with 30 mL/kg of crystalloid fluids is appropriate for all patients with sepsis based on recent sepsis guidelines who are hypotensive or who have an elevated serum lactate level (4 mmol/L or greater; normal, 0.5-1 mmol/L).3,21-23 Many clinicians cite safety concerns for patients with heart failure or renal failure.21

Corl and colleagues designed a randomized control pilot study in two hospitals to compare outcomes in patients treated with a restrictive fluid resuscitation strategy (60 mL/kg or less of I.V. fluid) versus those receiving higher-volume resuscitation.24 Patients with severe sepsis or septic shock were randomized in ED triage after an initial 1,000 mL of I.V. fluid to either a restrictive fluid strategy (55 patients) or usual care (54 patients) for the first 72 hours of treatment.24 The results showed no difference in 30-day mortality outcomes between the two groups (21.8% versus 22.2%).24 The restrictive fluid group received statistically significantly less fluid in the first 72 hours than the usual care group (3,785 ± 1,167 versus 5,150 ± 2,421, P < .0001).24 No differences were found between the two groups in development of new organ failure, hospital or ICU length of stay, or serious adverse events.24

Take-home points for this study: A restrictive fluid strategy in this small pilot study reduced the volume of fluid administered in patients with severe sepsis and septic shock without increase in mortality, organ failure, length of stay, or adverse events. This was a pilot study and was not intended to be conclusive but to test the concept in a small group. A larger study is planned to address the question of restrictive fluids.24 In addition, the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) study is currently underway. This study is designed to add to the body of evidence regarding fluid resucitation.25

Another study also looked at fluid resuscitation and outcomes to identify predictors of reaching the sepsis guideline goals for fluid resuscitation and examined the effects on clinical outcomes, including at-risk populations.26 In a retrospective cohort study conducted in one ED, Kuttab and colleagues compared patients with severe sepsis or septic shock who had received 30 mL/kg of fluid resuscitation in the first 3 hours (509 patients) versus patients (523 patients) who never received resuscitation fluids or for whom fluids were delayed.26 The results showed that certain patients were less likely to receive 30 mL/kg crystalloid bolus within 3 hours (30by3) sepsis onset: those who were older adults (odds ratio [OR], 0.62; 95%, 0.46-0.83), male (OR, 0.66; 95%, 0.49-0.87), obese (OR, 0.18; 95%, 0.13-0.25), had end-stage renal failure (OR, 0.23; 95%, 0.13-0.40), had heart failure (OR, 0.42; 95%, 0.29-0.60), or documented fluid overload (OR, 0.30; 95%, 0.20-0.45). Patients who did not meet 30by3 had increased odds of mortality (OR, 1.52; 95%, 1.03-2.24), delayed hypotension (OR, 1.42; 95%, 1.02-1.99), and increased ICU length of stay (regression coefficient, 2; 0.5-3.6).

Take-home points for this study: Patients with severe sepsis or septic shock who failed to meet a 30by3 fluid resuscitation strategy had increased odds of in-hospital mortality regardless of associated comorbidities such as end-stage renal failure and heart failure. Because this study was retrospective and homogeneous (limited to the population of one ED), additional prospective studies are needed to confirm the association. It does add knowledge to the discussion whether 30 mL/kg is safe for all patient populations with sepsis who meet criteria for fluid resuscitation.

Restoration of perfusion

Serum lactate levels have been used as a surrogate for tissue perfusion to assess sepsis resuscitation; however, persistent elevated levels may be associated with not only decreased mortality in sepsis but also with other nonsepsis causes.27 In addition, lactate levels may not be readily available in nonresourced countries.3 Capillary refill time, which nurses can easily assess, may reflect serum lactate levels. To investigate whether this simple assessment skill could be used instead of serum lactate levels to guide resuscitation, Hernandez and colleagues conducted a study comparing assessment of capillary refill time versus serum lactate levels and the effect on mortality in patients with septic shock. In a randomized, nonblinded, multicenter study, adult patients with septic shock were recruited within 4 hours of septic shock diagnosis and randomized to one of two groups.28 For the intervention group, capillary refill time was documented every 30 minutes (see Capillary refill time study procedure for the control group), and serum lactate levels were obtained every 2 hours.28 In each group, 212 patients were included in the analysis.28 The primary outcome of 28-day mortality, although not statistically significant, was lower in the capillary refill time group (34.9%) versus the lactate group (43.3%).28 The capillary refill time group was associated with less organ dysfunction at 72 hours as measured by the SOFA score.4,28 No statistical differences in other outcomes were found.28

Take-home points for this study: Guiding resuscitation by measuring capillary refill time was associated with decreased 28-day mortality and organ dysfunction at 72 hours in this study. But because these findings were not statistically significant, the evidence is not strong enough to move this strategy into practice.28

Recently the authors repeated the data analysis using a different statistical model, the Bayesian model.29 The Bayesian model provides a probability or likelihood of the effect. In the reanalysis, they found a high probability that capillary refill time was associated with lower mortality at both 28 and 90 days and a lower SOFA score (less organ dysfunction) at 72 hours when compared with the lactate group.29 This provides more evidence that a capillary refill time strategy for targeted resuscitation may be a reasonable alternative and associated with lower mortality and faster resolution of organ dysfunction.29 Expect to see more discussion in the literature about this promising use of a simple bedside assessment skill that every nurse could use in the future to guide sepsis resuscitation strategies.

Phenotypes and biomarkers

Ongoing investigation of phenotypes and biomarkers is likely to yield more treatment breakthroughs in the future. Part of the sepsis definition includes the terminology of dysregulated host response (see Sepsis terms).2 What is not known is how to identify individual clinical features that make patients more susceptible to developing sepsis. What if in the future, the healthcare team could more easily identify these patients and use this information to prescribe patient-specific therapy?

In a retrospective analysis, Seymour and colleagues used machine learning to determine phenotypes in patients identified with sepsis in databases from three clinical observational cohorts and three randomized control trials.30 A phenotype is a specific collection of clinical variables in patients who respond differently to treatment and have different risks for poorer outcomes.30,31 Four phenotypes were identified in this analysis based on 29 variables located in the electronic health record associated with sepsis onset or outcomes: alpha, beta, gamma, and delta.30 The four phenotypes were correlated with host immune response, mortality, and other clinical outcomes.30

Take-home points for this study: Further research would need to be done both retrospectively and prospectively to determine reproducibility and clinical utility in all sepsis patient populations, but the concept itself is intriguing and may be the beginning of future steps toward understanding sepsis. The ability to identify phenotypes would help clinicians individualize patient care, identify associations with biomarkers, and determine which patients are more likely to have better clinical response and outcomes related to treatment.

Looking to the future

We know that research is continually evolving to find the best evidence-based care that will provide optimal outcomes for our patients. The future for sepsis recognition and management relies on continued research and distillation of that research into guidelines and recommended strategies. While this brief review of recent sepsis literature is not all-inclusive, it gives nurses insight into the current evidence and highlights questions that still need to be answered.

Capillary refill time study procedure28

  1. Apply firm pressure to ventral surface of the right index finger distal phalanx with glass microscope slide.
  2. Increase pressure until skin blanches and maintain for 10 seconds.
  3. Measure time for return of normal skin color with chronometer.
  4. Abnormal ≥3 seconds.

Sepsis terms2

Sepsis: life-threatening organ dysfunction caused by a dysregulated host response to infection

Organ dysfunction: an acute change in a patient's total SOFA score 2 points consequent to the infection, based on a baseline SOFA score of zero in patients without preexisting organ dysfunction. A score of 2 indicates an overall mortality risk of approximately 10% in patients with suspected infection.

Septic shock: a subset of sepsis where underlying circulatory and cellular/metabolic abnormalities increase mortality. Patients in septic shock have persisting hypotension that requires vasopressors to maintain a MAP of 65 mm Hg and a serum lactate level over 2 mmol/L (18mg/dL) despite adequate volume resuscitation.

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2. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–810.
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(3):486–552.
4. Vincent JL, de Mendonca A, Cantraine F, et al. Working group on “Sepsis-Related Problems” of the European Society of intensive Care Medicine. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Crit Care Med. 1998;26(11):1793–1800.
5. U.S. Department of Health and Human Services; Centers for Disease Control and Prevention. Hospital toolkit for adult sepsis surveillance. 2018. www.cdc.gov/sepsis/pdfs/Sepsis-Surveillance-Toolkit-Aug-2018_508.pdf.
6. Rhee C, Zhang Z, Kadri SS, et al. Sepsis surveillance using adult sepsis events simplified eSOFA criteria versus Sepsis-3 Sequential Organ Failure Assessment criteria. Crit Care Med. 2019;47(3):307–314.
7. Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev. 2018;98(3):1627–1738.
8. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–430.
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12. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229–1238.
13. U.S. National Library of Medicine, ClinicalTrials.gov. Vitamin C, thiamine, and steroids in sepsis (VICTAS). 2018. https://clinicaltrials.gov/ct2/show/NCT03509350.
14. Costa NA, Gut AL, de Souza Dorna M, et al. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. 2014;29(2):249–252.
15. Donnino MW, Andersen LW, Chase M, et al. Center for Resuscitation Science Research Group. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2):360–367.
16. Woolum JA, Abner EL, Kelly A, Thompson Bastin ML, Morris PE, Flannery AH. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. 2018;46(11):1747–1752.
17. Alam N, Oskam E, Stassen PM, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med. 2018;6(1):40–50.
18. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797–808.
19. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378(9):809–818.
20. Fang F, Zhang Y, Tang J, et al. Association of corticosteroid treatment with outcomes in adult patients with sepsis: a systematic review and meta-analysis. JAMA Intern Med. 2019;179(2):213–223.
21. Kelm DJ, Perrin JT, Cartin-Ceba R, Gajic O, Schenck L, Kennedy CC. Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock. 2015;43(1):68–73.
22. Liu VX, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264–1270.
23. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235–2244.
24. Corl KA, Prodromou M, Merchant RC, et al. The restrictive IV fluid trial in severe sepsis and septic shock (RIFTS): a randomized pilot study. Crit Care Med. 2019;47(7):951–959.
25. U.S. National Library of Medicine, ClinicalTrials.gov. Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS). 2018. https://clinicaltrials.gov/ct2/show/NCT03434028.
26. Kuttab HI, Lykins JD, Hughes MD, et al. Evaluation and predictors of fluid resuscitation in patients with severe sepsis and septic shock. Crit Care Med. 2019;47(11):1582–1590.
27. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309–2319.
28. Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: The ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019;321(7):654–664.
29. Zampieri FG, Damiani LP, Bakker J, et al. Effects of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels among patients with septic shock: a Bayesian reanalysis of the ANDROMEDA-SHOCK trial. Am J Respir Crit Care Med. [e-pub Oct. 1, 2019].
30. Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321(20):2003–2017.
31. Knaus WA, Marks BD. New phenotype for sepsis: the promise of applying machine learning and artificial intelligence in clinical research. JAMA. 2019;321(20):1981–1982.
Keywords:

evidence-based practice; organ dysfunction; sepsis; septic shock; SOFA score

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