Recent Developments in the Diagnosis and Management of Severe Sepsis

doi:10.1378/chest.06-2535

Chest

Volume 132, Issue 6, December 2007, Pages 1967-1976

https://doi.org/10.1378/chest.06-2535 Get rights and content

The last 5 years have brought dramatic changes to the care of patients with severe sepsis. While early diagnosis remains a challenge and, regrettably, a rapid, sensitive, and specific diagnostic test is still lacking, the methods to identify those critically ill patients who are likely to die have become clearer. The presence of multiple organ failure, vasopressor-dependent shock, and high values in formalized scoring methods such as the APACHE (acute physiology and chronic health evaluation) and sequential organ failure assessment systems all have some utility for outcome prediction for groups of patients. Refinements in long-used supportive practices such as lower tidal volume ventilation and enhanced glucose control have improved outcomes. A growing appreciation of the importance of timely provision of antimicrobial therapy, circulatory resuscitation, and activated protein C administration have also improved survival. Optimal treatment candidates for, and the timing and dose of some treatments (eg, corticosteroids) remain controversial and are undergoing additional study. Perhaps the most important change in the care of patients with severe sepsis is awareness that the syndrome is more common, lethal, and expensive, than previously appreciated, and as such it warrants an organized approach to care provided by experts. Although there is still much to learn, numerous studies now indicate that improvements in outcomes are possible when treatment protocols that incorporate all known beneficial therapies are applied in a timely fashion.

Section snippets

Definition and Case Finding

Despite many advances, some things have not changed. Clinicians still long for a simple, reliable test to diagnose severe sepsis because medical history, examination, routine laboratory studies, and radiographs often leave the diagnosis in question. Procalcitonin and C-reactive protein have been advocated for diagnosis, and while the former has better predictive value, neither has gained widespread clinical use.⁴ Measurements of the soluble triggering receptor expressed on myeloid cells-1

Severity of Illness and Outcome Prediction

Studies in the last 5 years have undercut the long-held belief that microorganism characteristics are the predominant determinants of prognosis. The identity of the infecting organism is of little consequence for most patients provided that appropriate, prompt antimicrobial therapy is administered.¹²¹³¹⁴

The presence of coagulopathy is a powerful predictor of organ failure development and subsequent death.¹⁵ The occurrence of shock treated with vasoactive drugs and the total number of failing

Pathophysiology

The septic response was once believed to be simply exaggerated inflammation. The last decade has brought to light a major conceptual advance. Sepsis pathophysiology is very complex and remains incompletely understood, but clearly involves inflammatory, procoagulant, antifibrinolytic, and microvascular components²⁵²⁶ that have been nicely summarized elsewhere.²⁷²⁸

Potentiality Time-Sensitive Treatments

In the last few years, six beneficial therapies have been identified that form the core of the Surviving Sepsis Campaign, a joint effort of numerous professional organizations to expedite and standardize care of the patient with severe sepsis.³⁷ Beneficial treatments are advocated collectively in “bundles,” and several studies outlined below have examined the effectiveness of a standardized approach to care compared to historical control subjects.

Hemodynamic Management

In the last few years, physicians treating patients with severe sepsis have been reminded of what trauma and burn physicians have espoused for decades, which is that rapidly identifying patients with inadequate circulation and providing prompt resuscitation is a critical determinant of outcome. Although numerous studies, including the large randomized Saline versus Albumin Fluid Evaluation study,⁴⁹ have failed to definitively prove the superiority of colloids or crystalloids, studies in severe

Normal Tidal Volume Ventilation

Some degree of ALI develops in most patients with severe sepsis. In a study of ALI patients,⁶² investigators established that the use of a “normal” tidal volume (6 mL/kg) indexed to predicted body weight reduces absolute mortality by 9% compared to ventilation with a traditional tidal volume of 12 mL/kg. The beneficial effects of this strategy were confirmed among patients with sepsis as the risk factor for ALI.⁶³ In this approach, ventilation with 6 mL/kg predicted body weight was used

Glucocorticoids and Mineralocorticoids for Septic Shock

Numerous trials⁷³ using short courses of high-dose corticosteroids in patients with severe sepsis have failed to improve survival. Nonetheless, in the last few years interest in lower doses of glucocorticoids has been revived as a concept termed relative adrenal insufficiency. In a widely discussed study⁷⁴ of septic shock, approximately 300 patients who were identified within 8 h of shock onset were randomized to receive hydrocortisone plus fludrocortisone or placebo for 7 days. When evaluating

Glucose Control

Substantial data indicate that long-term inadequate glycemic control in diabetic patients is associated with poor long-term prognosis and that the outcomes of heterogeneous populations of critically ill patients are worse if they are hyperglycemic.⁸⁰ Now this concept has been extended to patients with or at risk of severe sepsis. In a prominent study⁸¹ of approximately 1,500 postoperative patients, a protocol in which glucose was targeted to a range of 80 to 110 mg/dL gained substantial

Drotrecogin Alfa Activated

The last few years have seen release of the first drug for the treatment of severe sepsis. Drotrecogin alfa activated, also known as recombinant human activated protein C (rhAPC) has been shown in a large randomized, multicenter, placebo-controlled trial⁸⁵ to reduce the absolute mortality of patients with severe sepsis by approximately 6%. Long-term follow-up demonstrated a persistent survival benefit 2 to 3 years after treatment.⁸⁶ In addition, treated patients had a shorter time spent

Changing Practice

Perhaps the most exciting development is the demonstration by numerous institutions that a standardized procedure or protocol can be used to improve process and outcomes, including survival and time spent on the ventilator, in the ICU and in the hospital. Collectively, hospitals initiating protocols have shown that best practices are achieved in a higher fraction of patients, and the time to begin almost all beneficial treatments decreases; with early intervention, many other treatments such as

Conclusion

The last 5 years have produced significant improvements in the care of patients with severe sepsis, including organ support and direct treatment of the underlying inflammatory and coagulopathic process. Although the treatments advocated today are almost certainly not the best that will ever be known, they are the best known now. Daily clinicians are faced with the following simple choice: ignore existing evidence because it may have some flaws and is incomplete in favor of non-evidence-based

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Cited by (34)

Organ protection during aortic cross-clamping
2016, Best Practice and Research: Clinical Anaesthesiology
Citation Excerpt :
Often, renal insufficiency precedes respiratory distress or multi organ failure (MOF) [55]. Renal insufficiency also plays an important role in the delayed recovery of lung injury or decreased cardiac function [56]. Renal failure is related to MOF and has been reported as a common complication after ruptured aortic aneurysm surgery, highly correlative with lethal outcomes [54].
Open surgical repair of an aortic aneurysm requires aortic cross-clamping, resulting in temporary ischemia of all organs and tissues supplied by the aorta distal to the clamp. Major complications of open aneurysm repair due to aortic cross-clamping include renal ischemia-reperfusion injury and postoperative colonic ischemia in case of supra- and infrarenal aortic aneurysm repair. Ischemia-reperfusion injury results in excessive production of reactive oxygen species and in oxidative stress, which can lead to multiple organ failure. Several perioperative protective strategies have been suggested to preserve renal function during aortic cross-clamping, such as pharmacotherapy and therapeutic hypothermia of the kidneys.
In this chapter, we will briefly discuss the pathophysiology of ischemia-reperfusion injury and the preventative measures that can be taken to avoid abdominal organ injury. Finally, techniques to minimize the risk of complications during and after open aneurysm repair will be presented.
Effect of IgM-Enriched Immunoglobulin as Adjunctive Therapy in a Patient Following Sepsis after Open Thoracoabdominal Aortic Aneurysm Repair
2016, Journal of Cardiothoracic and Vascular Anesthesia
Combination of Acute Physiology and Chronic Health Evaluation II score, early lactate area, and N-terminal prohormone of brain natriuretic peptide levels as a predictor of mortality in geriatric patients with septic shock
2015, Journal of Critical Care
Citation Excerpt :
Additionally, lactate clearance tends to be higher when initial lactate levels are low [25]. Systemic hypoxia is common in patients with septic shock and can lead to hyperlactatemia, multiple organ dysfunction, and death [30]. Increased lactate levels may also result from immune cell activation, in addition to impaired circulation during the systemic inflammatory response syndrome and sepsis.
Given the high mortality rates in elderly patients with septic shock, the early recognition of patients at greatest risk of death is crucial for the implementation of early intervention strategies. Serum lactate and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are often elevated in elderly patients with septic shock and are therefore important biomarkers of metabolic and cardiac dysfunction. We hypothesized that a risk stratification system that incorporates the Acute Physiology and Chronic Health Evaluation (APACHE) II score and lactate and NT-proBNP biomarkers would better predict mortality in geriatric patients with septic shock than the APACHE II score alone.
A single-center prospective study was conducted from January 2012 to December 2013 in a 30-bed intensive care unit of a triservice hospital. The lactate area score was defined as the sum of the area under the curve of serial lactate levels measured during the 24 hours following admission divided by 24. The NT-proBNP score was assigned based on NT-proBNP levels measured at admission. The combined score was calculated by adding the lactate area and NT-proBNP scores to the APACHE II score. Multivariate logistic regression analyses and receiver operating characteristic curves were used to evaluate which variables and scoring systems served as the best predictors of mortality in elderly septic patients.
A total of 115 patients with septic shock were included in the study. The overall 28-day mortality rate was 67.0%. When compared to survivors, nonsurvivors had significantly higher lactate area scores, NT-proBNP scores, APACHE II scores, and combined scores. In the multivariate regression model, the combined score, lactate area score, and mechanical ventilation were independent risk factors associated with death. Receiver operating characteristic curves indicated that the combined score had significantly greater predictive power when compared to the APACHE II score or the NT-proBNP score (P < .05).
A combined score that incorporates the APACHE II score with early lactate area and NT-proBNP levels is a useful method for risk stratification in geriatric patients with septic shock.
Impact of prothrombin time-International Normalized Ratio on outcome of patients with septic shock receiving polymyxin B cartridge hemoperfusion
2014, Surgery (United States)
Although most patients with septic shock have a poor outcome, some may survive after blood purification treatment such as polymyxin B cartridge hemoperfusion (PMX).
To explore the most significant characteristic associated with 28-day mortality in patients with septic shock receiving PMX.
Between April 2006 and March 2008, 116 patients with septic shock who had received PMX in a prospectively collected multicenter collaborative study were enrolled. Uni- and multivariate analyses using the Cox proportional hazard model were performed to assess the most significant clinical characteristic that was associated with 28-day mortality.
Among 33 clinicolaboratory characteristics, receiver operating characteristic (ROC) curve analyses selected 12 characteristics with recommended cutoff values such as HCO₃⁻ (≤19.8/>19.8; mEq/L), base excess (≤−5.35/>−5.35; mEq/L), diastolic blood pressure (≤48/>48 mmHg), mean arterial pressure (≤73/>73 mmHg), pH (≤7.29/>7.29), interleukin-6 (≤19,150/>19,150 pg/dL), prothrombin time–International Normalized Ratio (PT-INR; ≤2.05/>2.05), predictive value of Acute Physiology and Chronic Health Evaluation II (APACHE II; ≤0.4/>0.4), pyruvate (≤1.82/>1.82 mg/dL), APACHE II score (≤21/>21), acetate/pyruvate ratio (≤19/>19), and acetate (≤44.8/>44.8 mg/dL) on the basis of large area under the ROC curves for 28-day mortality. The results of uni- and multivariate analyses using these selected characteristics revealed that only PT-INR (≤2.05/>2.05; hazard ratio, 2.823; 95% CI, 1.243–6.412; P = .013) was associated with 28-day mortality. Survival curve analysis demonstrated a significant difference in 28-day mortality between patients with lower (≤2.05) and higher (>2.05) PT-INR (P < .001).
Prolonged PT-INR is an independent risk factor for 28-day mortality in patients receiving PMX for septic shock.
Open surgical repair of ruptured juxtarenal aortic aneurysms with and without renal cooling: Observations regarding morbidity and mortality
2010, Journal of Vascular Surgery
Citation Excerpt :
The need for temporary or permanent dialysis was recorded. To define MOF (ie, failure of two or more systems), the sequential organ failure assessment (SOFA) score was used.14-16 Organ failure was defined as a SOFA score of 3 or 4 (0 = no failure, 1-2 = mild dysfunction, 3-4 = severe dysfunction).
Little is known about the outcome of ruptured juxtarenal aortic aneurysm (RJAA) repair. Surgical treatment of RJAAs requires suprarenal aortic cross-clamping, which causes additional renal ischemia-reperfusion injury on top of the pre-existing hypovolemic shock syndrome. As endovascular alternatives rarely exist in this situation, open repair continues to be the gold standard. We analyzed our results of open RJAA repair during an 11-year period.
Retrospective observational study.
Between July 1997 and December 2008, all consecutive patients with RJAAs were included in the study. Part of these patients received cold perfusion of the kidneys during suprarenal aortic cross-clamping. Perioperative variables, morbidity, and 30-day or in-hospital mortality were assessed. Renal insufficiency was defined as an acute rise of ≥0.5 mg/dL in serum creatinine level. Multiple organ failure (MOF) was scored using the sequential organ failure assessment score (SOFA score).
A total of 29 consecutive patients with an RJAA, confirmed by computed tomography-scanning, presented to our hospital. In eight patients, the operation was aborted before the start of aortic repair, because no blood pressure could be regained in spite of maximal resuscitation measures. They were excluded from further analysis. Of the remaining 21 patients, 10 died during hospital stay. Renal insufficiency occurred in 11 out of 21 of the patients. Eleven out of 21 patients developed MOF postoperatively. In a subgroup of patients who received renal cooling during suprarenal aortic clamping, the 30-day or in-hospital mortality was two of 10 vs eight of 11 in patients who did not receive renal cooling (P = .03); renal insufficiency occurred in one out of 10 patients in the subgroup with renal cooling vs 10 out of 11 without renal cooling (P < .001) and MOF in two of 10 vs nine of 11, respectively (P = .009).
Open surgical repair of RJAAs is still associated with high mortality and morbidity. To our knowledge, this is the first report of cold perfusion of the kidneys during RJAA repair. Although numbers are small, a beneficial effect of renal cooling on the outcome of RJAA repair is suggested, warranting further research with this technique.
The absence of adrenal gland enlargement during septic shock predicts mortality: A computed tomography study of 239 patients
2011, Anesthesiology
Citation Excerpt :
In this study, patients younger than 18 yr, who are pregnant, with pituitary or adrenal disease, or with a history of steroid use were excluded. During the study period, septic shock management followed the 2004 Surviving Sepsis Campaign guidelines.4,5 All patients were treated with intravenous hydrocortisone, 50 mg four times a day, during 5–7 days regardless of the result of the cosyntropin stimulation test.2
Assessment and management of septic shock associated adrenal function remain controversial. The aim of this study was to explore the prognostic value of adrenal gland volume in adults with septic shock.
A short cosyntropin test and determination of adrenal volume by computed tomography were performed within 48 h of shock in patients with septic shock (n = 184) and in 2 control groups: 40 ambulatory patients and 15 nonseptic critically ill patients. The primary endpoint was intensive care unit mortality.
At intensive care unit discharge, 59 patients with septic shock died. Adrenal volume was 12.5 cm³ [95% CI, 11.3–13.3] and 8 cm³ [95% CI, 6.8–10.1] in the nonseptic group (P < 0.05 with both septic cohorts) and 7.2 cm³ [95%CI, 6.3–8.5] in the ambulatory patient group (P < 0.05 in patients with septic shock). In patients with septic shock, adrenal volume less than 10 cm³ was associated with higher 28-day mortality rates with an area under the receiver operating curve of 0.84 [95% CI, 0.78–0.89]. Adrenal volume above 10 cm³ was an independent predictor of intensive care unit survival (hazard ratio = 0.014; 95% CI [0.004–0.335]).
A total adrenal gland volume less than 10 cm³ during septic shock was associated in univariate and multivariate analysis with mortality at day 28 in patients with septic shock. Whether adrenal gland volume can be a surrogate of adrenal gland function and used to guide hydrocortisone therapy in septic shock patients needs to be further investigated.

View all citing articles on Scopus

: Dr. Wheeler has acted as a consultant for Astra-Zeneca, Cubist Pharmaceuticals, Cumberland Pharmaceuticals, Eli-Lilly, Sanofi-Aventis, and Takeda. He has worked for the speaker's bureaus of Boehringer-Ingleheim, Eli Lilly, Pfizer, and Sanofi-Aventis.

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Recent Advances in Chest MedicineRecent Developments in the Diagnosis and Management of Severe Sepsis

Section snippets

Definition and Case Finding

Severity of Illness and Outcome Prediction

Pathophysiology

Potentiality Time-Sensitive Treatments

Hemodynamic Management

Normal Tidal Volume Ventilation

Glucocorticoids and Mineralocorticoids for Septic Shock

Glucose Control

Drotrecogin Alfa Activated

Changing Practice

Conclusion

Chest

Chest

Chest

Blood

Lancet

Chest

Chest

Am J Med

Clin Microbiol Infect

Chest

Chest

Mayo Clin Proc

Chest

Chest

Critical care medicine: the essentials

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The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis

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Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis

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Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis

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Recent Advances in Chest Medicine
Recent Developments in the Diagnosis and Management of Severe Sepsis