Skip to main content

Main menu

  • Home
  • Our journals
    • Clinical Medicine
    • Future Healthcare Journal
  • Subject collections
  • About the RCP
  • Contact us

Clinical Medicine Journal

  • ClinMed Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Author guidance
    • Instructions for authors
    • Submit online
  • About ClinMed
    • Scope
    • Editorial board
    • Policies
    • Information for reviewers
    • Advertising

User menu

  • Log in

Search

  • Advanced search
RCP Journals
Home
  • Log in
  • Home
  • Our journals
    • Clinical Medicine
    • Future Healthcare Journal
  • Subject collections
  • About the RCP
  • Contact us
Advanced

Clinical Medicine Journal

clinmedicine Logo
  • ClinMed Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Author guidance
    • Instructions for authors
    • Submit online
  • About ClinMed
    • Scope
    • Editorial board
    • Policies
    • Information for reviewers
    • Advertising

Sepsis: an update for physicians

David JP O'Callaghan and Anthony C Gordon
Download PDF
DOI: https://doi.org/10.7861/clinmedicine.11-6-619
Clin Med December 2011
David JP O'Callaghan
Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, and Department of Critical Care Medicine, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London
Roles: Clinical research fellow
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: anthony.gordon@imperial.ac.uk
Anthony C Gordon
Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, and Department of Critical Care Medicine, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London
Roles: Clinical senior lecturer and consultant
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
Loading
Key Words
  • resuscitation
  • sepsis
  • septic shock
  • treatment guidelines
  • vasopressors

Key points

  • Mortality from severe sepsis and septic shock remains high

  • Prompt antimicrobials/source control reduce mortality

  • Initial resuscitation should be titrated against physiological goals

  • Vasopressors are frequently required; noradrenaline should be considered the preferred agent

  • Steroid use should be reserved for refractory shock

Sepsis is defined as the systemic inflammatory response syndrome due to confirmed or suspected infection.1 Currently, there are more than 31,000 admissions to intensive care units (ICUs) in England, Wales and Northern Ireland each year due to sepsis, resulting in more than 14,000 deaths. These numbers are increasing.2 Outcome is related to illness severity as patients progress through severe sepsis (acute organ dysfunction secondary to sepsis) and septic shock (severe sepsis with hypotension refractory to fluids) with mortality rates up to 50%.3 In order to improve outcomes, evidence-based guidelines have been published as part of the international Surviving Sepsis Campaign (SSC).4 This article is partly based on these recommendations but also provides additional, more recent data.

Early recognition of pathology and timely implementation of therapy improve outcomes in sepsis.5,6 Even short delays in administering antibiotics are associated with increased mortality.6 Wherever possible, patients must receive these within one hour of presentation. Blood cultures should ideally be drawn immediately prior to antimicrobial administration to maximise the potential for positive microbiology as they will often be rendered sterile by systemic antimicrobial therapy. The samples should be taken peripherally and from indwelling vascular access devices (unless < 48 hours since insertion) to help ascertain whether:

  • a peripherally grown organism is the primary pathogen (more likely if grown from more than one site), or

  • the indwelling catheter is the source of infection.4

Appropriate samples should be taken from other potentially infected areas, as guided by the clinical history and examination.

In severe sepsis, initial antibiotic treatment should be broad spectrum as the consequences of failing to treat the pathogenic organism are potentially catastrophic.6 Attention must be paid to the tissue penetration of the chosen antimicrobials, depending on the site of infection, and also to local pathogenic resistance patterns. Any recently used therapies are probably best avoided if there is concern about a new infection with a potentially resistant organism. Antibiotic therapy should be reassessed regularly with the spectrum narrowed when possible, ideally on the basis of positive microbiological data, to prevent superinfection and development of resistance.

Investigation of source of sepsis

Appropriate source control should be performed promptly (at least within six hours of presentation). It may involve debridement of necrotic tissue, evacuation of pus or removal of an infected catheter. Material should be sent for culture wherever possible to help guide antimicrobial treatment. Imaging may be required to locate the infected site, but care must be taken to ensure unstable patients are not exposed to unnecessary transfer and intervention. These investigations should take the form of the least destabilising procedure.4

Resuscitation

Resuscitation in septic shock should follow a protocol titrated against physiological goals during the initial six hours. Such ‘goal directed’ therapy reduced hospital mortality by 16% in a single-centre trial when commenced early in severe sepsis and septic shock.5 This study incorporated several measures to optimise oxygen delivery by increasing cardiac output and maximising oxygen content, so it is difficult to specify which intervention produced the mortality benefit.

A further trial performed across two sites in the UK used a series of similar goals packaged together as a ‘bundle’, to be instigated within six hours of presentation with sepsis. Non-compliance was associated with a more than twofold increase in hospital mortality.7 A UK multicentre trial is currently assessing the clinical efficacy and cost-effectiveness of resuscitation carried out with such protocols.8

Resuscitation goals

The goals of resuscitation, as recommended by the SSC, include:

  • central venous pressure 8–12 mmHg or 12–15 mmHg if mechanically ventilated, there is diastolic dysfunction, intra-abdominal hypertension or significant pulmonary artery hypertension

  • mean arterial pressure (MAP) 65 mmHg or above

  • urine output 0.5 ml/kg/h or higher

  • central venous (superior vena cava) oxygen saturation (ScvO2) at least 70% or mixed venous oxygen saturation (SVO2) 65%.4

ScvO2 and SVO2 targets are used as a measure of adequate oxygen delivery. Normalising serum lactate can be used as an alternative target.9

Resuscitation fluids

Resuscitation may be performed with boluses of either colloid (500 ml) or crystalloid (1,000 ml), reflecting an absence of definitive evidence suggesting the superiority of either type of fluid in this context. Initially, they should be infused rapidly (over ca 30 min), with boluses repeated whilst haemodynamics continue to improve.

Red cell transfusion may be required and should target a haemoglobin concentration of 10 g/dl or more in the initial stages of resuscitation.4 In many cases of severe sepsis and, by definition, in septic shock, fluid resuscitation will not be sufficient to achieve these goals, indicating the requirement for cardiovascular support.

Vasopressors

Vasopressors increase systemic vascular resistance and therefore blood pressure. Both noradrenaline and dopamine are recommended in the 2008 SSC guidelines.4 However, a recent large trial has demonstrated that dopamine infusion resulted in a significantly greater incidence of adverse events, particularly arrhythmias.10 Noradrenaline should now be considered the preferred vasopressor, with the infusion rate titrated against the target MAP (this may need individual revision depending on age and comorbidities).

Septic shock is associated with a relative deficiency of vasopressin. In recent years there has been an increased level of interest in its use as an adjunct vasopressor. In this context, vasopressin binds to vascular smooth muscle, producing vasoconstriction with minimal osmotic effects. In the Vasopressin And Septic Shock Trial (VASST), a multicentre randomised controlled trial (RCT) comparing vasopressin to noradrenaline in adults with established septicshock, there was no significant mortality benefit in the whole study population. However, the a priori defined subgroup analysis showed a survival benefit in patients with less severe shock.11

Post hoc analysis of the VASST data supports the theory that vasopressin may have protective effects on renal function. When the risk, injury, failure, loss, end-stage (RIFLE) criteria12 (Table 1) were applied to patients to categorise renal dysfunction at study entry, those patients receiving vasopressin in the risk category had significantly lower rates of progression to either renal failure or loss, as well as a reduced requirement for haemofiltration.13 The VASST study also found that a combination of vasopressin and steroids was associated with significantly lower rates of mortality and organ dysfunction compared with noradrenaline and steroids.14 This may reflect a degree of interaction between the drugs because patients treated with steroids and vasopressin had higher circulating vasopressin levels than those receiving vasopressin without steroids. The treatment implications of these findings are currently unclear, but another planned UK trial aims to answer some of these uncertainties.15

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table 1.

Use of risk, injury, failure, loss, end-stage (RIFLE) criteria to describe acute renal dysfunction.

Other abnormalities associated with sepsis

Effects on the myocardium

Sepsis can suppress the myocardium, with left ventricular dysfunction seen in up to 50% of patients with persistent septic shock.16 In the context of an adequate circulating intravascular volume but reduced cardiac output, inotropic support is indicated to augment oxygen delivery. Adrenaline can be used, but is associated with tachyarrhythmias, raised lactate and reduced splanchnic perfusion. Current evidence supports dobutamine use.5

Adrenal insufficiency

Many septic patients have occult adrenal insufficiency and display vascular insensitivity to circulating catecholamines. In a multicentre RCT enrolling septic shock patients responding poorly to vasopressors, steroid supplementation reduced both shock duration and mortality.17 A subsequent multicentre RCT enrolling patients all of whom had septic shock, found hydrocortisone treatment led to earlier shock resolution. However, there was no mortality benefit and an increased rate of adverse events.18 Current guidelines now recommend low-dose hydrocortisone (<300 mg/day) only for patients who have septic shock poorly responsive to fluid and vasopressors (ie refractory shock).4

Coagulation abnormalities

Sepsis produces abnormalities of coagulation ranging from microvascular thrombosis to disseminated intravascular coagulation, as well as derangement of many coagulation markers including reduced circulating levels of protein C.19 Deficiencies of this serine protease are thought to contribute to abnormal coagulation processes; recombinant human activated protein C (rhAPC) is used as an adjunct treatment in sepsis.

A multicentre RCT randomising patients with severe sepsis to receive either rhAPC or placebo was stopped early due to efficacy as treatment produced a 6.1% reduction in 28-day mortality.20 Subgroup analysis and additional studies revealed this to be confined to those patients who had severe sepsis and a high risk of death (in Europe generally defined as more than one acute organ system dysfunction). The use of rhAPC in sepsis increases the risk of bleeding; therefore, the balance between bleeding risk and expected clinical benefit must be carefully considered. An ongoing trial will hopefully clarify the risk/benefit ratio.21

Other procedures aimed at improving outcome

Many other measures are performed in the ICU to improve outcome in sepsis including:

  • protective ventilatory strategies (minimising pressure and volume trauma)

  • elevating the head of the bed to minimise aspiration

  • gastric protection to prevent stress ulceration

  • controlling blood glucose levels

  • sedation protocols

  • ensuring prophylaxis against venous thromboembolism.

Although mortality rates from severe sepsis and septic shock remain high, data are emerging to suggest that outcomes can be improved by following evidence-based guidelines.22

Conflict of interests

ACG is an inventor on a patent application submitted by the University of British Columbia related to the use of vasopressin in septic shock. He has received research funds and consulting fees from Sirius Genomics, and speaker and advisory board fees from Eli Lilly & Co. ACG is in receipt of an NIHR clinician scientist fellowship award, and is grateful for funding through the NIHR-BRC funding scheme. Both authors have also received research support from the Intensive Care Foundation.

  • © 2011 Royal College of Physicians

References

  1. ↵
    American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864–74doi:10.1097/00003246-199206000-00025
    OpenUrlCrossRefPubMed
  2. ↵
    1. Harrison DA,
    2. Welch CA,
    3. Eddleston JM
    . The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 2006; 10: R42
    OpenUrlCrossRefPubMed
  3. ↵
    1. Alberti C,
    2. Brun-Buisson C,
    3. Goodman SV,
    4. et al
    . Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients. Am J Respir Crit Care Med 2003; 168: 77–84doi:10.1164/rccm.200208-785OC
    OpenUrlCrossRefPubMed
  4. ↵
    1. Dellinger RP,
    2. Levy MM,
    3. Carlet JM,
    4. et al
    . Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34: 17–60
    OpenUrlCrossRefPubMed
  5. ↵
    1. Rivers E,
    2. Nguyen B,
    3. Havstad S,
    4. et al
    . Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368–77doi:10.1056/NEJMoa010307
    OpenUrlCrossRefPubMed
  6. ↵
    1. Kumar A,
    2. Roberts D,
    3. Wood KE,
    4. et al
    . Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34: 1589–96doi:10.1097/01.CCM.0000217961.75225.E9
    OpenUrlCrossRefPubMed
  7. ↵
    1. Gao F,
    2. Melody T,
    3. Daniels DF,
    4. Giles S,
    5. Fox S
    . The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care 2005; 9: R764–70
    OpenUrlCrossRefPubMed
  8. ↵
    www.controlled-trials.com/ISRCTN36307479/promise.
  9. ↵
    1. Jones AE,
    2. Shapiro NI,
    3. Trzeciak S,
    4. et al
    . Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010; 303: 739–46doi:10.1001/jama.2010.158
    OpenUrlCrossRefPubMed
  10. ↵
    1. De Backer D,
    2. Biston P,
    3. Devriendt J,
    4. et al
    . Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362: 779–89doi:10.1056/NEJMoa0907118
    OpenUrlCrossRefPubMed
  11. ↵
    1. Russell JA,
    2. Walley KR,
    3. Singer J,
    4. et al
    . Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358: 877–87doi:10.1056/NEJMoa067373
    OpenUrlCrossRefPubMed
  12. ↵
    1. Bellomo R,
    2. Ronco C,
    3. Kellum JA,
    4. Mehta RL,
    5. Palevsky P
    . Acute Dialysis Quality Initiative workgroup. Acute renal failure definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–12
    OpenUrlCrossRefPubMed
  13. ↵
    1. Gordon AC,
    2. Russell JA,
    3. Walley KR,
    4. et al
    . The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med 2010; 36: 83–91doi:10.1007/s00134-009-1687-x
    OpenUrlCrossRefPubMed
  14. ↵
    1. Russell JA,
    2. Walley KR,
    3. Gordon AC,
    4. et al
    . Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med 2009; 37: 811–8doi:10.1097/CCM.0b013e3181961ace
    OpenUrlCrossRefPubMed
  15. ↵
    www.ics.ac.uk/foundation_home/foundation_research_activities_and_achievements/vanish.
  16. ↵
    1. Rudiger A,
    2. Singer M
    . Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007; 35: 1599–608doi:10.1097/01.CCM.0000266683.64081.02
    OpenUrlCrossRefPubMed
  17. ↵
    1. Annane D,
    2. Sébille V,
    3. Charpentier C,
    4. et al
    . Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862–71
    OpenUrlCrossRefPubMed
  18. ↵
    1. Sprung CL,
    2. Annane D,
    3. Keh D,
    4. et al
    . Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358: 111–24doi:10.1056/NEJMoa071366
    OpenUrlCrossRefPubMed
  19. ↵
    1. Opal SM,
    2. Esmon CT
    . Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Crit Care 2003; 7: 23–38
    OpenUrlCrossRefPubMed
  20. ↵
    1. Bernard GR,
    2. Vincent JL,
    3. Laterre PF,
    4. et al
    . Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–709doi:10.1056/NEJM200103083441001
    OpenUrlCrossRefPubMed
  21. ↵
    1. Finfer S,
    2. Ranieri VM,
    3. Thompson BT,
    4. et al
    . Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med 2008; 34: 1935–47
    OpenUrlCrossRefPubMed
  22. ↵
    1. Levy MM,
    2. Dellinger RP,
    3. Townsend SR,
    4. et al
    . The Surviving Sepsis Campaign: results of an international guideline-based performance improvement programme targeting severe sepsis. Intensive Care Med 2010; 36: 222–31
    OpenUrlCrossRefPubMed
Back to top
Previous articleNext article

Article Tools

Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Sepsis: an update for physicians
David JP O'Callaghan, Anthony C Gordon
Clinical Medicine Dec 2011, 11 (6) 619-622; DOI: 10.7861/clinmedicine.11-6-619

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Sepsis: an update for physicians
David JP O'Callaghan, Anthony C Gordon
Clinical Medicine Dec 2011, 11 (6) 619-622; DOI: 10.7861/clinmedicine.11-6-619
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Investigation of source of sepsis
    • Resuscitation
    • Other abnormalities associated with sepsis
    • Other procedures aimed at improving outcome
    • Conflict of interests
    • References
  • Figures & Data
  • Info & Metrics

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Advances in post-resuscitation care
  • Acute lung injury
  • Who to admit to intensive care?
Show more CME Critical care medicine

Similar Articles

Navigate this Journal

  • Journal Home
  • Current Issue
  • Ahead of Print
  • Archive

Related Links

  • ClinMed - Home
  • FHJ - Home
clinmedicine Footer Logo
  • Home
  • Journals
  • Contact us
  • Advertise
HighWire Press, Inc.

Follow Us:

  • Follow HighWire Origins on Twitter
  • Visit HighWire Origins on Facebook

Copyright © 2020 by the Royal College of Physicians