such as l-arginine and omega-3 fatty acids, actuallyincrease mortality in patients with severe sepsis.
Inter-pretation of these studies is confounded by the effect of hyperglycaemia. The combination of glycogenolysisand insulin resistance means that hyperglycaemia iscommon in patients with sepsis and is associated with a poorer outcome.
Tight glycaemic control has beenshown to reduce morbidity and mortality in a prospec-tive randomised controlled trial in surgical patients.
A similar study in non-surgical patients resulted in a reduction only in morbidity.
We clearly need a moredefinitive understanding of the impact of hyper-glycaemia and insulin treatment in patients with severesepsis, which will hopefully be provided by an ongoing randomised controlled trial.
What specific treatments are available?
Firstandforemostamongspecifictreatmentsareprompt appropriate empirical antimicrobials. Treatment withinfour hours of admissionreducesmortality and length of stay.
Delayinhypotensivepatientsincreasesmortalityby 7.6% an hour.
Since the late 1980s, Gram positiveorganisms have replaced Gram negative ones as themost common bacteria causing sepsis. Retrospectively,around20%ofinfectionsoriginatefromeachofrespira-tory, intra-abdominal, and urinary tract sources.However, at presentation, the source of infection isoften unknown. Antibiotic treatment must be guidedby the patient
s susceptibility group (table) and localknowledge of bacterial resistance. Broad spectrum
lactam antibiotics would be the usual first line agent.If methicillin resistant
is a risk,empiricalvancomycinshouldbeadded.Inthepresenceof risk factors for fungal infection, an antifungal agent may be prescribed initially or within 48 hours if noimprovement occurs; decisions are guided by clinical judgment and the severity of the condition, ideally inconsultation with infectious disease or microbiologycolleagues. The importance of wide cover is illustratedby the much poorer prognosis in patients in whom thefirst line drugs are ineffective.
If strong clues to thesource of infection exist, targeted narrower spectrumtreatment is probably justified.Protein C is synthesised by the liver and activatedby thrombomodulin-bound thrombin, acquiring anti-inflammatory,antithrombotic,andanticoagulanteffects.A recombinant human protein (drotrecogin alfa (activated)) was evaluated in a large prospectiverandomised controlled trial.
It was, somewhat contro-versially, approved in November 2001 by the US Foodand Drug Administration on the basis of a reduction inthe absolute risk of death of 6.1% (P
0.005) and sub-group analysis of predefined high risk patients (definedas an acute physiology and chronic health evaluation II(APACHEII)scoreof
25).Intheinterveningtimetwofurther randomised controlled trials have beenpublished, one in children and the other in adults at low risk of death.
Both were stopped early ongrounds of inefficacy. In addition, the calculated risk of serious haemorrhage from drotrecogin alfa (activated)has increased progressively with accumulating clinicalexperience. Overall, whether the risks of drotrecoginalfa (activated) outweigh the benefits is now far fromclear, even in patients with a high risk of death.
Deficiencyofadrenalsteroidproductioninseveresepsiswas originally described as acute haemorrhagic necrosisof the adrenal glands precipitating addisonian crisis anddeath
the Waterhouse-Friderichsen syndrome. Highdosecorticosteroidtreatmentinseveresepsiswasinitiallyinvestigated as an anti-inflammatory treatment andfound to be of no benefit. Attention has now returnedto the problem of adrenal insufficiency in severe sepsis.Complete adrenal failure is rare, but relative adrenalinsufficiency is much more common, although the inci-dence depends on the definition used. In one study, forexample, which defined adrenal insufficiency as a corti-sol increment of
248 nmol/l (9
g/dl) 30-60 minutesafter 0.25 mg of tetracosactrin, 54% of the patients withsepticshockmetthecriteria.
Tworecentmeta-analysessuggestthatlowdosehydrocortisoneforfiveto11daysinunselected patients with severe sepsis or septic shocksignificantly reduces both the duration of shock and in-hospital mortality, without incurring additionalcomplications. The positive effect of low dose steroidreplacement treatment may be even greater if it isrestricted to patients selected on the basis of provedadrenal insufficiency.
Immunoglobulins and statins
Othertherapeutic approachesdeservefurtherinvestiga-tion. Of these, intravenous immunoglobulin and statinsare nearest to clinical evaluation. Intravenous immuno-globulin is not without adverse effects, which vary fromhypotensive reactions to aseptic meningitis. Most of theinfused antibody will not be specific for the organism
In hospitalorotherinstitution Resistant organisms,especiallymethicillinresistant
(MRSA) and extendedspectrum
lactamase producingGramnegative entericorganismsSplenectomy Capsulated bacteria, especially
School,university, or military
Intravascular catheter StaphylococciIntubationand ventilation Gram negative enteric organisms, pseudomonads,MRSA, CandidaPharmacologicallyimmunosuppressed
sppForeign travel Malaria, legionellaPotentialexposure torat urine LeptospirosisVeryyoungor very old
Central venous pressure of 8-12 mm Hg
Mean arterial pressure
65 mm Hg
Central venous oxygen saturation
3 NOVEMBER 2007