Wirz Y, Meier MA, Bouadma L et al.
Aim of Study
To investigate the impact of procalcitonin-guided antibiotic therapy (PCT) on mortality in ICU patients overall, but also on sub-groups of patients according to sepsis definition, severity and type of infection.
Design and Location
Meta-analysis of 11 RCTs assessing the safety of using PCT to aid antibiotic decisions in ICU. Trials included in the study from France (2), Belgium (1), The Netherlands (1), Switzerland (1), Germany (3), Brazil (2) and Australia (1).
Search strategy protocol published in Cochrane Library Feb 2018 according to PRISMA guidelines. Search executed in CENTRAL/MEDLINE Ovid/Embase with no language or publication restrictions. 2 authors independently assessed eligibility of 990 records by title and abstract screening, with 71 publications receiving full-text reviews. 32 of these were identified as potentially eligible, with 11 ultimately meeting full inclusion criteria. GRADE approach used to assess bias by 2 independent authors. Ultimately resulted in data from 4482 individual patients being included in the study.
Safety – all-cause mortality within 30 days of randomisation
Efficacy – antibiotic treatment duration
Length of hospital stay and length of ICU stay.
Odds ratios and confidence intervals according to multi-variable hierarchical logistic regression, with a “trial” variable added to the model as a random effect. Sub-group analysis was pre-specified and data included according to intention-to-treat principle.
Primary endpoint safety –
Significantly lower mortality in PCT arm with OR 0.89 (95% CI 0.8 – 0.99; p=0.03)
The effect of PCT was consistent across sub-group analysis of:
- Patients meeting sepsis 3 definition
- Sepsis severity as per SOFA score
- Presence/absence septic shock
- Patients with ventilatory failure
- Patients receiving renal support
- Type of infection (Respiratory, Urinary, Abdominal, Skin + Soft tissue, CNS)
However, there was no evidence of significance for each individual interaction, meaning results cannot be accounted for by 1 specific subgroup effect.
Primary endpoint efficacy –
Significantly shorter duration of antibiotic therapy in PCT arm with mean 10.4 +/- 9.7 days vs 9.3+/- 9.2 days. Regression co-efficient -1.19 days with 95% CI -1.73 to -0.66; p<0.001.
However, duration of therapy was not reduced in specific sub-groups – those with abdominal infections and renal impairment.
Secondary outcome –
No significant impact on length of ICU or hospital stay.
Impact on antibiotic therapy duration appeared to be greatest in SOFA 0-6 and those patients not requiring vasopressors, suggesting that PCT was potentially more persuasive when deciding to stop antibiotics in patients who were less unwell.
When comparing impact on treatment duration across subgroups, PCT was seen to have a statistical significance in Respiratory infections only– but unclear if this was due to the power of the study (2203/4423 patients enrolled had respiratory infections, less than 500 abdominal and only 73 CNS).
Potential theories for lack of significant in abdominal infection and renal impairment suggested include PCT kinetics impacted by bacterial translocation from mucositis and excretion impacted by renal impairment.
Unclear why PCT guided therapy reduces mortality. Potential theories include PCT allowing early identification of those not responding to antibiotics, that unexpected PCT results may prompt further investigation into alternative aetiology of illness and that PCT allows for reduced exposure to antibiotics and their associated toxicities.
Stated Limitations from the Study
- Incomplete adherence to PCT in included studies
- Exclusion of immunocompromised patients from most studies
- Heterogeneity in patient populations and length of follow-up
- No cost-effectiveness analysis
Discussion from Journal Club Meeting (?Change of Practice)
Should we be using procalcitonin in ITU? It might be useful in the decision to stop antibiotics early, potentially shortening patient stay, but it is an adjunct to clinical impression and the weight individual clinicians will put on procalcitonin is sure to vary. We know some ITUs in the UK are using procalcitonin but current NICE guidance states there is not enough evidence to recommend its use, and that more research is required. It is felt that perhaps this is the case at Kingston too, but it might be useful to build some real-world experience with the test in the department and discuss with other ITUs in the UK about their experience.
Summary by Dr H Jordan. Journal Club Meeting 23 January 2020.