Systematic Review and Meta-Analysis of
Procalcitonin-Guidance Versus Usual Care for
Antimicrobial Management in Critically Ill Patients:
Focus on Subgroups Based on Antibiotic Initiation,
Cessation, or Mixed Strategies
Simon W. Lam, PharmD, FCCM, BCCCP1; Seth R. Bauer, PharmD, FCCM, FCCP1;
Robert Fowler, MDCM, MS2; Abhijit Duggal, MD, MPH, MSc3
Objective: Numerous studies have evaluated the use of procalci-
tonin guidance during different phases of antibiotics management
(initiation, cessation, or a combination of both) in patients admit-
ted to ICUs. Several meta-analyses have attempted to generate
an overall effect of procalcitonin-guidance on patient outcomes.
However, combining studies from different phases of antibiotics
management may not be appropriate due to the risk of clinical
heterogeneity. The purpose of this systematic review and meta-
analysis was to evaluate the effect of procalcitonin-guided strate-
gies in different phases of antibiotics use.
Data Sources: We searched MEDLINE and EMBASE from incep-
tion until November 1, 2017.
Study Selection: We included randomized controlled trials that
evaluated procalcitonin guidance compared with usual care for
management of antibiotics in critically ill adult patients.
Data Extraction: We extracted study details, patient characteris-
tics, procalcitonin algorithm, and outcomes.
Data Synthesis: We included 15 studies, from 1,624 abstracts
identified based on our search strategy (three initiation, nine
1
Department of Pharmacy, Cleveland Clinic, Cleveland, OH.
2
Department of Critical Care Medicine, Sunnybrook Health Sciences Cen-
tre, Toronto, ON, Canada.
3
Department of Critical Care, Respiratory Institute, Cleveland Clinic,
Cleveland, OH.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/
ccmjournal).
No external financial support was received for the completion of this work.
Authors received institutional departmental support to complete this work.
The authors have disclosed that they do not have any potential conflicts
of interest.
For information regarding this article, E-mail: lams@ccf.org
Copyright © 2018 by the Society of Critical Care Medicine and Wolters
Kluwer Health, Inc. All Rights Reserved.
DOI: 10.1097/CCM.0000000000002953
Critical Care Medicine www.ccmjournal.org 1
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
cessation, and three mixed). The pooled risk ratio for short-term
mortality for the initiation, cessation, and mixed procalcitonin strat-
egies were 1.00 (95% CI, 0.86–1.15,;p = 0.91), 0.87 (95% CI,
0.77–0.98; p = 0.02), and 1.01 (95% CI, 0.80–1.29; p = 0.93),
respectively. Procalcitonin for cessation and mixed strategies
was associated with decrease antibiotics duration (–1.26 d
[p < 0.001] and –3.10 d [p =0.04], respectively). No differences
were observed in other outcome measures.
Conclusion: When evaluating all studies of procalcitonin-guided
antibiotics management in critically ill patients, no difference in
short-term mortality was observed. However, when only examin-
ing procalcitonin-guided cessation of antibiotics, lower mortality
was detected. Future studies should focus specifically on procal-
citonin for the cessation of antibiotics in critically ill patients. (Crit
Care Med 2017; XX:00–00)
Key Words: anti-bacterial agents; critical illness; meta-analysis;
mortality; procalcitonin
E
arly adequate empiric antibiotics is associated with
improved survival for patients with sepsis; however, the
failure to de-escalate or continuing antibiotics beyond
recommended durations contribute to 50% of antibiotics pre-
scribed in hospital settings being unnecessary or inappropriate
(1). This may contribute to increasing rates of resistant organ-
isms and unwarranted adverse effects associated with anti-
microbials. The Surviving Sepsis Campaign (SSC) guidelines
suggest that biomarkers such as procalcitonin may be used
to shorten the duration of antimicrobial use in patients with
sepsis (2). Numerous trials have evaluated the effects of pro-
calcitonin-guided strategies on antimicrobial use and clinical
outcomes in critically ill patients admitted to the ICU (3–18).
Several systematic reviews and meta-analyses have attempted
to summarize the available literature and generate an overall
Lam et al
effect size of procalcitonin-guided strategies on outcomes such
as antibiotic exposure, mortality, and hospital and ICU length of
stay (LOS) (19–26). In general, the previous meta-analyses dem-
onstrated a statistically significant decrease in antibiotics expo-
sure (weighted mean difference in antibiotics days ranging from
2.05 to 4.19 d) with procalcitonin-guided therapy compared
with standard care, but did not detect a difference in mortality,
ICU LOS, or hospital LOS between strategies. However, many
of these studies suffer from the limitation of combining studies
that evaluated procalcitonin-guided strategies in different phases
of antimicrobial use (initiation, cessation, or mixed) to provide
an average effect size (27). The combination of studies from dif-
ferent phases of antimicrobial use with meta-analytic methods
may not be appropriate due to substantial clinical heterogeneity.
This is also evident when evaluating the magnitude of statisti-
cal heterogeneity observed in available meta-analyses (22–25).
Furthermore, since the publication of the previous systematic
reviews, two additional large randomized control studies evaluat-
ing procalcitonin-guided strategies have been published (14, 15).
Therefore, we performed a systematic review and meta-analysis
to 1) evaluate the true effect size of procalcitonin-guided strate-
gies in different phases of antimicrobial use; and 2) incorporate
the findings from the most up-to-date clinical studies.
MATERIALS AND METHODS
This systematic review and meta-analysis was performed and
reported in accordance with the current guidelines as described
by the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses statement (28).
Literature Search and Data Extraction
A systematic review of the medical literature was performed
from MEDLINE and EMBASE databases from inception to
November 1, 2017. See Supplemental Table 1 (Supplemental
Digital Content 1, http://links.lww.com/CCM/D211) for Med-
ical Subject Headings search terms and search strategy. Each
abstract was reviewed by at least two authors independently
and assessed for inclusion based on study criteria. Inclusion
criteria encompassed randomized controlled study, procal-
citonin-guided antibiotics decision compared with standard
of care, critical care adult population, English language, and
reported at least one of the following outcomes: mortality, LOS,
or antibiotics use. Abstracts were excluded for full text review
if the study was performed in children or neonates; specifically
evaluated patients with neutropenia, osteomyelitis, endocar-
ditis, septic arthritis, or abscesses; or evaluated procalcitonin
guidance for strategies outside of antibiotics management.
Each full text article was reviewed independently by at least
two authors. All meta-analyses of procalcitonin use in critically
ill patients were reviewed to identify any additional studies that
may have been missed with the search strategy. Discrepancies
were settled by an independent review from a third reviewer.
Data were extracted from each included study by at least two
independent reviewers using a structured data collection sheet
to include the following items: publication details, country of
origin, design, setting, procalcitonin test and algorithm, patients’
2 www.ccmjournal.org XXX 2017 • Volume XX • Number XXX
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
characteristics, interventions, compliance with algorithm, and
outcomes. For all studies, the intention-to-treat outcomes were
utilized. Trials were classified based on whether the procalcito-
nin strategy guided the initiation, cessation, or both (mixed)
phases of antimicrobial management (27). Briefly, the classifica-
tion of the procalcitonin strategy was based on whether there
was a protocolized-driven approach to the antimicrobial deci-
sions surrounding the specific phase of antibiotics management.
Specifically, initiation is specified the period when clinicians
were deciding whether antibiotics should be initiated, and cessa-
tion as the period when clinicians were deciding how to manage
antibiotics that patients are currently prescribed. Discrepancies
in data extraction were discussed and solved by consensus.
Outcomes and Analyses
The primary outcome of this meta-analysis was short term, all-
cause mortality, defined as hospital mortality or mortality within
30 days. Secondary outcomes included antibiotics duration, long-
term mortality (60–100 d), hospital and ICU LOS, and recurrent
infections. If recurrent infections were evaluated at multiple time
points, the one reported that is closest to day 14 was utilized. For
each of the outcomes, meta-analysis was only performed if there
were sufficient data with at least three studies in each of the pro-
calcitonin strategy subgroups (initiation, cessation, mixed). If
any of the subgroups lacked sufficient data, then the studies from
that subgroup were excluded from the meta-analysis.
Risk of Bias
The included articles were reviewed, and a quality assessment was
performed using the Cochrane Collaboration tool for assessing
risk of bias (29). Overall quality was independently determined
by each reviewer with discrepancies solved by consensus. Funnel
plots were utilized to allow for a visual assessment of publication
bias based on the primary outcome analysis.
Statistical Analysis
Pooled risk ratios (RRs) and 95% CIs were calculated for dichoto-
mous variables. Continuous variables were analyzed using weighted
mean differences and 95% CIs. When means and variances were
not reported, they were estimated from the medians, ranges, and
size of the samples (30). Between-study statistical heterogeneity
was assessed by the Cochran’s Q test, and I.2 (31) For all analyses
performed, if no significant heterogeneity was noted (p < 0.10 and
I2 < 50%), fixed-effect model analyses using the Mantel-Haenszel
method were presented; otherwise, results of the random-effects
model analysis using the DerSimonian-Laird method were pre-
sented. Statistical calculations were performed using Revman 5.3.5
(The Cochrane Collaboration, London, United Kingdom).
RESULTS
Study Selection
Using the search strategy, we found 686 records through MED-
LINE and 938 through EMBASE totaling 1,624 unique records.
From 1,624 abstracts, 53 articles were selected for full text review.
Thirty eight of the articles were excluded, leaving 15 trials that
 Review Article

fulfilled all inclusion and no exclusion criteria (Fig. 1). Nine pre- The algorithms used for procalcitonin guidance varied
viously published meta-analyses were identified, which did not widely. For trials that utilized procalcitonin for initiation of
identify any additional trials to be included. antibiotics, the cutoffs were generally a procalcitonin value of
greater than 0.5–1 μg/L leading to initiation or escalation of
Study Description antibiotics. Trials that utilized procalcitonin for cessation or de-
Supplemental Table 2 (Supplemental Digital Content 1, http:// escalation of antibiotics usually had both a relative (greater than
links.lww.com/CCM/D211) summarizes the main charac- 50–90% drop from previous procalcitonin) and an absolute
teristics of the included trials, classified based on the phase of value (less than 0.1–0.5 μg/mL) to determine when antibiotics
antimicrobial use in which a procalcitonin-guided strategy was should be stopped or de-escalated. All trials utilized an ultra-
evaluated. All 15 trials were published after 2008, with three sensitive procalcitonin assay with a low limit of detection (0.06
evaluating procalcitonin for the initiation of antibiotics, nine for μg/L). Noncompliance to the trial protocol was documented in
cessation, and three for mixed strategies. The majority of the tri- the majority of trials and ranged from 0% (16) to 61% (14).
als (12 of 15) were performed in mixed ICU settings, with two
focused on surgical ICU and one on medical ICU. The number Risk of Bias
of included patients from each trial ranged from 27 to 1,546. A summary of the risk of biases of included trials based on the
Cochrane Collaboration tool
can be found in Supplemental
Figure 1 (Supplemental Digi-
tal Content 1, http://links.lww.
com/CCM/D211). Two trials
had high overall risks of bias
(16, 17), five with moderate risks
(4, 6–8, 11), and the remainder
with low risks. Supplemental
Figure 2 (Supplemental Digi-
tal Content 1, http://links.lww.
com/CCM/D211) illustrates
a visual representation of the
potential for publication bias
based on the primary outcome
(short-term mortality). No
gross asymmetry was observed,
suggesting that publication bias
was not likely to influence the
overall effect size.

Primary Outcome
Short-term, all-cause mortality
was reported in all trials, with at
least three in each procalcitonin
strategy subgroup. The com-
bined estimate of the pooled
RR for all studies based on the
fixed effects model for short-
term mortality is 0.93 (95% CI,
0.85–1.01; p = 0.08), with no
significant differences observed
between procalcitonin-guidance
and standard of care (Fig. 2). No
significant heterogeneity was
observed (Q = 8.62; df = 14; p =
0.85; I2 = 0%). Examining each
procalcitonin strategy subgroup,
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram illustrating the the pooled RR for the initiation,
number of abstracts reviewed and studies included. A total of 1,624 abstracts were reviewed, with 53 extracted
for full texts, 15 articles met all inclusion and exclusion criteria: 3 initiation, 9 cessation, and 3 mixed studies. cessation, and mixed procalci-
PCT = procalcitonin, RCT = randomized controlled trials. tonin strategies for short-term

Critical Care Medicine www.ccmjournal.org 3

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Lam et al

Figure 2. A Forest plot for short-term mortality. Df = degrees of freedom, M-H = Mantel-Haenszel; PCT = procalcitonin..

mortality were 1.00 (95% CI, 0.86–1.15; p = 0.96), 0.87 (95%
CI, 0.77–0.98; p = 0.02), and 1.01 (95% CI, 0.80–1.29; p = 0.93),
respectively. The test for subgroup heterogeneity was not signifi-
cant (p = 0.27).
Secondary Outcomes
Antibiotic duration was reported in 13 trials, with 12 able to
be included for meta-analyses (nine trials from the cessation
subgroup and three trials from the mixed subgroup). The
mean difference in antibiotic duration, using a random effects
model, was –1.26 days (95% CI, –1.98 to –0.54 d; p < 0.001) in
the cessation subgroup and –3.10 days (95% CI, –6.09 to –0.11
d; p = 0.04) in the mixed subgroup (Fig. 3). Significant hetero-
geneity was observed (Q = 66.8; df = 11; p < 0.001; I2 = 84%).
Five trials reported long-term mortality, but there was only
sufficient evidence to evaluate the cessation subgroup, which
had three studies reporting results (14, 15, 18). The pooled RR
for the cessation studies, calculated using the random-effects
model since substantial heterogeneity was observed (Q = 5.54;
df = 2; p = 0.06; I2 = 64%) was 0.91 (95% CI, 0.75–1.11; p = 0.36)
(Supplemental Fig. 3, Supplemental Digital Content 1, http://
links.lww.com/CCM/D211).
Hospital and ICU LOS were reported in 10 and 13 studies,
respectively. Due to the insufficient number of trials in each
subgroup, only seven trials were included in the analyses for
cessation and mixed subgroups for hospital LOS and 11 trials
were included the initiation and cessation subgroups for ICU
LOS. No differences in hospital and ICU LOS were observed
(Supplemental Figs. 4 and 5, Supplemental Digital Content 1,
http://links.lww.com/CCM/D211).
The occurrence of recurrent infections was also evaluated
as a secondary outcome. Eight trials reported recurrent infec-
tions, with six eligible to be combined for meta-analysis in
the cessation subgroup. No difference in recurrent infections
was observed with pooled risk ratios = 1.19 (95% CI, 0.86–
1.65; p = 0.29) using a fixed effects model (Supplemental

4 www.ccmjournal.org XXX 2017 • Volume XX • Number XXX

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Figure 3. A Forest plot for antibiotic duration. Df = degrees of freedom, PCT = procalcitonin.
Fig. 6, Supplemental Digital Content 1, http://links.lww.
com/CCM/D211).
DISCUSSION
This systematic review and meta-analysis sought to evalu-
ate the impact of procalcitonin-guided antimicrobial man-
agement compared with standard antibiotics initiation and
cessation practices in critically ill patients. Recognizing the
possibility that the true effect size of the impact of procalci-
tonin guidance may be altered if procalcitonin use in different
antibiotic phases yields different outcomes, this meta-analysis
specifically evaluated the different strategy subgroups. Overall,
a procalcitonin-guided strategy for antibiotic use did not lead
to a decrease in short-term mortality. However, procalcitonin
guidance for the cessation of antibiotics was associated with a
decrease in mortality. This is in contrast to the use of procalci-
tonin for the initiation of antibiotics or mixed strategies, where
no mortality benefit was observed. The SSC guidelines suggest
procalcitonin can be used to support the discontinuation of
empiric antibiotics, but are silent on the use of procalcitonin
for antibiotics initiation (2). These recommendations empha-
size the distinction of procalcitonin use between phases of anti-
biotics management and are supported by this meta-analysis.
Previous meta-analyses attempted to evaluate the effect of
procalcitonin guidance on mortality in critically ill patients
(20–25); however, none of them detected a significant differ-
ence between procalcitonin and standard of care. With the
exception of the evaluation by Soni et al (24), none of these
Critical Care Medicine www.ccmjournal.org 5
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Review Article
previous meta-analyses attempted to separate procalcitonin
studies based on the different phase of antibiotics manage-
ment. Soni et al (24) performed meta-analyses that evalu-
ated procalcitonin for the discontinuation of antibiotics and,
separately, procalcitonin for antibiotics initiation. However,
the meta-analysis included studies that utilized procalcito-
nin for both the initiation and discontinuation of antibiotics
(a “mixed” strategy). As demonstrated by this meta-analysis,
mixed strategy procalcitonin use was not associated with an
improvement of mortality. Therefore, combining mixed stud-
ies with discontinuation studies may have also lessened the
true overall effect of procalcitonin for the discontinuation of
antibiotics.
The secondary outcome findings in this meta-analysis
demonstrated no difference in ICU LOS, hospital LOS, or
recurrent infections. However, a significant decrease in anti-
biotic duration was observed with procalcitonin guidance.
These findings were similar to other meta-analyses published
on the topic (19–25). Significant heterogeneity was observed
in the antimicrobial duration meta-analysis. This may be due
to the differences in trial follow-up period, where antimi-
crobial duration was evaluated anywhere from 5 days after
enrollment (13) to the entire hospital LOS (up to 547 d) (11).
Lastly, noncompliance to study protocol was quite variable
among included trials, which may further increase heteroge-
neity observed in the meta-analysis of antimicrobial dura-
tion. To accurately capture the true effect of procalcitonin
guidance on antibiotic duration, future trials should stan-
dardize when and how antibiotic duration is captured and
Lam et al
have provisions within its protocol to account for effects of
protocol noncompliance.
The current meta-analysis clearly demonstrates that there
is considerable clinical heterogeneity associated with trials
that evaluate procalcitonin in different phases of antimicrobial
management. As such, it is suboptimal and likely inappropri-
ate to combine procalcitonin studies from different antibiotic
phases for meta-analyses. Furthermore, because improved
mortality with procalcitonin use was only observed in the
cessation phase of antimicrobial management, future inves-
tigations should focus on isolating this strategy in their trial
protocols. Inclusion of initiation or mixed strategies within
the same study protocol as cessation may lead to confounding
and dilution of true effects. The potential detrimental effects
of prolonged or unnecessary antibiotics may be crucial. In the
study by Jensen et al (12), which evaluated procalcitonin for
the initiation of antibiotics, those randomized to procalcitonin
guidance had significantly higher rates of mechanical ventila-
tion, duration of ICU stay, and incidence of renal dysfunction.
Our systematic review and meta-analysis has several limi-
tations. First, due to the low number of trials in each strat-
egy subgroup and the differences in reported outcomes of the
included trials, it was not feasible to clearly evaluate each sepa-
rate procalcitonin strategy for all evaluated outcomes. Second,
the procalcitonin algorithms evaluated varied widely, which
likely led to differences in antibiotics management and patient
outcomes. Third, with some of the analyses, there was a con-
siderable degree of statistical heterogeneity. This may partially
be due to the inconsistent procalcitonin algorithms evaluated
and the effects of combining critically ill patients from dif-
ferent types of ICUs from different countries. The statistical
heterogeneity was managed by using random-effects models
when appropriate. Fourth, due to the variance in mortality
reporting, the primary outcome combined reported hospital
mortality or mortality within 30 days. Although combining
measures such as 30-day mortality and hospital mortality may
confound the final finding, it allows for comparison across all
the studies. In our comparison, eight of the 15 studies utilized
28- or 30-day mortality, which accounted for about 80% of all
patients in the meta-analysis. Given that the average hospital
LOS among all the studies was about 23 days, we believe that
the merits of combining the mortality results outweighs the
potential for confounding the outcome. Furthermore, a sen-
sitivity analysis evaluating only studies that reported 28-day
mortality demonstrated similar decrease mortality finding
in the cessation group (Supplementary Fig. 7, Supplemental
Digital Content 1, http://links.lww.com/CCM/D211). Fifth, the
meta-analysis included studies that may have high or moderate
risk of bias. However, in a sensitivity analysis, when those stud-
ies were removed, similar decreases in mortality was seen in
the cessation subgroup (Supplementary Fig. 8, Supplemental
Digital Content 1, http://links.lww.com/CCM/D211). Lastly,
many of the included trials reported high rates of noncompli-
ance to procalcitonin algorithm, with the exception of one trial
where all patients with protocol violations were excluded (16).
Noncompliance with the procalcitonin algorithm likely reflects
6 www.ccmjournal.org XXX 2017 • Volume XX • Number XXX
Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
usual care practice, which would bias the trials toward find-
ing no difference between approaches. This may further dilute
the effects of procalcitonin guidance. Of note, for trials that
provided more granular information regarding compliance
rates (3, 5, 13), compliance depended on the recommendation;
compliance was lower when a low procalcitonin level suggested
antibiotics should be withheld or stopped and higher when a
high procalcitonin level suggested continuation or initiation of
antibiotics. For example, in the trial by Layios et al (5), when
the baseline procalcitonin level was less than 0.5 μg/L, only
36% of clinicians were compliant with the recommendation
to withhold antimicrobials (5). This is in contrast to those who
had a baseline procalcitonin level greater than 0.5 μg/L, where
86% of clinicians were compliant with the recommendation
to initiate antimicrobials. This preferential compliance to initi-
ate antibiotics and noncompliance toward withholding anti-
microbials would further bias finding no difference between
approaches in an intention-to-treat trial design.
CONCLUSION
In conclusion, when evaluating all studies of procalcitonin-
guided antimicrobial management in critically ill patients,
no difference in short-term mortality was observed. How-
ever, when only examining procalcitonin-guided cessation of
antibiotics, mortality was lower with procalcitonin-guided
approach. As such, future studies should focus specifically on
procalcitonin for the cessation of antibiotics in critically ill
patients.
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