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Procalcitonin in intensive care units: the PRORATA trial
In the PRORATA trial (Feb 6, p 463),1 use of a procalcitonin-guided strategy in the intensive-care unit reduced the number of days of antibiotic treatment, compared with a conventional strategy. No eﬀect was seen on mortality and relapses of infection. Lila Bouadma and colleagues conclude that this strategy can be applied to most non-surgical patients, including those who are immunocompromised. However, it is critical to balance the beneﬁts and risks of a procalcitonin-guided strategy in each subgroup of patients. In the procalcitonin group, antibiotics were encouraged for procalcitonin concentrations above 0·5 μg/L. Previous studies showed that increased concentrations of procalcitonin (up to 15 μg/L) may be found in patients treated with T-cell antibodies, alemtuzumab, interleukin 2, granulocyte transfusions, or patients with acute graft-versus-host disease or liver metatstasis.2–4 Therefore, procalcitonin should not be considered as an accurate marker of infection in patients that fall into the above categories, since a procalcitonin-guided strategy could result in treatment excess. In addition, the interferences between infection, malignant diseases, and immune treatment can hamper the interpretation of procalcitonin kinetics. In the PRORATA trial, patients with severe neutropenia were excluded, whereas those with mild-to-moderate neutropenia were included. To the best of our knowledge, guidelines recommend prolonging antibiotic treatment in patients with mildto-moderate neutropenia until neutropenia recovery and fever resolution. When appropriate antibiotics are given, a 5–7 day treatment duration is required before fever resolution.5 Guidelines also recommend that these patients have the option of systemic antibiotics to
www.thelancet.com Vol 375 May 8, 2010
be given until 5–7 afebrile days have elapsed, unless the patient is unstable. If antibiotic treatment is stopped during neutropenia, the patient must be carefully monitored and antibiotics restarted immediately on the recurrence of fever or other evidence of bacterial infection.5 According to Bouadma and colleagues,1 few data are available about the 98 patients who were immunocompromised. We would like to know about mortality, the duration of antibiotic therapy, and the relapsing infection rate in these patients with neutropenia.
We declare that we have no conﬂicts of interest.
*Djamel Mokart, Marc Leone
Département d’Anesthésie et de Réanimation, Institut Paoli-Calmettes, 13273 Marseille Cedex 9, France (DM); and Service d’Anesthésie et de Réanimation, Hôpital Nord, Assistance PubliqueHôpitaux de Marseille, Université de la Méditerranée, Marseille, France (ML) 1 Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010; 375: 463–74. Brodska H, Drabek T, Malickova K, et al. Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: a prospective study. Crit Care 2009; 13: R37. Dornbusch HJ, Strenger V, Sovinz P, et al. Noninfectious causes of elevated procalcitonin and C-reactive protein serum levels in pediatric patients with hematologic and oncologic disorders. Support Care Cancer 2008; 16: 1035–40. Matzaraki V, Alexandraki KI, Venetsanou K, et al. Evaluation of serum procalcitonin and interleukin-6 levels as markers of liver metastasis. Clin Biochem 2007; 40: 336–42. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34: 730–51.
group of up to 9·9% would not be inferior. This equates to a number needed to harm of ten. They conclude that the signiﬁcant reduction (p<0·0001) of 2·7 days in mean exposure to antibiotics is worth a possible extra death for every ten patients treated by the procalcitonin strategy. If a true excess mortality as great as 2% (one extra death for every 50 patients treated with the procalcitonin strategy) were considered acceptable for a few days fewer antibiotics, this would require a non-inferiority trial with 16 500 patients. A true excess mortality of 4%, similar to that seen in the trial, would require about 4220 patients. The PRORATA trial, which recruited 621 patients, was grossly underpowered to provide reliable evidence for policy, but could be valuable in a synthesis of similar studies. Few patients would accept up to a 9·9% extra risk of death for 3 days fewer antibiotics. Why should your readers?
We declare that we have no conﬂicts of interest.
*William Tarnow-Mordi, Val Gebski
Westmead International Network for Neonatal Education and Research (WINNER) Centre, Centre for Newborn Care, University of Sydney, Westmead Hospital, Sydney, 2125 NSW, Australia (WT-M, VG); and NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia (VG) 1 Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010; 375: 463–74.
We believe that the PRORATA trial1 is of major concern, and potentially misleading, in suggesting that a strategy guided by procalcitonin could “reduce antibiotic exposure and selective pressure with no apparent adverse outcomes”. Lila Bouadma and colleagues assumed that a true excess mortality, or risk diﬀerence, in the procalcitonin
Lila Bouadma and colleagues1 nicely showed that a strategy based on the daily measurement of procalcitonin concentration allowed for a reduction of antibiotic consumption in intensive care units (ICUs). Although this held true for most infections, the PRORATA trial mainly included patients with pneumonia and showed that measuring procalcitonin concentrations allowed the clinician to better adhere to the international guidelines on
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Bertele’ V. 50: 133–64.2. possible that almost one in ten more patients could die when treated with a procalcitonin-based algorithm compared with usual care. indeed. With regard to mortality. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. et al. et al. Eﬃcacy and safety of recombinant human activated protein C for severe sepsis. Clin Infect Dis 2007. I declare that I have no conﬂicts of interest. Bouadma and colleagues are right to conclude that a procalcitonin-guided strategy could reduce antibiotic exposure in non-surgical patients in intensive care units. This could mean that it is.5 Should we accept a 3·8% increase with a procalcitoninguided strategy? Obviously. no patients in either group who died after day 28 had an infection relapse. et al.w. Vincent JL. blood culture results. Lancet 2010. Internal Medicine (GWL) and Diabetes Centre (NK). location before ICU. et al. 345: 1359–67. these patients had signiﬁcantly lower antibiotic exposure in the procalcitonin group than in the control group (3·6 days). They discuss the issue of the non-inferiority margin.landman@isala. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. septic shock. Tubach F. Second. Importantly. 8000 GK Zwolle. 375: 463–74. Non-inferiority trials are unethical because they disregard patients’ interests. France 1 Bouadma L. since no study in an ICU setting has ever shown such a dramatic diﬀerence in mortality— we are happy when intensive insulin therapy is associated with a 3% reduction in mortality. type of infection. We declare that we have no conﬂicts of interest. But concluding that there are no apparent adverse eﬀects. and Gijs Landman and Nanne Kleefstra raise concerns about the safety of a procalcitonin-guided strategy to limit antibiotic use in critically ill patients. The 60-day mortality turned out to be 3·8% lower in the group receiving usual care (90% CI –9·7 to 2·1). 4 5 van den Berghe G. This 10% cutoﬀ is questionable. et al. we should increase educational eﬀorts to better diﬀuse accepted guidelines. Clin Infect Dis 2010. Wouters P.com Vol 375 May 8. Before implementing costly biological analyses that could be unduly overinterpreted. After adjustment for age. *Gijs W Landman. In 2007. Luyt CE. Weekers F. Solomkin JE.d. 2010 Sébastien Gibot s. Laterre PF. perhaps more appropriate. Garattini and Bertele’2 discussed some important issues of non-inferiority trials. is only statistically true. the use of a 90% CI is questionable.3 this trial would have had negative results. Lancet 2010. Lila Bouadma and colleagues1 succeeded in reducing antibiotic use by 2·7 days in the procalcitonin group. since a slightly higher number of patients in the procalcitonin group than in the control group died between days 29 and 60. Another concern is that the PRORATA trial was designed to exclude a 10% diﬀerence in mortality between procalcitonin-guided and control groups. Luyt CE. SOFA score at admission. Mazuski JS. sex. However.2. Tubach F. or at least treated for a too long. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. and mechanical ventilation at inclusion. suggesting that this slightly higher mortality rate at day 60 is not biologically plausible. respectively.nl Isala Clinics. given the late separation in mortality between the two groups. But had the patients in the control group been managed according to current recommendations.gibot@chu-nancy. We must not hide behind procalcitonin or other sophisticated biomarkers and must always ask ourselves about the appropriateness of pursuing antibiotics in any given patient. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of communityacquired pneumonia in adults. without signiﬁcant diﬀerences in mortality and relapse rates. N Engl J Med 2001. the lower limit of the 90% CI is –9·7%. we agree that more trials are needed to conﬁrm that a procalcitonin-guided strategy can reduce antibiotic use without adversely aﬀecting outcomes in that speciﬁc subset of patients. In our trial. 2 3 2 1606 . Wunderink RG. the results of the PRORATA trial looked reassuring since the results are within the non-inferiority margin. Joseph S. www. pre-existing comorbidities. William Tarnow-Mordi and Val Gebski. Bernard GR. 344: 699–709. Netherlands 1 Bouadma L. which was set at 10% to calculate our trial’s sample size.3 These results remind us that patients in ICUs are frequently overtreated. Garattini S. there were some slight imbalances at intensive care unit (ICU) admission and random allocation between the procalcitonin and the usual care groups. The non-inferiority margin for mortality was set at 10%. 95% CI had been used. Sébastien Gibot.4 or activated protein C with a 6% reduction. including a higher Simpliﬁed Acute Physiology Score II and a higher Sequential Organ Failure Assessment (SOFA) score in patients randomly assigned to the procalcitonin group. 54035 Nancy Cedex. N Engl J Med 2001. Authors’ reply Djamel Mokart and Marc Leone point out potential diﬃculties for interpreting procalcitonin concentrations in immunocompromised patients. but the design and the power of the trial means that the trial cannot deﬁnitely exclude such a negative impact on mortality attributable to the procalcitonin strategy. Nanne Kleefstra g. the odds ratios for death by day 28 or 60 for procalcitonin-group patients versus controls were 0·89 (90% CI 0·62–1·28) and 1·09 (0·79–1·51). Hôpital Central. Mandell LA. 370: 1875–77. 44 (suppl 2): S27–72. this 3·8% increase is not statistically signiﬁcant. 375: 463–74. Anzueto A. et al.Correspondence antibiotherapy duration. The non-inferiority margin would have been crossed if the. First. reason for ICU admission.thelancet. and one of the problems they discussed pertains to the PRORATA trial. Lancet 2007. when there is a possibility of an absolute increased risk of death of around 10%. First. Intensive insulin therapy in the critically ill patients. for the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group.fr Service de Réanimation Médicale. We do not share their concerns for the following reasons.
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