- Email: [email protected]
Procalcitonin in intensive care units: the PRORATA trial
Correspondence
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 [email protected] 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
2
3
4
5
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.
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
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?
Science Photo Library
Procalcitonin in intensive care units: the PRORATA trial
We declare that we have no conflicts of interest.
*William Tarnow-Mordi, Val Gebski [email protected] 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.
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
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1605
Correspondence
antibiotherapy duration.2,3 These results remind us that patients in ICUs are frequently overtreated, or at least treated for a too long. But had the patients in the control group been managed according to current recommendations,2,3 this trial would have had negative results. Before implementing costly biological analyses that could be unduly overinterpreted, we should increase educational efforts to better diffuse accepted guidelines. Another concern is that the PRORATA trial was designed to exclude a 10% difference in mortality between procalcitonin-guided and control groups. This 10% cutoff is questionable, 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,4 or activated protein C with a 6% reduction.5 Should we accept a 3·8% increase with a procalcitoninguided strategy? Obviously, this 3·8% increase is not statistically significant, 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. 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. I declare that I have no conflicts of interest.
Sébastien Gibot [email protected] Service de Réanimation Médicale, Hôpital Central, 54035 Nancy Cedex, France 1
2
3
1606
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. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of communityacquired pneumonia in adults. Clin Infect Dis 2007; 44 (suppl 2): S27–72. Joseph S, Solomkin JE, Mazuski JS, et al. 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. Clin Infect Dis 2010; 50: 133–64.
4
5
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359–67. Bernard GR, Vincent JL, Laterre PF, et al, for the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–709.
Lila Bouadma and colleagues1 succeeded in reducing antibiotic use by 2·7 days in the procalcitonin group. With regard to mortality, the results of the PRORATA trial looked reassuring since the results are within the non-inferiority margin. In 2007, Garattini and Bertele’2 discussed some important issues of non-inferiority trials, and one of the problems they discussed pertains to the PRORATA trial. The non-inferiority margin for mortality was set at 10%. The 60-day mortality turned out to be 3·8% lower in the group receiving usual care (90% CI –9·7 to 2·1). First, the lower limit of the 90% CI is –9·7%. This could mean that it is, indeed, possible that almost one in ten more patients could die when treated with a procalcitonin-based algorithm compared with usual care. Second, the use of a 90% CI is questionable. The non-inferiority margin would have been crossed if the, perhaps more appropriate, 95% CI had been used. Bouadma and colleagues are right to conclude that a procalcitonin-guided strategy could reduce antibiotic exposure in non-surgical patients in intensive care units. But concluding that there are no apparent adverse effects, when there is a possibility of an absolute increased risk of death of around 10%, is only statistically true. We declare that we have no conflicts of interest.
*Gijs W Landman, Nanne Kleefstra [email protected] Isala Clinics, Internal Medicine (GWL) and Diabetes Centre (NK), 8000 GK Zwolle, Netherlands 1
2
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. Garattini S, Bertele’ V. Non-inferiority trials are unethical because they disregard patients’ interests. Lancet 2007; 370: 1875–77.
Authors’ reply Djamel Mokart and Marc Leone point out potential difficulties for interpreting procalcitonin concentrations in immunocompromised patients. In our trial, these patients had significantly lower antibiotic exposure in the procalcitonin group than in the control group (3·6 days), without significant differences in mortality and relapse rates. However, 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. William Tarnow-Mordi and Val Gebski, Sébastien Gibot, and Gijs Landman and Nanne Kleefstra raise concerns about the safety of a procalcitonin-guided strategy to limit antibiotic use in critically ill patients, since a slightly higher number of patients in the procalcitonin group than in the control group died between days 29 and 60. They discuss the issue of the non-inferiority margin, which was set at 10% to calculate our trial’s sample size. We do not share their concerns for the following reasons. First, there were some slight imbalances at intensive care unit (ICU) admission and random allocation between the procalcitonin and the usual care groups, 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. After adjustment for age, sex, pre-existing comorbidities, location before ICU, reason for ICU admission, SOFA score at admission, type of infection, blood culture results, septic shock, and mechanical ventilation at inclusion, 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), respectively. Importantly, no patients in either group who died after day 28 had an infection relapse, suggesting that this slightly higher mortality rate at day 60 is not biologically plausible, given the late separation in mortality between the two groups. www.thelancet.com Vol 375 May 8, 2010
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 [email protected] 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
2
3
4
5
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.
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
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?
Science Photo Library
Procalcitonin in intensive care units: the PRORATA trial
We declare that we have no conflicts of interest.
*William Tarnow-Mordi, Val Gebski [email protected] 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.
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
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1605
Correspondence
antibiotherapy duration.2,3 These results remind us that patients in ICUs are frequently overtreated, or at least treated for a too long. But had the patients in the control group been managed according to current recommendations,2,3 this trial would have had negative results. Before implementing costly biological analyses that could be unduly overinterpreted, we should increase educational efforts to better diffuse accepted guidelines. Another concern is that the PRORATA trial was designed to exclude a 10% difference in mortality between procalcitonin-guided and control groups. This 10% cutoff is questionable, 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,4 or activated protein C with a 6% reduction.5 Should we accept a 3·8% increase with a procalcitoninguided strategy? Obviously, this 3·8% increase is not statistically significant, 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. 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. I declare that I have no conflicts of interest.
Sébastien Gibot [email protected] Service de Réanimation Médicale, Hôpital Central, 54035 Nancy Cedex, France 1
2
3
1606
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. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of communityacquired pneumonia in adults. Clin Infect Dis 2007; 44 (suppl 2): S27–72. Joseph S, Solomkin JE, Mazuski JS, et al. 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. Clin Infect Dis 2010; 50: 133–64.
4
5
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359–67. Bernard GR, Vincent JL, Laterre PF, et al, for the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–709.
Lila Bouadma and colleagues1 succeeded in reducing antibiotic use by 2·7 days in the procalcitonin group. With regard to mortality, the results of the PRORATA trial looked reassuring since the results are within the non-inferiority margin. In 2007, Garattini and Bertele’2 discussed some important issues of non-inferiority trials, and one of the problems they discussed pertains to the PRORATA trial. The non-inferiority margin for mortality was set at 10%. The 60-day mortality turned out to be 3·8% lower in the group receiving usual care (90% CI –9·7 to 2·1). First, the lower limit of the 90% CI is –9·7%. This could mean that it is, indeed, possible that almost one in ten more patients could die when treated with a procalcitonin-based algorithm compared with usual care. Second, the use of a 90% CI is questionable. The non-inferiority margin would have been crossed if the, perhaps more appropriate, 95% CI had been used. Bouadma and colleagues are right to conclude that a procalcitonin-guided strategy could reduce antibiotic exposure in non-surgical patients in intensive care units. But concluding that there are no apparent adverse effects, when there is a possibility of an absolute increased risk of death of around 10%, is only statistically true. We declare that we have no conflicts of interest.
*Gijs W Landman, Nanne Kleefstra [email protected] Isala Clinics, Internal Medicine (GWL) and Diabetes Centre (NK), 8000 GK Zwolle, Netherlands 1
2
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. Garattini S, Bertele’ V. Non-inferiority trials are unethical because they disregard patients’ interests. Lancet 2007; 370: 1875–77.
Authors’ reply Djamel Mokart and Marc Leone point out potential difficulties for interpreting procalcitonin concentrations in immunocompromised patients. In our trial, these patients had significantly lower antibiotic exposure in the procalcitonin group than in the control group (3·6 days), without significant differences in mortality and relapse rates. However, 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. William Tarnow-Mordi and Val Gebski, Sébastien Gibot, and Gijs Landman and Nanne Kleefstra raise concerns about the safety of a procalcitonin-guided strategy to limit antibiotic use in critically ill patients, since a slightly higher number of patients in the procalcitonin group than in the control group died between days 29 and 60. They discuss the issue of the non-inferiority margin, which was set at 10% to calculate our trial’s sample size. We do not share their concerns for the following reasons. First, there were some slight imbalances at intensive care unit (ICU) admission and random allocation between the procalcitonin and the usual care groups, 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. After adjustment for age, sex, pre-existing comorbidities, location before ICU, reason for ICU admission, SOFA score at admission, type of infection, blood culture results, septic shock, and mechanical ventilation at inclusion, 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), respectively. Importantly, no patients in either group who died after day 28 had an infection relapse, suggesting that this slightly higher mortality rate at day 60 is not biologically plausible, given the late separation in mortality between the two groups. www.thelancet.com Vol 375 May 8, 2010