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Empirical micafungin falls short for treating suspected fungal infection in the ICU
MILAN – Empirical antifungal treatment did not improve the rate of survival free of invasive fungal infection among high-risk colonized patients in the intensive care unit, based on results from the EMPIRICUS randomized controlled trial.
Trial participants were 260 nonneutropenic, nontransplanted critically ill patients with ICU-acquired sepsis, Candida colonization of at least one site, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. They were randomized to 14 days of empirical treatment with micafungin (Mycamine, 100 mg once daily) or placebo.
By day 28, about two-thirds of patients overall remained alive and free of proven invasive fungal infection, with no significant difference between groups, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published online (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.14655). Results were similar in subsets of patients having established risk factors for candidemia.
The EMPIRICUS (Empirical Antifungal Treatment in ICUs) findings add to data from other studies suggesting that, in this patient population, sepsis is seldom a result of invasive fungal infection and Candida colonization status is not helpful for guiding treatment, according to the researchers, who were led by Dr. Jean-Francois Timsit of Inserm/Paris Diderot University and department of medical intensive care and infectious diseases, Hôpital Bichat-Claude-Bernard, Paris.
“Altogether, these results call into question the routine use of systematic surveillance for Candida colonization. Besides sparing unnecessary use of health care resources, it may also avoid inducing resistances to antifungals,” they maintain. “Whether this trial closes 3 decades of clinical research on Candida colonization deserves consideration.”
Patients were recruited to EMPIRICUS from 19 ICUs in France. On average, study participants had three Candida-colonized sites.
A modified intent-to-treat analysis showed that, by day 28 after enrollment, 68% of patients in the micafungin group and 60.2% in the placebo group were alive and free of invasive fungal infection, a nonsignificant difference.
Findings were similar in the subset of patients having high serum levels of (1-3)-beta-D-glucan and in the subset of patients having high Sepsis-Related Organ Failure Assessment (SOFA) scores – both risk factors for candidemia – and regardless of the number of colonized sites.
In analyses of secondary outcomes, empirical micafungin was associated with a lower rate of new invasive fungal infection when compared with placebo (3% vs. 12%; P = .008), but the rate of mortality was statistically indistinguishable (30% vs. 29.7%).
The groups were statistically indistinguishable with respect to the number of organ failure–free days and the rate of ventilator-acquired pneumonia.
Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he disclosed participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
Taken together, findings from EMPIRICUS and similar trials suggest that empirical antifungal treatment may reduce rates of invasive infection in critically ill patients, but does not improve survival.
These findings highlight two emerging themes in critical care medicine – less is more and targeted therapies are important when treating invasive fungal infection. In particular, the safety and efficacy of the newer antifungal agents are driving greater empirical use, yet this practice increases the cost of care and may contribute to antifungal resistance.
Guidelines have been implemented for empirical treatment of Candida and serial surveillance, yet there are no conclusive mortality benefits for this approach. Data have not ruled out the possibility that some subgroups of patients may see a survival benefit but, in light of the situation, guidelines concerning empirical treatment and surveillance should be revisited.
Like other prophylactic interventions, the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU need to be studied. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.
Trishul Siddharthan, MD, Petros C. Karakousis, MD, and William Checkley, MD, PhD, are with the Johns Hopkins University in Baltimore. They made their remarks in an accompanying editorial in JAMA (2016 Oct 5. doi: 10.1001/jama.2016.13801).
Taken together, findings from EMPIRICUS and similar trials suggest that empirical antifungal treatment may reduce rates of invasive infection in critically ill patients, but does not improve survival.
These findings highlight two emerging themes in critical care medicine – less is more and targeted therapies are important when treating invasive fungal infection. In particular, the safety and efficacy of the newer antifungal agents are driving greater empirical use, yet this practice increases the cost of care and may contribute to antifungal resistance.
Guidelines have been implemented for empirical treatment of Candida and serial surveillance, yet there are no conclusive mortality benefits for this approach. Data have not ruled out the possibility that some subgroups of patients may see a survival benefit but, in light of the situation, guidelines concerning empirical treatment and surveillance should be revisited.
Like other prophylactic interventions, the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU need to be studied. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.
Trishul Siddharthan, MD, Petros C. Karakousis, MD, and William Checkley, MD, PhD, are with the Johns Hopkins University in Baltimore. They made their remarks in an accompanying editorial in JAMA (2016 Oct 5. doi: 10.1001/jama.2016.13801).
Taken together, findings from EMPIRICUS and similar trials suggest that empirical antifungal treatment may reduce rates of invasive infection in critically ill patients, but does not improve survival.
These findings highlight two emerging themes in critical care medicine – less is more and targeted therapies are important when treating invasive fungal infection. In particular, the safety and efficacy of the newer antifungal agents are driving greater empirical use, yet this practice increases the cost of care and may contribute to antifungal resistance.
Guidelines have been implemented for empirical treatment of Candida and serial surveillance, yet there are no conclusive mortality benefits for this approach. Data have not ruled out the possibility that some subgroups of patients may see a survival benefit but, in light of the situation, guidelines concerning empirical treatment and surveillance should be revisited.
Like other prophylactic interventions, the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU need to be studied. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.
Trishul Siddharthan, MD, Petros C. Karakousis, MD, and William Checkley, MD, PhD, are with the Johns Hopkins University in Baltimore. They made their remarks in an accompanying editorial in JAMA (2016 Oct 5. doi: 10.1001/jama.2016.13801).
MILAN – Empirical antifungal treatment did not improve the rate of survival free of invasive fungal infection among high-risk colonized patients in the intensive care unit, based on results from the EMPIRICUS randomized controlled trial.
Trial participants were 260 nonneutropenic, nontransplanted critically ill patients with ICU-acquired sepsis, Candida colonization of at least one site, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. They were randomized to 14 days of empirical treatment with micafungin (Mycamine, 100 mg once daily) or placebo.
By day 28, about two-thirds of patients overall remained alive and free of proven invasive fungal infection, with no significant difference between groups, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published online (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.14655). Results were similar in subsets of patients having established risk factors for candidemia.
The EMPIRICUS (Empirical Antifungal Treatment in ICUs) findings add to data from other studies suggesting that, in this patient population, sepsis is seldom a result of invasive fungal infection and Candida colonization status is not helpful for guiding treatment, according to the researchers, who were led by Dr. Jean-Francois Timsit of Inserm/Paris Diderot University and department of medical intensive care and infectious diseases, Hôpital Bichat-Claude-Bernard, Paris.
“Altogether, these results call into question the routine use of systematic surveillance for Candida colonization. Besides sparing unnecessary use of health care resources, it may also avoid inducing resistances to antifungals,” they maintain. “Whether this trial closes 3 decades of clinical research on Candida colonization deserves consideration.”
Patients were recruited to EMPIRICUS from 19 ICUs in France. On average, study participants had three Candida-colonized sites.
A modified intent-to-treat analysis showed that, by day 28 after enrollment, 68% of patients in the micafungin group and 60.2% in the placebo group were alive and free of invasive fungal infection, a nonsignificant difference.
Findings were similar in the subset of patients having high serum levels of (1-3)-beta-D-glucan and in the subset of patients having high Sepsis-Related Organ Failure Assessment (SOFA) scores – both risk factors for candidemia – and regardless of the number of colonized sites.
In analyses of secondary outcomes, empirical micafungin was associated with a lower rate of new invasive fungal infection when compared with placebo (3% vs. 12%; P = .008), but the rate of mortality was statistically indistinguishable (30% vs. 29.7%).
The groups were statistically indistinguishable with respect to the number of organ failure–free days and the rate of ventilator-acquired pneumonia.
Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he disclosed participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
MILAN – Empirical antifungal treatment did not improve the rate of survival free of invasive fungal infection among high-risk colonized patients in the intensive care unit, based on results from the EMPIRICUS randomized controlled trial.
Trial participants were 260 nonneutropenic, nontransplanted critically ill patients with ICU-acquired sepsis, Candida colonization of at least one site, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. They were randomized to 14 days of empirical treatment with micafungin (Mycamine, 100 mg once daily) or placebo.
By day 28, about two-thirds of patients overall remained alive and free of proven invasive fungal infection, with no significant difference between groups, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published online (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.14655). Results were similar in subsets of patients having established risk factors for candidemia.
The EMPIRICUS (Empirical Antifungal Treatment in ICUs) findings add to data from other studies suggesting that, in this patient population, sepsis is seldom a result of invasive fungal infection and Candida colonization status is not helpful for guiding treatment, according to the researchers, who were led by Dr. Jean-Francois Timsit of Inserm/Paris Diderot University and department of medical intensive care and infectious diseases, Hôpital Bichat-Claude-Bernard, Paris.
“Altogether, these results call into question the routine use of systematic surveillance for Candida colonization. Besides sparing unnecessary use of health care resources, it may also avoid inducing resistances to antifungals,” they maintain. “Whether this trial closes 3 decades of clinical research on Candida colonization deserves consideration.”
Patients were recruited to EMPIRICUS from 19 ICUs in France. On average, study participants had three Candida-colonized sites.
A modified intent-to-treat analysis showed that, by day 28 after enrollment, 68% of patients in the micafungin group and 60.2% in the placebo group were alive and free of invasive fungal infection, a nonsignificant difference.
Findings were similar in the subset of patients having high serum levels of (1-3)-beta-D-glucan and in the subset of patients having high Sepsis-Related Organ Failure Assessment (SOFA) scores – both risk factors for candidemia – and regardless of the number of colonized sites.
In analyses of secondary outcomes, empirical micafungin was associated with a lower rate of new invasive fungal infection when compared with placebo (3% vs. 12%; P = .008), but the rate of mortality was statistically indistinguishable (30% vs. 29.7%).
The groups were statistically indistinguishable with respect to the number of organ failure–free days and the rate of ventilator-acquired pneumonia.
Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he disclosed participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
FROM ESICM CONGRESS 2016
Key clinical point:
Major finding: The day 28 invasive fungal infection–free survival was 68% with empirical micafungin and 60.2% with placebo, a nonsignificant difference.
Data source: A randomized controlled trial among 260 critically ill patients with ICU-acquired sepsis, Candida colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents (EMPIRICUS trial).
Disclosures: Dr. Timsit disclosed that he receives lecture fees from Gilead, Pfizer, Merck, and Astellas; research grants to his university and research organization from Astellas, Gilead, Merck, and Pfizer companies; a consultancy honorarium from Bayer; and personal fees from Abbott for scientific board participation; additionally, he discloses participation on a scientific committee of epidemiological studies organized by Astellas and Merck companies outside the submitted work. Astellas provided a research grant to the Grenoble Alpes University Hospital based on the final study protocol. The study was sponsored by the University of Grenoble 1/Albert Michallon University Hospital. The University of Grenoble provided compensation to the participating hospitals and universities for extra costs associated with the study.
Conservative oxygen therapy in the ICU reduces mortality
A strategy of conservatively controlling oxygen delivery to patients in the intensive care unit results in lower mortality than the conventional, more liberal approach whereby patients are often kept in a hyperoxemic state, finds a randomized controlled trial.
The trial, known as Oxygen-ICU, enrolled more than 400 adult ICU patients from an Italian center. Initially planned to last 2 years, it was terminated early because of slow enrollment after an earthquake reduced ICU capacity, with the decision supported by positive results of an interim analysis.
Patients had an absolute nearly 9% lower risk of dying in the ICU with use of the conservative oxygen strategy as compared with the conventional one, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.11993).
“To our knowledge, this is the first randomized clinical trial to evaluate the effect of a conservative oxygen therapy on mortality compared with a standard, more liberal approach in a medical-surgical population of adult critically ill patients,” write the investigators, who were led by Massimo Girardis, MD, of the Intensive Care Unit, Department of Anesthesiology and Intensive Care, University Hospital of Modena (Italy).
Among critically ill patients with an ICU length of stay of 72 hours or longer, a conservative protocol for oxygen therapy compared with conventional therapy resulted in a lower ICU mortality,” they conclude. “However, these preliminary findings were based on unplanned early termination of the trial, and a larger multicenter trial is needed to evaluate the potential benefit of such conservative oxygen therapy in critically ill patients.”
In the trial, consecutive patients were randomized evenly to receive conservative oxygen therapy (maintenance of PaO2 between 70 and 100 mm Hg or arterial oxyhemoglobin saturation [SpO2] between 94% and 98%) or conventional oxygen therapy (allowance of PaO2 values up to 150 mm Hg or SpO2 values between 97% and 100%) on an open-label basis.
The originally targeted enrollment was 660 patients, but the study was stopped early after only 480 patients had been enrolled.
Results of modified intent-to-treat analyses showed that daily time-weighted PaO2 averages during patients’ ICU stays were higher in the conventional group than in the conservative group (median PaO2, 102 vs. 87 mm Hg; P less than .001).
The rate of ICU mortality, the trial’s primary endpoint, was 11.6% with conservative therapy, about half of the 20.2% seen with conventional therapy (absolute mean difference, 0.086; P = .01).
The conservative group also had lower rates of shock (3.7% vs. 10.6%, P = .006), liver failure (1.9% vs. 6.4%, P = .02), and bacteremia (5.1% vs. 10.1%, P = .049). And they spent a day less on the ventilator (median mechanical ventilation–free hours, 72 vs. 48; P = .02).
Lengths of ICU stay and hospital stay did not differ between the two groups.
One of the study authors reports serving as the data monitoring chair for a phase II study sponsored by InflaRx, on the antibiotic advisory board for Bayer, and on sepsis advisory boards for Biotest and Merck. The study was supported by the National Fund for Scientific Research of the University of Modena and Reggio Emilia.
The reduction in mortality seen with conservative oxygen therapy in the Oxygen-ICU trial was “striking,” according to editorialist Dr. Niall D. Ferguson. However, “it is likely that to some extent, this trial has overestimated the true treatment effect of conservative oxygen therapy,” he cautions, given baseline imbalances between groups, early stopping based in part on an unplanned interim analysis, and the small number of deaths. The editorialist noted that the study was underpowered and criticized its use of a modified intent-to-treat analysis.
The trial’s findings contrast with those of a pilot study conducted by the ANZICS clinical trials group that did not find better outcomes with use of lower oxygen targets, according to Dr. Ferguson. However, in that trial, both arms had lower target and actual PaO2 levels. Thus, the optimal clinical approach remains uncertain.
“Until the results of further trials addressing this issue are available, there appears to be little downside in the careful titration and monitoring of supplemental oxygen in the ICU to achieve physiologically normal levels of PaO2 while avoiding potentially dangerous hyperoxia,” he concludes.
Dr. Ferguson disclosed that he has no relevant conflicts of interest.
Niall D. Ferguson, MD, MSc, is with the Interdepartmental Division of Critical Care Medicine and Departments of Medicine and Physiology, University of Toronto; the Institute of Health Policy, Management, & Evaluation, University of Toronto; the Division of Respirology, Department of Medicine, University Health Network and Mount Sinai Hospital; and the Toronto General Research Institute.
The reduction in mortality seen with conservative oxygen therapy in the Oxygen-ICU trial was “striking,” according to editorialist Dr. Niall D. Ferguson. However, “it is likely that to some extent, this trial has overestimated the true treatment effect of conservative oxygen therapy,” he cautions, given baseline imbalances between groups, early stopping based in part on an unplanned interim analysis, and the small number of deaths. The editorialist noted that the study was underpowered and criticized its use of a modified intent-to-treat analysis.
The trial’s findings contrast with those of a pilot study conducted by the ANZICS clinical trials group that did not find better outcomes with use of lower oxygen targets, according to Dr. Ferguson. However, in that trial, both arms had lower target and actual PaO2 levels. Thus, the optimal clinical approach remains uncertain.
“Until the results of further trials addressing this issue are available, there appears to be little downside in the careful titration and monitoring of supplemental oxygen in the ICU to achieve physiologically normal levels of PaO2 while avoiding potentially dangerous hyperoxia,” he concludes.
Dr. Ferguson disclosed that he has no relevant conflicts of interest.
Niall D. Ferguson, MD, MSc, is with the Interdepartmental Division of Critical Care Medicine and Departments of Medicine and Physiology, University of Toronto; the Institute of Health Policy, Management, & Evaluation, University of Toronto; the Division of Respirology, Department of Medicine, University Health Network and Mount Sinai Hospital; and the Toronto General Research Institute.
The reduction in mortality seen with conservative oxygen therapy in the Oxygen-ICU trial was “striking,” according to editorialist Dr. Niall D. Ferguson. However, “it is likely that to some extent, this trial has overestimated the true treatment effect of conservative oxygen therapy,” he cautions, given baseline imbalances between groups, early stopping based in part on an unplanned interim analysis, and the small number of deaths. The editorialist noted that the study was underpowered and criticized its use of a modified intent-to-treat analysis.
The trial’s findings contrast with those of a pilot study conducted by the ANZICS clinical trials group that did not find better outcomes with use of lower oxygen targets, according to Dr. Ferguson. However, in that trial, both arms had lower target and actual PaO2 levels. Thus, the optimal clinical approach remains uncertain.
“Until the results of further trials addressing this issue are available, there appears to be little downside in the careful titration and monitoring of supplemental oxygen in the ICU to achieve physiologically normal levels of PaO2 while avoiding potentially dangerous hyperoxia,” he concludes.
Dr. Ferguson disclosed that he has no relevant conflicts of interest.
Niall D. Ferguson, MD, MSc, is with the Interdepartmental Division of Critical Care Medicine and Departments of Medicine and Physiology, University of Toronto; the Institute of Health Policy, Management, & Evaluation, University of Toronto; the Division of Respirology, Department of Medicine, University Health Network and Mount Sinai Hospital; and the Toronto General Research Institute.
A strategy of conservatively controlling oxygen delivery to patients in the intensive care unit results in lower mortality than the conventional, more liberal approach whereby patients are often kept in a hyperoxemic state, finds a randomized controlled trial.
The trial, known as Oxygen-ICU, enrolled more than 400 adult ICU patients from an Italian center. Initially planned to last 2 years, it was terminated early because of slow enrollment after an earthquake reduced ICU capacity, with the decision supported by positive results of an interim analysis.
Patients had an absolute nearly 9% lower risk of dying in the ICU with use of the conservative oxygen strategy as compared with the conventional one, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.11993).
“To our knowledge, this is the first randomized clinical trial to evaluate the effect of a conservative oxygen therapy on mortality compared with a standard, more liberal approach in a medical-surgical population of adult critically ill patients,” write the investigators, who were led by Massimo Girardis, MD, of the Intensive Care Unit, Department of Anesthesiology and Intensive Care, University Hospital of Modena (Italy).
Among critically ill patients with an ICU length of stay of 72 hours or longer, a conservative protocol for oxygen therapy compared with conventional therapy resulted in a lower ICU mortality,” they conclude. “However, these preliminary findings were based on unplanned early termination of the trial, and a larger multicenter trial is needed to evaluate the potential benefit of such conservative oxygen therapy in critically ill patients.”
In the trial, consecutive patients were randomized evenly to receive conservative oxygen therapy (maintenance of PaO2 between 70 and 100 mm Hg or arterial oxyhemoglobin saturation [SpO2] between 94% and 98%) or conventional oxygen therapy (allowance of PaO2 values up to 150 mm Hg or SpO2 values between 97% and 100%) on an open-label basis.
The originally targeted enrollment was 660 patients, but the study was stopped early after only 480 patients had been enrolled.
Results of modified intent-to-treat analyses showed that daily time-weighted PaO2 averages during patients’ ICU stays were higher in the conventional group than in the conservative group (median PaO2, 102 vs. 87 mm Hg; P less than .001).
The rate of ICU mortality, the trial’s primary endpoint, was 11.6% with conservative therapy, about half of the 20.2% seen with conventional therapy (absolute mean difference, 0.086; P = .01).
The conservative group also had lower rates of shock (3.7% vs. 10.6%, P = .006), liver failure (1.9% vs. 6.4%, P = .02), and bacteremia (5.1% vs. 10.1%, P = .049). And they spent a day less on the ventilator (median mechanical ventilation–free hours, 72 vs. 48; P = .02).
Lengths of ICU stay and hospital stay did not differ between the two groups.
One of the study authors reports serving as the data monitoring chair for a phase II study sponsored by InflaRx, on the antibiotic advisory board for Bayer, and on sepsis advisory boards for Biotest and Merck. The study was supported by the National Fund for Scientific Research of the University of Modena and Reggio Emilia.
A strategy of conservatively controlling oxygen delivery to patients in the intensive care unit results in lower mortality than the conventional, more liberal approach whereby patients are often kept in a hyperoxemic state, finds a randomized controlled trial.
The trial, known as Oxygen-ICU, enrolled more than 400 adult ICU patients from an Italian center. Initially planned to last 2 years, it was terminated early because of slow enrollment after an earthquake reduced ICU capacity, with the decision supported by positive results of an interim analysis.
Patients had an absolute nearly 9% lower risk of dying in the ICU with use of the conservative oxygen strategy as compared with the conventional one, according to data reported at the annual congress of the European Society of Intensive Care Medicine and simultaneously published (JAMA. 2016 Oct 5. doi: 10.1001/jama.2016.11993).
“To our knowledge, this is the first randomized clinical trial to evaluate the effect of a conservative oxygen therapy on mortality compared with a standard, more liberal approach in a medical-surgical population of adult critically ill patients,” write the investigators, who were led by Massimo Girardis, MD, of the Intensive Care Unit, Department of Anesthesiology and Intensive Care, University Hospital of Modena (Italy).
Among critically ill patients with an ICU length of stay of 72 hours or longer, a conservative protocol for oxygen therapy compared with conventional therapy resulted in a lower ICU mortality,” they conclude. “However, these preliminary findings were based on unplanned early termination of the trial, and a larger multicenter trial is needed to evaluate the potential benefit of such conservative oxygen therapy in critically ill patients.”
In the trial, consecutive patients were randomized evenly to receive conservative oxygen therapy (maintenance of PaO2 between 70 and 100 mm Hg or arterial oxyhemoglobin saturation [SpO2] between 94% and 98%) or conventional oxygen therapy (allowance of PaO2 values up to 150 mm Hg or SpO2 values between 97% and 100%) on an open-label basis.
The originally targeted enrollment was 660 patients, but the study was stopped early after only 480 patients had been enrolled.
Results of modified intent-to-treat analyses showed that daily time-weighted PaO2 averages during patients’ ICU stays were higher in the conventional group than in the conservative group (median PaO2, 102 vs. 87 mm Hg; P less than .001).
The rate of ICU mortality, the trial’s primary endpoint, was 11.6% with conservative therapy, about half of the 20.2% seen with conventional therapy (absolute mean difference, 0.086; P = .01).
The conservative group also had lower rates of shock (3.7% vs. 10.6%, P = .006), liver failure (1.9% vs. 6.4%, P = .02), and bacteremia (5.1% vs. 10.1%, P = .049). And they spent a day less on the ventilator (median mechanical ventilation–free hours, 72 vs. 48; P = .02).
Lengths of ICU stay and hospital stay did not differ between the two groups.
One of the study authors reports serving as the data monitoring chair for a phase II study sponsored by InflaRx, on the antibiotic advisory board for Bayer, and on sepsis advisory boards for Biotest and Merck. The study was supported by the National Fund for Scientific Research of the University of Modena and Reggio Emilia.
FROM ESICM CONGRESS 2016
Key clinical point:
Major finding: Relative to conventional therapy, conservative therapy was associated with a lower ICU mortality (absolute risk reduction, 0.086; P = .01).
Data source: A randomized controlled trial among 434 patients admitted to a medical-surgical ICU and expected to stay at least 72 hours (Oxygen-ICU trial).
Disclosures: One of the study authors reports serving as the data monitoring chair for a phase II study sponsored by InflaRx, on the antibiotic advisory board for Bayer, and on sepsis advisory boards for Biotest and Merck. The study was supported by the National Fund for Scientific Research of the University of Modena and Reggio Emilia. Dr. Ferguson disclosed that he has no relevant conflicts of interest.
Levosimendan does not reduce organ dysfunction risk in sepsis
Levosimendan does not reduce the likelihood of severe organ dysfunction in adults with sepsis, nor does it lower the mortality rate, according to research presented at the annual congress of the European Society of Intensive Care Medicine and published in the New England Journal of Medicine.
Levosimendan is a calcium-sensitizing drug with inotropic and vasodilatory properties, which is commonly used to treat decompensated heart failure. “Small studies that have investigated the use of levosimendan in patients with septic shock have shown improvements in hemodynamic variables, microcirculatory flow, and renal and hepatic function, as compared with dobutamine,” wrote Anthony C. Gordon, MD, of Imperial College London and Imperial College Healthcare NHS Trust and his coauthors.
In the Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial, 516 patients were randomized to 24 hours of a blinded infusion either of levosimendan (.05-0.2 mcg per kilogram of body weight per minute) or placebo in addition to standard care.
Researchers saw no significant difference in the mean daily Sequential Organ Failure Assessment (SOFA) score between the two groups (mean difference, 0.61; 95% confidence interval, −0.07 to 1.29; P = .053). When the SOFA score was analyzed by system, the mean daily cardiovascular score was significantly higher in the levosimendan group, compared with the placebo group, indicating greater dysfunction in that system.
“The cardiovascular SOFA score was higher in the levosimendan group than in the placebo group, which reflects the higher doses of norepinephrine that were required to maintain the mean arterial pressure,” researchers reported.
There was no significant difference in 28-day mortality between the levosimendan and placebo groups (34.5% vs. 30.9%; 95% CI, −4.5 to 11.7; P = .43), and both groups had a similar number of catecholamine-free days. However, among the patients who required ventilation at baseline, those treated with levosimendan were less likely than those given placebo to be successfully weaned from ventilation over the 28-day follow-up.
Patients treated with levosimendan also had a higher incidence of serious adverse events, and supraventricular tachyarrhythmia was significantly more common in the levosimendan group than in the placebo group (3.1% vs. 0.4%; 95% CI, 0.1- 5.3; P = .04).
The two groups showed similar cardiac index, stroke volume, central venous oxygen saturations or pressure, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and serum creatinine and bilirubin levels.
The authors drew attention to several limitations of the study, including the fact that levosimendan was added to standard care rather than being compared with an alternative inotrope such as dobutamine.
“Less than 10% of the patients in the placebo group received dobutamine, although the rate of use in the placebo group was higher than in the levosimendan group and may explain in part why the cardiac index and stroke volume were not higher in the levosimendan group than in the placebo group,” they wrote.
The study did not include echocardiographic analysis to discover any changes in myocardial function with levosimendan, and there were only a small number of patients with low cardiac index.
“Therefore, this trial cannot provide guidance as to which inotrope is best to use in the management of sepsis if a low cardiac index is present,” the authors said. “The target mean arterial pressure of 65-70 mm Hg, which was recommended in the protocol and reiterated at investigator meetings, was frequently exceeded (as in other trials involving patients with shock), which suggests that the norepinephrine doses that were administered could have been reduced in the two trial groups.”
The study was supported by the Medical Research Council and National Institute for Health Research, United Kingdom, and Tenax Therapeutics. Four authors declared grants, personal fees, advisory board positions, and other funding from the pharmaceutical industry, including one author receiving support from Tenax Therapeutics. No other conflicts of interest were declared.
Levosimendan does not reduce the likelihood of severe organ dysfunction in adults with sepsis, nor does it lower the mortality rate, according to research presented at the annual congress of the European Society of Intensive Care Medicine and published in the New England Journal of Medicine.
Levosimendan is a calcium-sensitizing drug with inotropic and vasodilatory properties, which is commonly used to treat decompensated heart failure. “Small studies that have investigated the use of levosimendan in patients with septic shock have shown improvements in hemodynamic variables, microcirculatory flow, and renal and hepatic function, as compared with dobutamine,” wrote Anthony C. Gordon, MD, of Imperial College London and Imperial College Healthcare NHS Trust and his coauthors.
In the Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial, 516 patients were randomized to 24 hours of a blinded infusion either of levosimendan (.05-0.2 mcg per kilogram of body weight per minute) or placebo in addition to standard care.
Researchers saw no significant difference in the mean daily Sequential Organ Failure Assessment (SOFA) score between the two groups (mean difference, 0.61; 95% confidence interval, −0.07 to 1.29; P = .053). When the SOFA score was analyzed by system, the mean daily cardiovascular score was significantly higher in the levosimendan group, compared with the placebo group, indicating greater dysfunction in that system.
“The cardiovascular SOFA score was higher in the levosimendan group than in the placebo group, which reflects the higher doses of norepinephrine that were required to maintain the mean arterial pressure,” researchers reported.
There was no significant difference in 28-day mortality between the levosimendan and placebo groups (34.5% vs. 30.9%; 95% CI, −4.5 to 11.7; P = .43), and both groups had a similar number of catecholamine-free days. However, among the patients who required ventilation at baseline, those treated with levosimendan were less likely than those given placebo to be successfully weaned from ventilation over the 28-day follow-up.
Patients treated with levosimendan also had a higher incidence of serious adverse events, and supraventricular tachyarrhythmia was significantly more common in the levosimendan group than in the placebo group (3.1% vs. 0.4%; 95% CI, 0.1- 5.3; P = .04).
The two groups showed similar cardiac index, stroke volume, central venous oxygen saturations or pressure, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and serum creatinine and bilirubin levels.
The authors drew attention to several limitations of the study, including the fact that levosimendan was added to standard care rather than being compared with an alternative inotrope such as dobutamine.
“Less than 10% of the patients in the placebo group received dobutamine, although the rate of use in the placebo group was higher than in the levosimendan group and may explain in part why the cardiac index and stroke volume were not higher in the levosimendan group than in the placebo group,” they wrote.
The study did not include echocardiographic analysis to discover any changes in myocardial function with levosimendan, and there were only a small number of patients with low cardiac index.
“Therefore, this trial cannot provide guidance as to which inotrope is best to use in the management of sepsis if a low cardiac index is present,” the authors said. “The target mean arterial pressure of 65-70 mm Hg, which was recommended in the protocol and reiterated at investigator meetings, was frequently exceeded (as in other trials involving patients with shock), which suggests that the norepinephrine doses that were administered could have been reduced in the two trial groups.”
The study was supported by the Medical Research Council and National Institute for Health Research, United Kingdom, and Tenax Therapeutics. Four authors declared grants, personal fees, advisory board positions, and other funding from the pharmaceutical industry, including one author receiving support from Tenax Therapeutics. No other conflicts of interest were declared.
Levosimendan does not reduce the likelihood of severe organ dysfunction in adults with sepsis, nor does it lower the mortality rate, according to research presented at the annual congress of the European Society of Intensive Care Medicine and published in the New England Journal of Medicine.
Levosimendan is a calcium-sensitizing drug with inotropic and vasodilatory properties, which is commonly used to treat decompensated heart failure. “Small studies that have investigated the use of levosimendan in patients with septic shock have shown improvements in hemodynamic variables, microcirculatory flow, and renal and hepatic function, as compared with dobutamine,” wrote Anthony C. Gordon, MD, of Imperial College London and Imperial College Healthcare NHS Trust and his coauthors.
In the Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial, 516 patients were randomized to 24 hours of a blinded infusion either of levosimendan (.05-0.2 mcg per kilogram of body weight per minute) or placebo in addition to standard care.
Researchers saw no significant difference in the mean daily Sequential Organ Failure Assessment (SOFA) score between the two groups (mean difference, 0.61; 95% confidence interval, −0.07 to 1.29; P = .053). When the SOFA score was analyzed by system, the mean daily cardiovascular score was significantly higher in the levosimendan group, compared with the placebo group, indicating greater dysfunction in that system.
“The cardiovascular SOFA score was higher in the levosimendan group than in the placebo group, which reflects the higher doses of norepinephrine that were required to maintain the mean arterial pressure,” researchers reported.
There was no significant difference in 28-day mortality between the levosimendan and placebo groups (34.5% vs. 30.9%; 95% CI, −4.5 to 11.7; P = .43), and both groups had a similar number of catecholamine-free days. However, among the patients who required ventilation at baseline, those treated with levosimendan were less likely than those given placebo to be successfully weaned from ventilation over the 28-day follow-up.
Patients treated with levosimendan also had a higher incidence of serious adverse events, and supraventricular tachyarrhythmia was significantly more common in the levosimendan group than in the placebo group (3.1% vs. 0.4%; 95% CI, 0.1- 5.3; P = .04).
The two groups showed similar cardiac index, stroke volume, central venous oxygen saturations or pressure, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and serum creatinine and bilirubin levels.
The authors drew attention to several limitations of the study, including the fact that levosimendan was added to standard care rather than being compared with an alternative inotrope such as dobutamine.
“Less than 10% of the patients in the placebo group received dobutamine, although the rate of use in the placebo group was higher than in the levosimendan group and may explain in part why the cardiac index and stroke volume were not higher in the levosimendan group than in the placebo group,” they wrote.
The study did not include echocardiographic analysis to discover any changes in myocardial function with levosimendan, and there were only a small number of patients with low cardiac index.
“Therefore, this trial cannot provide guidance as to which inotrope is best to use in the management of sepsis if a low cardiac index is present,” the authors said. “The target mean arterial pressure of 65-70 mm Hg, which was recommended in the protocol and reiterated at investigator meetings, was frequently exceeded (as in other trials involving patients with shock), which suggests that the norepinephrine doses that were administered could have been reduced in the two trial groups.”
The study was supported by the Medical Research Council and National Institute for Health Research, United Kingdom, and Tenax Therapeutics. Four authors declared grants, personal fees, advisory board positions, and other funding from the pharmaceutical industry, including one author receiving support from Tenax Therapeutics. No other conflicts of interest were declared.
Key clinical point: Levosimendan does not reduce the likelihood of severe organ dysfunction or lower the mortality rate in adults with sepsis.
Major finding: There were no significant differences in mean daily Sequential Organ Failure Assessment score or mortality between patients treated with levosimendan or placebo in addition to standard care.
Data source: Randomized, placebo-controlled LeoPARDS trial in 516 adults with sepsis.
Disclosures: The study was supported by the Medical Research Council and National Institute for Health Research, United Kingdom, and Tenax Therapeutics. Four authors declared grants, personal fees, advisory board positions and other funding from the pharmaceutical industry, including one author receiving support from Tenax Therapeutics. No other conflicts of interest were declared.