Intensive Care Med DOI 10.1007/s00134-014-3598-8
LETTER
Luciano Gattinoni V. Marco Ranieri Antonio Pesenti
Sepsis: needs for defining severity
Accepted: 2 December 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014
Dear Editor, In the current year, The New England Journal of Medicine published five trials [1–5] testing different interventions in patients with severe sepsis. For all trials, the entry criteria were the presence of C2 signs of systemic inflammatory response syndrome associated with an infection and C1 organ failure. One would expect grosso modo a similar outcome being the possible differences caused by the
different interventions. These differences were not significant and limited to a few percentage points. What is striking, however, is the outcome difference between trials performed in Europe versus the ones performed in the Anglo-Saxon areas. As shown in the Table 1 below, the relative outcome difference was up to 200 % across the ocean. The geographical location, indeed, seems, at first sight, of paramount importance in dictating patient survival! However, if one accepts (we hope reasonably!) that the outcome differences are not due to a sharply different quality of care, it follows that the European population must be different from those in the USA and Australia/New Zealand, despite identical enrollment criteria. Actually, these criteria encompass a population with an expected mortality rate ranging from 62 %, as inferred from Simplified Acute Physiology Score II of the French trial (SEPSISPAM [2]), to 23 %, as inferred from Acute Physiology and Chronic Health Evaluation II of the Australian/New
Zealand trial (ARISE [5]). It appears therefore that, for some unknown reason (different bed availability or randomization in intensive care instead of the emergency department?), the European trials picked up a subset of septic patients more severe than in the USA and Australia, as also suggested by the sharply different incidence of mechanical ventilation. If the populations are indeed different, one cannot exclude that a treatment/procedure found useless in a patient subset of lower severity may be effective if applied to a subset of patients with higher severity and vice versa. Targeting, as an example, a central-venous oxygen saturation (SvO2) of 70 % in a population where the baseline SvO2 is 73 % may be different from applying the same target in a population with lower baseline values. The different effect of treatment in populations with different degrees of severity has been shown in patients with acute respiratory distress syndrome (ARDS): a prone position is useless in mild ARDS and effective in a severe case.
Table 1 Clinical trials on severe sepsis/septic shock Study
ALBIOS [1]
SEPSISPAM [2]
TRISS [3]
ProCESS [4]
ARISE [5]
Geographical area
Europe (Italy) 1,810 754/1,781 (42.2 %) 1,446/1,810 (79.8 %) SAPS II &48
Europe (Scandinavia) 998 439/998 (44.0 %)
USA
Patients enrolled (N) Death at 90 days, no./total (%) Mechanical ventilation
Europe (France) 776 334/776 (43.0 %) 594/776 (76.5 %) SAPS II & 56.1–57.2 60–62 %a
Australia/New Zealand (90 %) 1,591 297/1,588 (18.7 %)
Severity score
Expected hospital mortality 41 %
a
695/998 (69.0 %)
1,341 396/1,232 (32.0 %) 188/1,341 (14 %)
SAPS II & 51–52 48–51 %a
APACHE II &20–21 38.1–41.6 %a
243/1,591 (15.2 %) APACHE II &15–16 22.9–25.6 %a
a Expected hospital mortality was computed according to mean or com/IcuMortality/APACHEII.aspx (patient required emergency median baseline severity scores of the trials using online calculators surgery: no reason for ICU admission: sepsis) http://clincalc.com/IcuMortality/SAPSII.aspx and http://clincalc.
The primary lesson from the sepsis References trials is that we urgently need a better classification of sepsis severity to 1. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M et al avoid producing misleading guide(2014) Albumin replacement in patients lines and recommendations. Conflicts of interest LG reports grant support from the Italian Medicines Agency (AIFA, Agenzia Italiana del Farmaco) while conducting the ALBIOS study as well as speaker’s fees from Grifols, Kedrion and Baxter and Advisory Board honoraria from Grifols outside the submitted work. VMR reports consultancies for MAQUET and a grant for the FARON_FPCLI001 clinical study with FP-1201 in acute lung injuries outside the submitted work. AP reports grant support from the Italian Medicines Agency (AIFA, Agenzia Italiana del Farmaco) while conducting the ALBIOS study, grant support from Chiesi Farmaceutici, consultancies for Maquet and Novalung, and fees for mechanical ventilation courses from Draeger outside the submitted work. The authors state that the subject discussed in the submitted manuscript was not dependent on financial support.
2.
3.
4.
5.
with severe sepsis or septic shock. N Engl J Med 370:1412–1421 Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N et al (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370:1583–1593 Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S et al (2014) Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 371:1381–1391 Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F et al (2014) A randomized trial of protocolbased care for early septic shock. N Engl J Med 370:1683–1693 The ARISE Investigators and the ANZICS Clinical Trials Group (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506
L. Gattinoni ()) Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca` Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy e-mail: [email protected] Tel.: ?39-02-55033232 V. M. Ranieri Department of Anesthesia and Intensive Care Medicine, S.Giovanni Battista Molinette Hospital, University of Turin, Turin, Italy A. Pesenti Dipartimento di Scienze della Salute, Universita` degli Studi di Milano Bicocca, Milan, Italy L. Gattinoni Dipartimento di Fisiopatologia MedicoChirurgica e dei Trapianti, Universita` degli Studi di Milano, Via Francesco Sforza 35, 20122 Milan, Italy
LETTER
Luciano Gattinoni V. Marco Ranieri Antonio Pesenti
Sepsis: needs for defining severity
Accepted: 2 December 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014
Dear Editor, In the current year, The New England Journal of Medicine published five trials [1–5] testing different interventions in patients with severe sepsis. For all trials, the entry criteria were the presence of C2 signs of systemic inflammatory response syndrome associated with an infection and C1 organ failure. One would expect grosso modo a similar outcome being the possible differences caused by the
different interventions. These differences were not significant and limited to a few percentage points. What is striking, however, is the outcome difference between trials performed in Europe versus the ones performed in the Anglo-Saxon areas. As shown in the Table 1 below, the relative outcome difference was up to 200 % across the ocean. The geographical location, indeed, seems, at first sight, of paramount importance in dictating patient survival! However, if one accepts (we hope reasonably!) that the outcome differences are not due to a sharply different quality of care, it follows that the European population must be different from those in the USA and Australia/New Zealand, despite identical enrollment criteria. Actually, these criteria encompass a population with an expected mortality rate ranging from 62 %, as inferred from Simplified Acute Physiology Score II of the French trial (SEPSISPAM [2]), to 23 %, as inferred from Acute Physiology and Chronic Health Evaluation II of the Australian/New
Zealand trial (ARISE [5]). It appears therefore that, for some unknown reason (different bed availability or randomization in intensive care instead of the emergency department?), the European trials picked up a subset of septic patients more severe than in the USA and Australia, as also suggested by the sharply different incidence of mechanical ventilation. If the populations are indeed different, one cannot exclude that a treatment/procedure found useless in a patient subset of lower severity may be effective if applied to a subset of patients with higher severity and vice versa. Targeting, as an example, a central-venous oxygen saturation (SvO2) of 70 % in a population where the baseline SvO2 is 73 % may be different from applying the same target in a population with lower baseline values. The different effect of treatment in populations with different degrees of severity has been shown in patients with acute respiratory distress syndrome (ARDS): a prone position is useless in mild ARDS and effective in a severe case.
Table 1 Clinical trials on severe sepsis/septic shock Study
ALBIOS [1]
SEPSISPAM [2]
TRISS [3]
ProCESS [4]
ARISE [5]
Geographical area
Europe (Italy) 1,810 754/1,781 (42.2 %) 1,446/1,810 (79.8 %) SAPS II &48
Europe (Scandinavia) 998 439/998 (44.0 %)
USA
Patients enrolled (N) Death at 90 days, no./total (%) Mechanical ventilation
Europe (France) 776 334/776 (43.0 %) 594/776 (76.5 %) SAPS II & 56.1–57.2 60–62 %a
Australia/New Zealand (90 %) 1,591 297/1,588 (18.7 %)
Severity score
Expected hospital mortality 41 %
a
695/998 (69.0 %)
1,341 396/1,232 (32.0 %) 188/1,341 (14 %)
SAPS II & 51–52 48–51 %a
APACHE II &20–21 38.1–41.6 %a
243/1,591 (15.2 %) APACHE II &15–16 22.9–25.6 %a
a Expected hospital mortality was computed according to mean or com/IcuMortality/APACHEII.aspx (patient required emergency median baseline severity scores of the trials using online calculators surgery: no reason for ICU admission: sepsis) http://clincalc.com/IcuMortality/SAPSII.aspx and http://clincalc.
The primary lesson from the sepsis References trials is that we urgently need a better classification of sepsis severity to 1. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M et al avoid producing misleading guide(2014) Albumin replacement in patients lines and recommendations. Conflicts of interest LG reports grant support from the Italian Medicines Agency (AIFA, Agenzia Italiana del Farmaco) while conducting the ALBIOS study as well as speaker’s fees from Grifols, Kedrion and Baxter and Advisory Board honoraria from Grifols outside the submitted work. VMR reports consultancies for MAQUET and a grant for the FARON_FPCLI001 clinical study with FP-1201 in acute lung injuries outside the submitted work. AP reports grant support from the Italian Medicines Agency (AIFA, Agenzia Italiana del Farmaco) while conducting the ALBIOS study, grant support from Chiesi Farmaceutici, consultancies for Maquet and Novalung, and fees for mechanical ventilation courses from Draeger outside the submitted work. The authors state that the subject discussed in the submitted manuscript was not dependent on financial support.
2.
3.
4.
5.
with severe sepsis or septic shock. N Engl J Med 370:1412–1421 Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N et al (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370:1583–1593 Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S et al (2014) Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 371:1381–1391 Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F et al (2014) A randomized trial of protocolbased care for early septic shock. N Engl J Med 370:1683–1693 The ARISE Investigators and the ANZICS Clinical Trials Group (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506
L. Gattinoni ()) Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca` Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy e-mail: [email protected] Tel.: ?39-02-55033232 V. M. Ranieri Department of Anesthesia and Intensive Care Medicine, S.Giovanni Battista Molinette Hospital, University of Turin, Turin, Italy A. Pesenti Dipartimento di Scienze della Salute, Universita` degli Studi di Milano Bicocca, Milan, Italy L. Gattinoni Dipartimento di Fisiopatologia MedicoChirurgica e dei Trapianti, Universita` degli Studi di Milano, Via Francesco Sforza 35, 20122 Milan, Italy
