Intensive Care Med DOI 10.1007/s00134-015-3913-z
Ahmad Sabry Saleh
Early goal-directed therapy versus ‘‘early’’, ‘‘goal-directed’’ therapy
Accepted: 5 June 2015 Ó Springer-Verlag Berlin Heidelberg and ESICM 2015 A response to these comments can be found at doi:10.1007/s00134-015-3928-5.
Dear Editor, I read with great interest the systematic review and meta-analysis by the ARISE, ProCESS and ProMISe investigators [1] that showed no difference in mortality between early goal-directed therapy (EGDT) and usual care in resuscitating patients with septic shock. I admire their work and this is a great opportunity to speak directly with them. The term early goal-directed therapy refers to the protocolised quantitative resuscitation of patients with septic shock [2]. The EGDT protocol involves early recognition of septic shock, early antibiotic use, early aggressive fluid resuscitation and early initiation of vasopressors in order to early achieve predetermined haemodynamic goals of central venous pressure, mean arterial blood
CO RRESPONDENCE
pressure, urine output and central venous oxygen saturation (ScvO2). The three recent trials (ARISE, ProCESS and ProMISe) and the metaanalysis did not define the details of their comparator—‘‘usual care’’. Actually, in the setting of a clinical trial, usual care is more or less a protocolised care and the treating physicians were subjected to the Hawthorne effect. All patients were identified early in the trial screening. In the usual care group, patients were started on antibiotics early before randomisation, and they received fluids early in the same amount as the EGDT group (mean 4.2 liters), with early vasopressor initiation. Each treating physician must have his/her predetermined haemodynamic goals that led him/her to give the same amount of fluids as the EGDT group. This effect of being in a clinical trial setting is clearly illustrated by the difference in the usual care between the ARISE observational study [3] and the ARISE randomised trial [4] (Table 1). The investigators’ conclusion that EGDT was associated with increased utilization of health care resources was mainly due to the use of continuous monitoring of ScvO2 via an expensive catheter and monitors. However, the current practice in most areas of the world measures ScvO2 intermittently via a blood gas analyser which is supported by the current guidelines [2]. The design of the three trials (ARISE, ProCESS and ProMISe)
could not answer the question of whether targeting ScvO2 of at least 70 % is an effective intervention or not as most of the patients were at target ScvO2 on presentation. To answer that question we need a trial that randomises patients with low ScvO2 to receive a red blood cell transfusion and dobutamine versus placebo. Finally, the recent sepsis trials’ great difference in mortality rate despite utilizing the same inclusion criteria highlights the urgent need for a better classification of sepsis severity [5]. I suggest that the investigators in their upcoming individual patient meta-analysis use an analytic framework to propose homogenous subclasses of sepsis severity that can lead the future management of patients with sepsis as well as the design of future trials. Conflicts of interest None.
References
1. Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, Davies A, Delaney A, Harrison DA, Holdgate A, Howe B, Huang DT, Iwashyna T, Kellum JA, Peake SL, Pike F, Reade MC, Rowan KM, Singer M, Webb SA, Weissfeld LA, Yealy DM, Young JD (2015) A systematic review and metaanalysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. doi: 10.1007/s00134-015-3822-1 2. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Table 1 Difference in the usual care between the ARISE observational study and the Townsend SR, Reinhart K, Kleinpell ARISE randomised trial RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, ARISE ARISE Beale RJ, Vincent JL, Moreno R, The observational [3] randomised [4] Surviving Sepsis Campaign Guidelines Committee including The Pediatric Total fluid till end of the 6 h, ml (mean) 3442 4228 Subgroup (2013) Surviving Sepsis Vasopressor infusion in the first 6 h (%) 32.1 57.8 Campaign: international guidelines for Time to first antimicrobial dose, h (median) 2.2 1.1 management of severe sepsis and septic In-hospital mortality (%) 23.1 15.9 shock, 2012. Intensive Care Med 39(2):165–228
4. Peake SL, Delaney A, Bailey M, 3. Peake SL, Bailey M, Bellomo R, Bellomo R, Cameron PA, Cooper DJ, Cameron PA, Cross A, Delaney A, Finfer Higgins AM, Holdgate A, Howe BD, S, Higgins A, Jones DA, Myburgh JA, Webb SA, Williams P (2014) GoalSyres GA, Webb SA, Williams P (2009) directed resuscitation for patients with Australasian resuscitation of sepsis early septic shock. N Engl J Med evaluation (ARISE): a multi-centre, 371(16):1496–1506 prospective, inception cohort study. Resuscitation 80(7):811–818
5. Gattinoni L, Ranieri VM, Pesenti A (2015) Sepsis: needs for defining severity. Intensive Care Med 41(3):551–552 A. S. Saleh ()) Intensive Care Unit, Aboukir General Hospital, Aboukir, Alexandria 21913, Egypt e-mail: [email protected]
Ahmad Sabry Saleh
Early goal-directed therapy versus ‘‘early’’, ‘‘goal-directed’’ therapy
Accepted: 5 June 2015 Ó Springer-Verlag Berlin Heidelberg and ESICM 2015 A response to these comments can be found at doi:10.1007/s00134-015-3928-5.
Dear Editor, I read with great interest the systematic review and meta-analysis by the ARISE, ProCESS and ProMISe investigators [1] that showed no difference in mortality between early goal-directed therapy (EGDT) and usual care in resuscitating patients with septic shock. I admire their work and this is a great opportunity to speak directly with them. The term early goal-directed therapy refers to the protocolised quantitative resuscitation of patients with septic shock [2]. The EGDT protocol involves early recognition of septic shock, early antibiotic use, early aggressive fluid resuscitation and early initiation of vasopressors in order to early achieve predetermined haemodynamic goals of central venous pressure, mean arterial blood
CO RRESPONDENCE
pressure, urine output and central venous oxygen saturation (ScvO2). The three recent trials (ARISE, ProCESS and ProMISe) and the metaanalysis did not define the details of their comparator—‘‘usual care’’. Actually, in the setting of a clinical trial, usual care is more or less a protocolised care and the treating physicians were subjected to the Hawthorne effect. All patients were identified early in the trial screening. In the usual care group, patients were started on antibiotics early before randomisation, and they received fluids early in the same amount as the EGDT group (mean 4.2 liters), with early vasopressor initiation. Each treating physician must have his/her predetermined haemodynamic goals that led him/her to give the same amount of fluids as the EGDT group. This effect of being in a clinical trial setting is clearly illustrated by the difference in the usual care between the ARISE observational study [3] and the ARISE randomised trial [4] (Table 1). The investigators’ conclusion that EGDT was associated with increased utilization of health care resources was mainly due to the use of continuous monitoring of ScvO2 via an expensive catheter and monitors. However, the current practice in most areas of the world measures ScvO2 intermittently via a blood gas analyser which is supported by the current guidelines [2]. The design of the three trials (ARISE, ProCESS and ProMISe)
could not answer the question of whether targeting ScvO2 of at least 70 % is an effective intervention or not as most of the patients were at target ScvO2 on presentation. To answer that question we need a trial that randomises patients with low ScvO2 to receive a red blood cell transfusion and dobutamine versus placebo. Finally, the recent sepsis trials’ great difference in mortality rate despite utilizing the same inclusion criteria highlights the urgent need for a better classification of sepsis severity [5]. I suggest that the investigators in their upcoming individual patient meta-analysis use an analytic framework to propose homogenous subclasses of sepsis severity that can lead the future management of patients with sepsis as well as the design of future trials. Conflicts of interest None.
References
1. Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, Davies A, Delaney A, Harrison DA, Holdgate A, Howe B, Huang DT, Iwashyna T, Kellum JA, Peake SL, Pike F, Reade MC, Rowan KM, Singer M, Webb SA, Weissfeld LA, Yealy DM, Young JD (2015) A systematic review and metaanalysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. doi: 10.1007/s00134-015-3822-1 2. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Table 1 Difference in the usual care between the ARISE observational study and the Townsend SR, Reinhart K, Kleinpell ARISE randomised trial RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, ARISE ARISE Beale RJ, Vincent JL, Moreno R, The observational [3] randomised [4] Surviving Sepsis Campaign Guidelines Committee including The Pediatric Total fluid till end of the 6 h, ml (mean) 3442 4228 Subgroup (2013) Surviving Sepsis Vasopressor infusion in the first 6 h (%) 32.1 57.8 Campaign: international guidelines for Time to first antimicrobial dose, h (median) 2.2 1.1 management of severe sepsis and septic In-hospital mortality (%) 23.1 15.9 shock, 2012. Intensive Care Med 39(2):165–228
4. Peake SL, Delaney A, Bailey M, 3. Peake SL, Bailey M, Bellomo R, Bellomo R, Cameron PA, Cooper DJ, Cameron PA, Cross A, Delaney A, Finfer Higgins AM, Holdgate A, Howe BD, S, Higgins A, Jones DA, Myburgh JA, Webb SA, Williams P (2014) GoalSyres GA, Webb SA, Williams P (2009) directed resuscitation for patients with Australasian resuscitation of sepsis early septic shock. N Engl J Med evaluation (ARISE): a multi-centre, 371(16):1496–1506 prospective, inception cohort study. Resuscitation 80(7):811–818
5. Gattinoni L, Ranieri VM, Pesenti A (2015) Sepsis: needs for defining severity. Intensive Care Med 41(3):551–552 A. S. Saleh ()) Intensive Care Unit, Aboukir General Hospital, Aboukir, Alexandria 21913, Egypt e-mail: [email protected]
