Septic Shock Resuscitation: Assembling the Puzzle* Marc Leone, MD, PhD Service d’anesthésie et de réanimation Hôpital Nord Assistance Publique–Hôpitaux de Marseille Aix Marseille Université Marseille, France
D
uring the last decade, the hemodynamic management of septic shock has been simplified. Indeed, in patients with septic shock, randomized clinical trials show that hydroxyethyl starches cause more harms than benefits (1, 2). Thus, crystalloids are considered the first-choice fluid for volume resuscitation in septic shock (3). The use of albumin 20% was associated with improved survival in a subgroup of patients with severe sepsis and shock (4). Guidelines recommend the addition of albumin in patients who require a large amount of crystalloids (3). Meta-analysis clearly shows that as compared with dopamine, norepinephrine was associated with improved survival (5). A large randomized clinical trial reports reduced side effects in patients treated with norepinephrine (6). Then, guidelines recommend norepinephrine as the first-choice vasopressor (3). Epinephrine keeps a modest place as second-line agent in patients with refractory shock (3). Vasopressin can probably be useful in specific patient populations, but its best positioning remains difficult to determine (3). Positive inotrope is required in few patients with low cardiac output and impaired oxygen delivery. In this indication, dobutamine remains the first-line agent (3). In septic shock, use of adjuvant treatments is disappointing. Hydrocortisone use was associated with contrasting effects (7). The recombinant human–activated protein C failed to improve the outcome (8). Although the immune response modulation remains an attractive pathway, we are forced to note the failure of translating animal models at the bedside. Today, adjuvant agents are not useful in septic shock (3). Most of the pieces for managing septic shock patients are available. We have improved our knowledge about the goals of resuscitation (9). Crystalloids and norepinephrine represent the basic interventions for initial hemodynamic resuscitation. Albumin, dobutamine, and vasopressin may have a role in few selected patients. Guidelines discarded hydroxyethyl starches and recombinant human–activated protein C (3). However,
*See also p. 2158. Key Words: crystalloids; resuscitation; septic shock; vasopressor Dr. Leone consulted for LFB Biomédicaments. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000536
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as there is no link between these pieces, our duty is now to assemble the puzzle. In this issue of Critical Care Medicine, Waechter et al (10) paved the way. They assessed the interactions between fluids and vasoactive agents on mortality in septic shock. Using 81 combinations, they determined the role of volume of fluid (low, moderate, and large), vasoactive agent (binary response), and time (0–1 hr, 1–6 hr, and 6–24 hr). Briefly, lowest mortality was associated with the combination of treatments in which vasoactive agent was started 1–6 hours after hypotension onset, high volumes were administered during the six first hours, and moderate volumes of fluid during the 6- to 24-hour interval. Total fluid volume during the 1- to 6-hour interval was the most influential variable in the analysis. The restriction of fluid during the first hour and the early use of vasoactive agent (< 1 hr) were associated with increased mortality. For the first time, this study focuses on the link between timing, fluid volume, and vasoactive agent onset. The authors should be commended for this investigation. The absolute mortality rate associated with the most and least favorable combinations differed by 46%. This means that the considerable variability observed in the management of septic shock is probably a major determinant of the patient’s outcome. The reader should keep in mind several limitations of this study. Statistics used a sophisticated model of equations that serves to analyze longitudinal and other correlated data. Several concerns have been raised about this method, especially when data are missing (11). Data were collected during an 18-year interval. In average, seven patients were included yearly in each center. Thus, the patients were both highly selected and heterogeneous in time (10). The conclusions cannot be extrapolated to patients with severe shock causing immediate life-threatening conditions. In those patients, infusion of vasopressors is mandatory. Other limitations include the coding strategy, calculation of fluid volume, and mixing several vasoactive agents. Due to its retrospective design, this study only generates hypothesis for future investigations. The findings of this elegant study question our current practices. These data contrast with the concept of fluid restriction in patient with septic shock. This concept is based on the poor outcomes of patients with positive fluid balance (12). The current results suggest that a too restrictive strategy can be deleterious in the early phase of septic shock resuscitation (10). Use of vasoactive agents during the first hour after hypotension was associated with reduced fluid volume but also an increased mortality. This finding is confirmed in a recent retrospective study suggesting that an increased fluid administration in the first 3 hours after septic shock onset was associated with reduced mortality (13). Thus, for the first 6 hours after hypotension, the resuscitation should be based on large fluid intake. Next, a progressive reduction October 2014 • Volume 42 • Number 10
Editorials 3. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637 4. Caironi P, Tognoni G, Masson S, et al; ALBIOS Study Investigators: Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370:1412–1421 5. De Backer D, Aldecoa C, Njimi H, et al: Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis. Crit Care Med 2012; 40:725–730
Figure 1. Key interventions in septic shock: Interactions and timing between fluids, vasoactive drugs, antibiotics, and source control.
of fluid intake should probably result in a negative fluid balance. Monitoring assessment is probably the lacking piece of those studies. Early interventions based on a semi-invasive monitoring improved survival in septic shock (14). However, the effect of monitoring on outcome remains a matter of debate (15). Independently of monitoring, an early and large amount of crystalloids seems the most adequate decision in septic shock (10). Otherwise, the article helps to assess our practices. A decline of mortality was observed during the 18-year interval. In agreement with previous findings (16), this can be related to a myriad of progress including the implementation of guidelines (3). Although no difference was observed in patients treated with crystalloids or colloids, the need for antibiotics during the first hour after hypotension is confirmed. This is probably the key intervention in septic shock. In summary, this study shows that septic shock resuscitation is a process in constant motion, requiring our attention every moment. Timing of interventions is probably the most critical variable to consider in septic shock (Fig. 1). The puzzle assembling just begins, and the game is worth the candle.
REFERENCES
1. Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012; 367: 124–134 2. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367:1901–1911
Critical Care Medicine
6. D e Backer D, Biston P, Devriendt J, et al; SOAP II Investigators: Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779–789
7. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111–124 8. Ranieri VM, Thompson BT, Barie PS, et al; PROWESS-SHOCK Study Group: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:2055–2064 9. Asfar P, Meziani F, Hamel JF, et al; SEPSISPAM Investigators: High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014; 370:1583–1593 10. Waechter J, Kumar A, Lapinsky SE, et al; for the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group: Interaction Between Fluids and Vasoactive Agents on Mortality in Septic Shock: A Multicenter, Observational Study. Crit Care Med 2014; 42:2158–2168 11. DeSouza CM, Legedza AT, Sankoh AJ: An overview of practical approaches for handling missing data in clinical trials. J Biopharm Stat 2009; 19:1055–1073 12. Micek ST, McEvoy C, McKenzie M, et al: Fluid balance and cardiac function in septic shock as predictors of hospital mortality. Crit Care 2013; 17:R246 13. Lee SJ, Ramar K, Park JG, et al: Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: A retrospective cohort study. Chest 2014 May 22 [Epub ahead of print] 14. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–1377 15. ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, et al: A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683–1693 16. Kaukonen KM, Bailey M, Suzuki S, et al: Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 311:1308–1316 www.ccmjournal.org
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D
uring the last decade, the hemodynamic management of septic shock has been simplified. Indeed, in patients with septic shock, randomized clinical trials show that hydroxyethyl starches cause more harms than benefits (1, 2). Thus, crystalloids are considered the first-choice fluid for volume resuscitation in septic shock (3). The use of albumin 20% was associated with improved survival in a subgroup of patients with severe sepsis and shock (4). Guidelines recommend the addition of albumin in patients who require a large amount of crystalloids (3). Meta-analysis clearly shows that as compared with dopamine, norepinephrine was associated with improved survival (5). A large randomized clinical trial reports reduced side effects in patients treated with norepinephrine (6). Then, guidelines recommend norepinephrine as the first-choice vasopressor (3). Epinephrine keeps a modest place as second-line agent in patients with refractory shock (3). Vasopressin can probably be useful in specific patient populations, but its best positioning remains difficult to determine (3). Positive inotrope is required in few patients with low cardiac output and impaired oxygen delivery. In this indication, dobutamine remains the first-line agent (3). In septic shock, use of adjuvant treatments is disappointing. Hydrocortisone use was associated with contrasting effects (7). The recombinant human–activated protein C failed to improve the outcome (8). Although the immune response modulation remains an attractive pathway, we are forced to note the failure of translating animal models at the bedside. Today, adjuvant agents are not useful in septic shock (3). Most of the pieces for managing septic shock patients are available. We have improved our knowledge about the goals of resuscitation (9). Crystalloids and norepinephrine represent the basic interventions for initial hemodynamic resuscitation. Albumin, dobutamine, and vasopressin may have a role in few selected patients. Guidelines discarded hydroxyethyl starches and recombinant human–activated protein C (3). However,
*See also p. 2158. Key Words: crystalloids; resuscitation; septic shock; vasopressor Dr. Leone consulted for LFB Biomédicaments. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000536
2294
www.ccmjournal.org
as there is no link between these pieces, our duty is now to assemble the puzzle. In this issue of Critical Care Medicine, Waechter et al (10) paved the way. They assessed the interactions between fluids and vasoactive agents on mortality in septic shock. Using 81 combinations, they determined the role of volume of fluid (low, moderate, and large), vasoactive agent (binary response), and time (0–1 hr, 1–6 hr, and 6–24 hr). Briefly, lowest mortality was associated with the combination of treatments in which vasoactive agent was started 1–6 hours after hypotension onset, high volumes were administered during the six first hours, and moderate volumes of fluid during the 6- to 24-hour interval. Total fluid volume during the 1- to 6-hour interval was the most influential variable in the analysis. The restriction of fluid during the first hour and the early use of vasoactive agent (< 1 hr) were associated with increased mortality. For the first time, this study focuses on the link between timing, fluid volume, and vasoactive agent onset. The authors should be commended for this investigation. The absolute mortality rate associated with the most and least favorable combinations differed by 46%. This means that the considerable variability observed in the management of septic shock is probably a major determinant of the patient’s outcome. The reader should keep in mind several limitations of this study. Statistics used a sophisticated model of equations that serves to analyze longitudinal and other correlated data. Several concerns have been raised about this method, especially when data are missing (11). Data were collected during an 18-year interval. In average, seven patients were included yearly in each center. Thus, the patients were both highly selected and heterogeneous in time (10). The conclusions cannot be extrapolated to patients with severe shock causing immediate life-threatening conditions. In those patients, infusion of vasopressors is mandatory. Other limitations include the coding strategy, calculation of fluid volume, and mixing several vasoactive agents. Due to its retrospective design, this study only generates hypothesis for future investigations. The findings of this elegant study question our current practices. These data contrast with the concept of fluid restriction in patient with septic shock. This concept is based on the poor outcomes of patients with positive fluid balance (12). The current results suggest that a too restrictive strategy can be deleterious in the early phase of septic shock resuscitation (10). Use of vasoactive agents during the first hour after hypotension was associated with reduced fluid volume but also an increased mortality. This finding is confirmed in a recent retrospective study suggesting that an increased fluid administration in the first 3 hours after septic shock onset was associated with reduced mortality (13). Thus, for the first 6 hours after hypotension, the resuscitation should be based on large fluid intake. Next, a progressive reduction October 2014 • Volume 42 • Number 10
Editorials 3. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637 4. Caironi P, Tognoni G, Masson S, et al; ALBIOS Study Investigators: Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370:1412–1421 5. De Backer D, Aldecoa C, Njimi H, et al: Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis. Crit Care Med 2012; 40:725–730
Figure 1. Key interventions in septic shock: Interactions and timing between fluids, vasoactive drugs, antibiotics, and source control.
of fluid intake should probably result in a negative fluid balance. Monitoring assessment is probably the lacking piece of those studies. Early interventions based on a semi-invasive monitoring improved survival in septic shock (14). However, the effect of monitoring on outcome remains a matter of debate (15). Independently of monitoring, an early and large amount of crystalloids seems the most adequate decision in septic shock (10). Otherwise, the article helps to assess our practices. A decline of mortality was observed during the 18-year interval. In agreement with previous findings (16), this can be related to a myriad of progress including the implementation of guidelines (3). Although no difference was observed in patients treated with crystalloids or colloids, the need for antibiotics during the first hour after hypotension is confirmed. This is probably the key intervention in septic shock. In summary, this study shows that septic shock resuscitation is a process in constant motion, requiring our attention every moment. Timing of interventions is probably the most critical variable to consider in septic shock (Fig. 1). The puzzle assembling just begins, and the game is worth the candle.
REFERENCES
1. Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012; 367: 124–134 2. Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367:1901–1911
Critical Care Medicine
6. D e Backer D, Biston P, Devriendt J, et al; SOAP II Investigators: Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779–789
7. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111–124 8. Ranieri VM, Thompson BT, Barie PS, et al; PROWESS-SHOCK Study Group: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:2055–2064 9. Asfar P, Meziani F, Hamel JF, et al; SEPSISPAM Investigators: High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014; 370:1583–1593 10. Waechter J, Kumar A, Lapinsky SE, et al; for the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group: Interaction Between Fluids and Vasoactive Agents on Mortality in Septic Shock: A Multicenter, Observational Study. Crit Care Med 2014; 42:2158–2168 11. DeSouza CM, Legedza AT, Sankoh AJ: An overview of practical approaches for handling missing data in clinical trials. J Biopharm Stat 2009; 19:1055–1073 12. Micek ST, McEvoy C, McKenzie M, et al: Fluid balance and cardiac function in septic shock as predictors of hospital mortality. Crit Care 2013; 17:R246 13. Lee SJ, Ramar K, Park JG, et al: Increased fluid administration in the first three hours of sepsis resuscitation is associated with reduced mortality: A retrospective cohort study. Chest 2014 May 22 [Epub ahead of print] 14. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–1377 15. ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, et al: A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683–1693 16. Kaukonen KM, Bailey M, Suzuki S, et al: Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 311:1308–1316 www.ccmjournal.org
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