Online Letter to the Editors
had highly significantly decreased norepinephrine requirements (3). Furthermore, this beneficial effect was consistent in both the more and the less-severe shock subgroups. The norepinephrine sparing effect of vasopressin was also confirmed in two recent meta-analyses (4, 5). We could not determine and now ask how the meta-analysis of vasopressin trials reported in the guidelines was done and especially how the relative risk of death was calculated (risk ratio [RR], 1.12 [95% CI, 0.96–1.30]; fixed effects) (1). The two previously published meta-analyses of vasopressin/terlipressin in adult septic shock found very similar results to each other (despite using slightly different methodology) with decreased relative risk with the use of vasopressin (RR, 0.87 [95% CI 0.75–1.00], fixed effect (4); and RR, 0.90 [95% CI, 0.77–1.04], random effect) (5). These previous meta-analyses appear to conflict with the results presented in the sepsis guidelines. Without further information about this analysis, it is difficult for the reader to properly interpret the recommendations about the use of vasopressin/terlipressin in septic shock. Dr. Gordon has received grant support from NIHR, patent from University of British Columbia, and has stock options from Sirius Genomics. Dr. Russell has consulted for Ferring Pharmaceuticals and has a patent from the University of British Columbia. Anthony C. Gordon, MD, Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK; James A. Russell, MD, Heart & Lung Institute, Division of Critical Care Medicine, University of British Columbia, Canada
REFERENCES
1. 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 2. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887 3. Gordon AC, Wang N, Walley KR, et al: The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock. Chest 2012; 142:593–605 4. Serpa Neto A, Nassar AP Jr, Cardoso SO, et al: Vasopressin and terlipressin in adult vasodilatory shock: A systematic review and metaanalysis of nine randomized controlled trials. Crit Care 2012; 16:R154 5. Polito A, Parisini E, Ricci Z, et al: Vasopressin for treatment of vasodilatory shock: An ESICM systematic review and meta-analysis. Intensive Care Med 2012; 38:9–19 DOI: 10.1097/CCM.0b013e3182916fd3
that expected desirable effects of adherence to that recommendation would outweigh the undesirable effects. In fact, information from seven randomized controlled trials, including the one multicenter trial (Vasopressin in Septic Shock Trial) (2), and accounting for 963 patients, showed no evidence for any added value of vasopressin infusion in terms of mortality or safety (3). Because some people may find values to the norepinephrine sparring effects of vasopressin in septic shock, the panel decision was to make it an ungraded statement rather than to suggest against the use of vasopressin. Gordon and Russel (1) also questioned the Surviving Sepsis Campaign meta-analysis. In fact, there is no discrepancy with previously published meta-analyses (3, 4). In our meta-analyses for vasopressor therapy in the management of septic shock, we consistently considered norepinephrine as the experimental intervention when compared with dopamine, epinephrine, phenylephrine, and vasopressin (5). This is why the direction of the risk ratio in our meta-analysis went in the opposite way (i.e., above 1) than in the previous meta-analyses (i.e., below 1) (3, 4). The authors have disclosed that they do not have any potential conflicts of interest. Djillali Annane, MD, Department of Intensive Care Medicine, Versailles University and Raymond Poincaré Hospital, Garches, France; Roman Jaeschke, MD, Department of Medicine and Department of Clinical Epidemiology and Biostatistics, McMaster University and St. Joseph's Hospital, Hamilton, Canada; R. Phillip Dellinger, MD, MCCM, Department of Medicine, Cooper Medical School of Rowan University and Chief, Medicine Service at Cooper University Hospital, Camden, NJ
REFERENCES
1. Gordon AC, Russell JA: Vasopressin Guidelines in Surviving Sepsis Campaign: 2012. Crit Care Med 2013; 41:e482–e483 2. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887 3. Polito A, Parisini E, Ricci Z, et al: Vasopressin for treatment of vasodilatory shock: An ESICM systematic review and meta-analysis. Intensive Care Med 2012; 38:9–19 4. Serpa Neto A, Nassar AP Jr, Cardoso SO, et al: Vasopressin and terlipressin in adult vasodilatory shock: A systematic review and metaanalysis of nine randomized controlled trials. Crit Care 2012; 16:R154 5. 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 DOI: 10.1097CCM.0000000000000014
The authors reply:
T
hank you for your comment on the role of vasopressin in the management of septic patients. Gordon and Russel (1) questioned the panel decision to leave ungraded rather than to make a strong recommendation for vasopressin 0.03 U/min to be added to norepinephrine with the aim of increasing blood pressure or decreasing the dose of norepinephrine. According to the Grading of Recommendations Assessment, Development and Evaluation system, a strong recommendation would mean that the panel was very confident
Critical Care Medicine
Vasopressor Dosing in Septic Shock To the Editor:
T
he Surviving Sepsis Campaign Guidelines suggest norepinephrine as the initial vasopressor of choice with addition of epinephrine or possibly vasopressin if a second agent is required (1). Unfortunately, the specific dose at which a second agent should be added to norepinephrine has not yet been identified. Consequently, the addition of a www.ccmjournal.org
e483
Online Letter to the Editors
second vasopressor has occurred over a broad range of doses in the literature. Studies cited in the campaign guidelines are illustrative. DeBacker et al (2) stated a maximum dose of 0.19 μg/kg/min prior to use of open-label norepinephrine. Martin et al (3) had 15 of 16 patients who were treated successfully with norepinephrine monotherapy. Norepinephrine was started at 0.5 μg/kg/min (maximum of 5 μg/kg/min) with patients receiving a mean norepinephrine dose of 1.5 μg/kg/ min. Finally, Patel et al (4) set a maximum dose of norepinephrine at 20 μg/min at which point vasopressin was added. At this relatively low maximum dose, vasopressin was used in 43% of the patients, and a third agent was required in 19% of the patients. The overwhelming success of the guidelines may suggest that identifying a maximum dose of norepinephrine may not be essential. But given the varied dosing strategies used in the literature, it is likely that improvements can be realized. As data continue to emerge regarding selection of vasopressors in the management of septic shock, we urge increased scrutiny of dosing of all vasopressors in order to ensure optimum benefit at minimum risk. The authors have disclosed that they do not have any potential conflicts of interest. Cesar Alaniz, PharmD, Department of Pharmacy, University of Michigan Hospitals and College of Pharmacy, Ann Arbor, MI; Sacha Pollard, PharmD, BCPS, Critical Care, The University of Chicago Medicine, Chicago, IL
REFERENCES
1. 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 2. De 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 3. Martin C, Papazian L, Perrin G, et al: Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103:1826–1831 4. Patel GP, Grahe JS, Sperry M, et al: Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Shock 2010; 33:375–380 DOI: 10.1097/CCM.0b013e3182916fe7
The authors reply:
W
e thank Alaniz and Pollard (1) for raising the important issue of maximal dose of vasopressors in the management of patients with septic shock. In fact, the panel did not address the question of the maximal dose of vasopressor to be used and it was not included in the literature search. We rather addressed the issue of the optimal dose of vasopressor based on the achievement of a mean arterial pressure of 65 mm Hg or more. We suggested to add on or to substitute norepinephrine with epinephrine or vasopressin when norepinephrine fails to maintain mean arterial pressure of 65 mm Hg or more, or is poorly tolerated. The panel considered it unrealistic to define a maximal dose e484
www.ccmjournal.org
of norepinephrine that could be used for all patients. The authors have disclosed that they do not have any potential conflicts of interest. Djillali Annane, MD, Department of Intensive Care Medicine, Raymond Poincaré Hospital, Garches, France; R. Phillip Dellinger, MD, MCCM, CoDivision of Critical Care Medicine, Cooper Medical School of Rowan University, Cooper Health Systems, Camden, NJ
REFERENCES
1. Alaniz C, Pollard S: Vasopressor Dosing in Septic Shock. Crit Care Med 2013; 41:e483–e484 DOI: 10.1097CCM.0000000000000015
Fluid Therapy in Severe Sepsis and Septic Shock To Editor:
I
n patients with sepsis-induced tissue hypoperfusion who are suspected of having hypovolemia, the revised and updated edition of the Surviving Sepsis Campaign recommends an initial fluid challenge to achieve a minimum of 30 mL/kg of crystalloids. The recommendation is that the fluid challenge be administered until there is hemodynamic improvement in dynamic (e.g., changes in pulse pressure and stroke volume variation) or static (e.g., arterial pressure and heart rate) variables (1). In shock patients, IV fluids are administered to increase cardiac output through stroke volume, and if the mechanism is correct, systemic hypoperfusion will improve; if there is no increase, the administration of more fluids would be harmful (2, 3). IV fluids should be administered in patients who have positive responses, such as increased cardiac output, and the fluids should be continued until the perfusion markers are correct or until the patient responds/deteriorates (2). The best way to test for a response is with fluid challenge, which differs from a fluid load or fluid bolus (3). The fluid challenge is a dynamic test of the circulatory system that evaluates changes in cardiac output that are related to changes in preload (or preload surrogate, central venous pressure); these changes are induced by an infusion of IV fluids, a fluid load, or fluid bolus (2–4). The current recommendation for the initial management of septic shock is the use of IV fluids and ideally with a fluid challenge at the beginning of the resuscitation. The fluid challenge can be with a fluid bolus of up to 30 mL/kg. Unfortunately, cardiac output is not always possible to directly measure, so indirect markers, such as pulse pressure variation and Svco2 variation, can be correlated with cardiac output. However, indirect markers should not be used to predict a priori fluid responsiveness. Instead, indirect markers should be used before and after the fluid challenge (4). In patients with septic shock, dynamic changes in mean arterial pressure do not correlate with changes in cardiac output during a fluid challenge, so dynamic changes should not be used to determine the response during a fluid challenge (5). December 2013 • Volume 41 • Number 12
had highly significantly decreased norepinephrine requirements (3). Furthermore, this beneficial effect was consistent in both the more and the less-severe shock subgroups. The norepinephrine sparing effect of vasopressin was also confirmed in two recent meta-analyses (4, 5). We could not determine and now ask how the meta-analysis of vasopressin trials reported in the guidelines was done and especially how the relative risk of death was calculated (risk ratio [RR], 1.12 [95% CI, 0.96–1.30]; fixed effects) (1). The two previously published meta-analyses of vasopressin/terlipressin in adult septic shock found very similar results to each other (despite using slightly different methodology) with decreased relative risk with the use of vasopressin (RR, 0.87 [95% CI 0.75–1.00], fixed effect (4); and RR, 0.90 [95% CI, 0.77–1.04], random effect) (5). These previous meta-analyses appear to conflict with the results presented in the sepsis guidelines. Without further information about this analysis, it is difficult for the reader to properly interpret the recommendations about the use of vasopressin/terlipressin in septic shock. Dr. Gordon has received grant support from NIHR, patent from University of British Columbia, and has stock options from Sirius Genomics. Dr. Russell has consulted for Ferring Pharmaceuticals and has a patent from the University of British Columbia. Anthony C. Gordon, MD, Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK; James A. Russell, MD, Heart & Lung Institute, Division of Critical Care Medicine, University of British Columbia, Canada
REFERENCES
1. 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 2. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887 3. Gordon AC, Wang N, Walley KR, et al: The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock. Chest 2012; 142:593–605 4. Serpa Neto A, Nassar AP Jr, Cardoso SO, et al: Vasopressin and terlipressin in adult vasodilatory shock: A systematic review and metaanalysis of nine randomized controlled trials. Crit Care 2012; 16:R154 5. Polito A, Parisini E, Ricci Z, et al: Vasopressin for treatment of vasodilatory shock: An ESICM systematic review and meta-analysis. Intensive Care Med 2012; 38:9–19 DOI: 10.1097/CCM.0b013e3182916fd3
that expected desirable effects of adherence to that recommendation would outweigh the undesirable effects. In fact, information from seven randomized controlled trials, including the one multicenter trial (Vasopressin in Septic Shock Trial) (2), and accounting for 963 patients, showed no evidence for any added value of vasopressin infusion in terms of mortality or safety (3). Because some people may find values to the norepinephrine sparring effects of vasopressin in septic shock, the panel decision was to make it an ungraded statement rather than to suggest against the use of vasopressin. Gordon and Russel (1) also questioned the Surviving Sepsis Campaign meta-analysis. In fact, there is no discrepancy with previously published meta-analyses (3, 4). In our meta-analyses for vasopressor therapy in the management of septic shock, we consistently considered norepinephrine as the experimental intervention when compared with dopamine, epinephrine, phenylephrine, and vasopressin (5). This is why the direction of the risk ratio in our meta-analysis went in the opposite way (i.e., above 1) than in the previous meta-analyses (i.e., below 1) (3, 4). The authors have disclosed that they do not have any potential conflicts of interest. Djillali Annane, MD, Department of Intensive Care Medicine, Versailles University and Raymond Poincaré Hospital, Garches, France; Roman Jaeschke, MD, Department of Medicine and Department of Clinical Epidemiology and Biostatistics, McMaster University and St. Joseph's Hospital, Hamilton, Canada; R. Phillip Dellinger, MD, MCCM, Department of Medicine, Cooper Medical School of Rowan University and Chief, Medicine Service at Cooper University Hospital, Camden, NJ
REFERENCES
1. Gordon AC, Russell JA: Vasopressin Guidelines in Surviving Sepsis Campaign: 2012. Crit Care Med 2013; 41:e482–e483 2. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887 3. Polito A, Parisini E, Ricci Z, et al: Vasopressin for treatment of vasodilatory shock: An ESICM systematic review and meta-analysis. Intensive Care Med 2012; 38:9–19 4. Serpa Neto A, Nassar AP Jr, Cardoso SO, et al: Vasopressin and terlipressin in adult vasodilatory shock: A systematic review and metaanalysis of nine randomized controlled trials. Crit Care 2012; 16:R154 5. 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 DOI: 10.1097CCM.0000000000000014
The authors reply:
T
hank you for your comment on the role of vasopressin in the management of septic patients. Gordon and Russel (1) questioned the panel decision to leave ungraded rather than to make a strong recommendation for vasopressin 0.03 U/min to be added to norepinephrine with the aim of increasing blood pressure or decreasing the dose of norepinephrine. According to the Grading of Recommendations Assessment, Development and Evaluation system, a strong recommendation would mean that the panel was very confident
Critical Care Medicine
Vasopressor Dosing in Septic Shock To the Editor:
T
he Surviving Sepsis Campaign Guidelines suggest norepinephrine as the initial vasopressor of choice with addition of epinephrine or possibly vasopressin if a second agent is required (1). Unfortunately, the specific dose at which a second agent should be added to norepinephrine has not yet been identified. Consequently, the addition of a www.ccmjournal.org
e483
Online Letter to the Editors
second vasopressor has occurred over a broad range of doses in the literature. Studies cited in the campaign guidelines are illustrative. DeBacker et al (2) stated a maximum dose of 0.19 μg/kg/min prior to use of open-label norepinephrine. Martin et al (3) had 15 of 16 patients who were treated successfully with norepinephrine monotherapy. Norepinephrine was started at 0.5 μg/kg/min (maximum of 5 μg/kg/min) with patients receiving a mean norepinephrine dose of 1.5 μg/kg/ min. Finally, Patel et al (4) set a maximum dose of norepinephrine at 20 μg/min at which point vasopressin was added. At this relatively low maximum dose, vasopressin was used in 43% of the patients, and a third agent was required in 19% of the patients. The overwhelming success of the guidelines may suggest that identifying a maximum dose of norepinephrine may not be essential. But given the varied dosing strategies used in the literature, it is likely that improvements can be realized. As data continue to emerge regarding selection of vasopressors in the management of septic shock, we urge increased scrutiny of dosing of all vasopressors in order to ensure optimum benefit at minimum risk. The authors have disclosed that they do not have any potential conflicts of interest. Cesar Alaniz, PharmD, Department of Pharmacy, University of Michigan Hospitals and College of Pharmacy, Ann Arbor, MI; Sacha Pollard, PharmD, BCPS, Critical Care, The University of Chicago Medicine, Chicago, IL
REFERENCES
1. 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 2. De 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 3. Martin C, Papazian L, Perrin G, et al: Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103:1826–1831 4. Patel GP, Grahe JS, Sperry M, et al: Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Shock 2010; 33:375–380 DOI: 10.1097/CCM.0b013e3182916fe7
The authors reply:
W
e thank Alaniz and Pollard (1) for raising the important issue of maximal dose of vasopressors in the management of patients with septic shock. In fact, the panel did not address the question of the maximal dose of vasopressor to be used and it was not included in the literature search. We rather addressed the issue of the optimal dose of vasopressor based on the achievement of a mean arterial pressure of 65 mm Hg or more. We suggested to add on or to substitute norepinephrine with epinephrine or vasopressin when norepinephrine fails to maintain mean arterial pressure of 65 mm Hg or more, or is poorly tolerated. The panel considered it unrealistic to define a maximal dose e484
www.ccmjournal.org
of norepinephrine that could be used for all patients. The authors have disclosed that they do not have any potential conflicts of interest. Djillali Annane, MD, Department of Intensive Care Medicine, Raymond Poincaré Hospital, Garches, France; R. Phillip Dellinger, MD, MCCM, CoDivision of Critical Care Medicine, Cooper Medical School of Rowan University, Cooper Health Systems, Camden, NJ
REFERENCES
1. Alaniz C, Pollard S: Vasopressor Dosing in Septic Shock. Crit Care Med 2013; 41:e483–e484 DOI: 10.1097CCM.0000000000000015
Fluid Therapy in Severe Sepsis and Septic Shock To Editor:
I
n patients with sepsis-induced tissue hypoperfusion who are suspected of having hypovolemia, the revised and updated edition of the Surviving Sepsis Campaign recommends an initial fluid challenge to achieve a minimum of 30 mL/kg of crystalloids. The recommendation is that the fluid challenge be administered until there is hemodynamic improvement in dynamic (e.g., changes in pulse pressure and stroke volume variation) or static (e.g., arterial pressure and heart rate) variables (1). In shock patients, IV fluids are administered to increase cardiac output through stroke volume, and if the mechanism is correct, systemic hypoperfusion will improve; if there is no increase, the administration of more fluids would be harmful (2, 3). IV fluids should be administered in patients who have positive responses, such as increased cardiac output, and the fluids should be continued until the perfusion markers are correct or until the patient responds/deteriorates (2). The best way to test for a response is with fluid challenge, which differs from a fluid load or fluid bolus (3). The fluid challenge is a dynamic test of the circulatory system that evaluates changes in cardiac output that are related to changes in preload (or preload surrogate, central venous pressure); these changes are induced by an infusion of IV fluids, a fluid load, or fluid bolus (2–4). The current recommendation for the initial management of septic shock is the use of IV fluids and ideally with a fluid challenge at the beginning of the resuscitation. The fluid challenge can be with a fluid bolus of up to 30 mL/kg. Unfortunately, cardiac output is not always possible to directly measure, so indirect markers, such as pulse pressure variation and Svco2 variation, can be correlated with cardiac output. However, indirect markers should not be used to predict a priori fluid responsiveness. Instead, indirect markers should be used before and after the fluid challenge (4). In patients with septic shock, dynamic changes in mean arterial pressure do not correlate with changes in cardiac output during a fluid challenge, so dynamic changes should not be used to determine the response during a fluid challenge (5). December 2013 • Volume 41 • Number 12
