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Looking to the future of physiologically informed sepsis resuscitation: The role of dynamic fluid-responsive measurement
Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.
The triad of sepsis studies
In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.
PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).
PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).
ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).
In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.
Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.
Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).
In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).
The FRESH trial
The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).
FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.
Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).
Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.
Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.
Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.
The triad of sepsis studies
In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.
PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).
PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).
ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).
In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.
Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.
Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).
In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).
The FRESH trial
The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).
FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.
Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).
Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.
Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.
Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.
The triad of sepsis studies
In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.
PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).
PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).
ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).
In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.
Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.
Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).
In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).
The FRESH trial
The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).
FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.
Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).
Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.
Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.