Resuscitation goals for the patient with sepsis and septic shock are to return the patient to a physiologic state that promotes adequate end-organ perfusion along with matching metabolic supply and demand. Ideal resuscitation end points should assess the adequacy of tissue oxygen delivery and oxygen consumption, and be quantifiable and reproducible. Despite years of research, a single resuscitation end point to assess adequacy of resuscitation has yet to be found. Thus, the clinician must rely on multiple end points to assess the patient’s overall response to therapy. This review will discuss the role and limitations of central venous pressure (CVP), mean arterial pressure (MAP), and cardiac output/index as macrocirculatory resuscitation targets along with lactate, central venous oxygen saturation (ScvO 2 ), central venous-arterial CO 2 gradient, urine output, and capillary refill time as microcirculatory resuscitation endpoints in patients with sepsis.
Key points
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Using the CVP as an initial resuscitation end point and estimate of preload adequacy in the patient with sepsis is fraught with error; dynamic indices are preferred.
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Peripheral vasoactive infusions are acceptable in the short-term while assessing response to additional fluid challenges or central venous access is being secured.
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Targeting a supranormal cardiac index to provide higher levels of tissue oxygen delivery has not been shown to improve clinical outcomes.
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A peripheral lactate level of greater than 2 mmol/L is now recommended as a threshold that indicates sepsis-induced organ dysfunction.
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Serial assessment of capillary refill time, with normalization at 6 hours, is independently associated with successful resuscitation when compared with traditional microcirculatory resuscitation targets, such as ScvO 2 , Pcv-aCO 2 gap, and lactate normalization.
Introduction
Sepsis is defined as a syndrome of life-threatening organ dysfunction caused by a dysregulated host response to infection. If unrecognized and left untreated, patients with sepsis can quickly deteriorate, develop multisystem organ failure, and die. Physiologic changes that occur include peripheral vasodilation, myocardial depression, systemic microcapillary injury, coagulopathy, and end-organ malperfusion.
Resuscitation goals for the patient with sepsis and septic shock attempt to return the patient to a physiologic state that promotes adequate organ perfusion along with matching metabolic supply and demand. Ideal resuscitation end points should assess the adequacy of tissue oxygen delivery (DO 2 ), oxygen consumption (V o 2 ), and should be quantifiable and reproducible. Despite years of research, a single resuscitation end point to assess the adequacy of sepsis resuscitation has yet to be found. As a result, the clinician must rely on multiple end points to determine the patient’s overall response to therapy. This article discusses the roles and limitations of currently recommended resuscitation end points, and identifies novel resuscitation targets that may help guide therapeutic interventions in the patient with sepsis and septic shock.
Introduction
Sepsis is defined as a syndrome of life-threatening organ dysfunction caused by a dysregulated host response to infection. If unrecognized and left untreated, patients with sepsis can quickly deteriorate, develop multisystem organ failure, and die. Physiologic changes that occur include peripheral vasodilation, myocardial depression, systemic microcapillary injury, coagulopathy, and end-organ malperfusion.
Resuscitation goals for the patient with sepsis and septic shock attempt to return the patient to a physiologic state that promotes adequate organ perfusion along with matching metabolic supply and demand. Ideal resuscitation end points should assess the adequacy of tissue oxygen delivery (DO 2 ), oxygen consumption (V o 2 ), and should be quantifiable and reproducible. Despite years of research, a single resuscitation end point to assess the adequacy of sepsis resuscitation has yet to be found. As a result, the clinician must rely on multiple end points to determine the patient’s overall response to therapy. This article discusses the roles and limitations of currently recommended resuscitation end points, and identifies novel resuscitation targets that may help guide therapeutic interventions in the patient with sepsis and septic shock.
Current resuscitation targets for sepsis and septic shock
To address the many physiologic derangements that occur in patients with sepsis, and also provide objective resuscitation triggers to guide clinical intervention, several organizations have developed treatment “bundles” that include hemodynamic and physiologic markers used to assess physiologic status of the patient with sepsis. The Surviving Sepsis Campaign has become one of the international leaders of bundled or protocolized sepsis care, and has made a significant impact on the mortality attributed to sepsis and septic shock. The most recent iteration of the Surviving Sepsis Campaign guidelines focuses on several resuscitation targets identified by the original early goal-directed therapy (EGDT) protocol, with an emphasis on macrocirculatory and microcirculatory end points ( Box 1 ).
- 1.
Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined as hypotension persisting after initial fluid challenge or blood lactate concentration ≥4 mmol/L).
- a.
Central venous pressure
- i.
Spontaneously breathing patients: 8 to 12 mm Hg
- ii.
Mechanically ventilated patients: 12 to 15 mm Hg
- i.
- b.
Mean arterial pressure ≥65 mm Hg
- c.
Urine output ≥0.5 mL/kg/h
- d.
Central venous oxygen saturation 70% or mixed venous oxygen saturation ≥65%
- a.
- 2.
In patients with elevated lactate levels targeting resuscitation to normalize lactate as rapidly as possible.
Protocolized sepsis resuscitation is not without controversy. To test the current paradigm of sepsis care, three separate multicenter randomized control trials compared the EGDT protocol with contemporary care and found no difference in clinical outcomes. The results of ProCESS, ARISE, and ProMISe trials have generated a significant debate about the value of a “one size fits all” approach in sepsis resuscitation.
Macrocirculatory resuscitation end points
In the initial phase of sepsis resuscitation, it is important to first target macrocirculatory resuscitation end points. Macrocirculatory targets can usually be measured rapidly at the bedside and address intravascular volume status, mean arterial pressure (MAP), and cardiac output. Early recognition of macrocirculatory derangements often prevents early cardiovascular collapse and is a good initial step in the resuscitation of the patient with sepsis or septic shock.
Intravascular Volume Status
Intravenous fluid administration is a cornerstone of sepsis resuscitation. Rapid fluid administration in the setting of hypovolemia or significant vasoplegia often restores visceral blood flow and tissue DO 2 by improving cardiac output and consequently MAP. An initial, empiric fluid challenge of 500 mL of intravenous crystalloid solution up to a maximum of 30 mL/kg is a reasonable first approach to improve a patient’s hemodynamic status.
Additional crystalloid administration should be driven by objective clinical findings that suggest additional fluid therapy would improve cardiac output and organ perfusion. The utility of intravascular fluid resuscitation is limited by the amount of time resuscitative fluids remain within the intravascular space. Overresuscitation can lead to significant downstream complications, which include significant third spacing and reduced delivery of oxygen to end-organ tissues.
Static measures of volume responsiveness are defined as pressure or volumetric hemodynamic indices that are measured at a single point in time for preload assessment (ie, central venous pressure [CVP], pulmonary artery occlusion pressure). Static measures of preload assessment have largely been replaced with dynamic indices that take advantage of heart-lung interactions to predict volume responsiveness. Stroke volume variation, pulse pressure variation, and inferior vena cava variability all have a better positive predictive value, sensitivity, and specificity than static measures. Direct measurement tests of volume responsiveness include the end-expiratory occlusion test and passive leg raise and may be preferred over dynamic measures, because these tests can be used in patients who are spontaneously breathing, have arrhythmias, and can help avoid unnecessary fluid administration.
Central Venous Pressure
The CVP is a static, barometric measurement that requires a central venous catheter for measurement, and describes the pressure generated by the intravascular blood volume present in the superior vena cava. It is a directly measured estimate of right atrial and right ventricular end-diastolic pressure. Traditionally, the CVP has been used as an estimate of intravascular volume status and a predictor of volume responsiveness. In a healthy, nonintubated patient, the CVP is approximately 2 mm Hg to 4 mm Hg.
Current recommendations suggest that CVP in the patient with sepsis should be increased with intravenous fluids to a goal of 8 mm Hg to 12 mm Hg in spontaneously breathing patients, or 12 mm Hg to 15 mm Hg in mechanically ventilated patients, to ensure adequate preload to optimize cardiac output. Unfortunately, several patient-related and physiologic changes can impact the CVP and make it an unreliable tool for preload optimization. Even traditional teaching, that a low CVP is often a reliable measure of volume responsiveness, has been found to have a positive predictive value of only 47% in patients with sepsis.
Using the CVP as an initial resuscitation target and estimate of preload adequacy is fraught with error, because there are several confounding factors that can impact the CVP outside of intravascular volume status ( Box 2 ). In general, initial fluid resuscitation should be actively guided by dynamic measures of volume responsiveness to improve cardiac output and end-organ perfusion.
- 1.
Central venous blood volume
- a.
Venous return/cardiac output
- b.
Total blood volume
- c.
Regional vascular tone
- a.
- 2.
Thoracic, cardiac, and vascular compliance
- a.
Pulmonary hypertension
- b.
Right ventricular compliance, diastolic dysfunction
- c.
Pericardial disease
- d.
Tamponade
- a.
- 3.
Valvular disease
- a.
Tricuspid stenosis
- b.
Tricuspid regurgitation
- a.
- 4.
Cardiac rhythm
- a.
Junctional rhythm
- b.
Atrial fibrillation
- c.
Nonsinus rhythm
- a.
- 5.
Intrathoracic pressure
- a.
Spontaneous or noncontrolled respiration
- b.
Intermittent positive pressure ventilation
- c.
Positive end-expiratory pressure
- a.
- 6.
Reference level of pressure transducer and patient positioning
Mean Arterial Pressure
One of the hallmark hemodynamic derangements that can lead to organ dysfunction in sepsis is hypotension. Diagnostic criteria for sepsis-related arterial hypotension include a systolic blood pressure of less than 100 mm Hg (recently increased from 90 mm Hg), MAP less than 70 mm Hg, or an systolic blood pressure decrease of more than 40 mm Hg in adults or less than two standard deviations below normal for a given age.
An initial MAP target of 65 mm Hg during the acute phases of sepsis resuscitation is generally recommended, with individualized MAP titration after stabilization. The threshold target of 65 mm Hg is largely based off of a small set of retrospective, prospective, and observational studies that found adequate perfusion measures and a reduction in associated mortality with MAP threshold of 65 mm Hg. Targeting a higher MAP has not been found to reduce organ dysfunction or improve global outcomes, but may improve microvascular perfusion on an individualized basis.
In 2014, the multicenter Sepsis and Mean Arterial Pressure (SEPSISPAM) randomized controlled trial was conducted to look specifically at outcomes related to higher MAP compared with standard goals (target of 80–85 mm Hg vs 65–70 mm Hg) and found no significant difference in 28- or 90-day mortality. A predefined subset of patients with chronic hypertension required less renal-replacement therapy than those in the low-target group. The SEPSISPAM trial reinforced the need for clinicians to recognize the potential benefit of individualized blood pressure titration, especially in patients with chronic disease.
Interventions to achieve a MAP greater than 65 mm Hg in the patient presenting with sepsis or septic shock should begin with an assessment of intravascular volume status to determine the clinical utility of intravascular fluid loading to improve cardiac output and mean blood pressure. Once adequate intravascular volume status has been achieved, early administration of vasopressors should be initiated if the patient remains hypotensive. Norepinephrine is generally the initial vasopressor of choice in septic shock, starting at a dose of 0.05 μg/kg/min.
Rapid initiation of vasopressor therapy in the setting of fluid-refractory shock is a time-critical intervention. Delayed initiation of vasopressor therapy can lead to excessive fluid resuscitation and increased morbidity and mortality. A mortality increase of 5.3% has been estimated to occur for every 1-hour delay in vasopressor initiation during the first 6 hours of septic shock. In patients who are not responding to escalating doses of norepinephrine, early administration of adjunctive therapies should also be considered. The addition of stress-dose hydrocortisone, along with vasopressin-replacement therapy, or an epinephrine infusion is generally recommended as second-line agents.
Traditionally, vasoactive administration required a central venous catheter out of fear of complications related to extravasation and soft tissue necrosis; however, more recent literature suggests that this complication is rare. Delays in vasoactive support are avoided safely by administering vasopressors through a proximal, large-bore peripheral intravenous access line. Peripheral vasoactive infusions are acceptable in the short-term while assessing response to additional fluid challenges or central venous access is being secured.
Cardiac Output and Cardiac Index
The early phase of septic shock is often characterized by a low systemic vascular resistance and a high cardiac output or cardiac index. Most patients with sepsis present with “warm shock,” a term used to describe a hypotensive patient with flushed skin, bounding peripheral pulse, yet a significant mismatch between DO 2 and metabolic demand. The patient with sepsis with “cold shock,” presenting with poor peripheral perfusion and cool extremities, suggesting poor cardiac output, is less common. An abnormally low cardiac output presenting as cold shock is associated with inadequate volume resuscitation, but can occur in the setting of acute sepsis-induced cardiac dysfunction or during the late phases of septic shock.
Sepsis-induced cardiac dysfunction is a well-described phenomenon that leads to a reduction in left ventricular stroke volume and impaired myocardial performance. The incidence of myocardial depression is estimated to occur in up to 60% of patients with septic shock. The exact cause of cardiac dysfunction in sepsis is unclear, but is believed to be a multifactorial cellular insult on myocardial tissues that includes decreased β-adrenergic receptor sensitivity, calcium sensitivity, increased nitric oxide production, mitochondrial dysfunction, and cell death.
Assessing cardiac output in patients with septic shock is performed by several minimally invasive and noninvasive methods, including pulse wave contour analysis devices, such as the LiDCO (LiDCO Ltd, London, UK); PiCCO (Pulsion Maquet, Munich, Germany); FloTrac/Vigileo system (Edwards Lifesciences Corp, Irvine, CA); bioreactance measurement systems, such as the NICOM (Cheetah Medical, Boston, MA); or bedside echocardiography. The routine use of invasive cardiac output monitoring devices, such as the pulmonary artery catheter, has been associated with increased patient risks without significant benefit, and as a result their use has fallen out of favor.
Despite the increased recognition of sepsis-induced cardiac dysfunction, not all patients with a reduced left ventricular ejection fraction require inotropic therapy. Using equipment that is generally available in most acute care settings, a general assessment of cardiac function is acquired with minimal training. Calculating a patient’s cardiac output is performed by obtaining two, simple echocardiographic measurements ( Fig. 1 ). Stroke volume is estimated by calculating the product of the patient’s left ventricular outflow tract (LVOT) velocity-time integral and the patient’s aortic valve area measured with bedside echocardiography. The LVOT velocity-time integral is measured in the apical five-chamber view using the pulsed-wave Doppler function, with the marker placed within the LVOT. The aortic valve area is estimated by measuring the diameter of the patient’s LVOT approximately 1 cm below the aortic valve in the parasternal long axis. Multiplying the patient’s estimated stroke volume by their current heart rate yields the cardiac output. Cardiac index is calculated by dividing the patient’s cardiac output by their body surface area. Note that cardiac dysrhythmias and inaccurate LVOT diameter measurements can significantly impact the accuracy of cardiac output measurement.
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