Maintenance of tissue normoxia, reversal of tissue hypoxia and avoidance of tissue dysoxia are essential to prevent oxygen debt, cell injury, organ failure and death. Oxygen extraction and perfusion markers define the presence of illness, quantify severity, provide a clinical road map to guide interventions and provide prognostication. The ability to characterize patients according to a distinct haemodynamic phenotype decreases patient heterogeneity and clarifies patient selection and results of related outcome trials . By controlling for these factors, the signal fidelity of intervention outcome trials may be improved.
THE EARLY HAEMODYNAMIC PATHOGENESIS OF SEVERE SEPSIS AND SEPTIC SHOCK
Animal and human models of early sepsis have repeatedly shown that circulatory insufficiency results in an imbalance between systemic oxygen delivery (DO2) and consumptive demands (VO2). Depending on the severity of insult and comorbidities, there is decrease in DO2 as a result of decreased intravascular volume, loss of vasomotor tone, myocardial depression and increased metabolic demands (i.e. fever and increased work of breathing). As a result, the untreated haemodynamic picture of early sepsis is hypotension, a decrease in central/mixed venous oxygen saturation (ScvO2/SvO2), and decreased central venous pressure (CVP) and cardiac index followed by lactate production [2–4].
Unlike the experimental animal model, in humans, the onset and duration of infection is frequently unknown and thus the temporal progression from sepsis to severe sepsis and septic shock. Upon presentation, patients will present along a continuum of disease whose illness severity may be cryptic or obvious. The characterization of patients from a haemodynamic, oxygen transport and utilization perspective provides a clinical phenotype. This is potentially of diagnostic, therapeutic and prognostic utility to the treating clinician and future research studies.
THE CONCEPT OF EARLY INTERVENTION
In the last two decades, a convergence of the basic principles of early detection, antimicrobial therapy, source control, risk stratification and an early balance between DO2 and VO2 led to a fundamental change in sepsis management called early goal-directed therapy (EGDT) in 2001 . EGDT was a standard operating procedure (SOP) based on components recommended by expert opinion and haemodynamic optimization studies over 50 years prior to its conception and publication. The mortality benefit of EGDT has been robustly replicated for over a decade, leading to the general adoption as basis of early care in septic patients by the Surviving Sepsis Campaign (SCC) [6▪]. This adoption has led to universal decline in sepsis mortality over the last decade and a change in the haemodynamic phenotype.
Seven years after the EGDT publication and dissemination of SCC guidelines, a recent triad of clinical trials that incorporated many aspects of EGDT as usual or control care ‘re-examined’ EGDT [7▪▪–9▪▪]. Although it was an SOP, some investigators considered EGDT a controversial haemodynamic optimization study using a 50-year-old haemodynamic technology and principles called central venous oximetry [10,11]. These trials concluded that an early resuscitation targeting CVP and ScvO2 of 70% did not improve outcomes compared with ‘usual care’ [7▪▪–9▪▪]. Although these trials add an important insight, rendering the understanding of the early pathogenesis to vital signs and physical examination may not advance the scientific understanding of this disease. Before the findings of these trials are translated into practice, the clinician should examine these trials on the basis of the physiology of oxygen transport and utilization. This physiology provides the perfusion parameters that allow objective comparisons and clarity regarding the patient populations. This is important not only for patient management but also for the future interpretation of trials that include haemodynamic optimization .
THE HAEMODYNAMIC PHENOTYPES OF SEVERE SEPSIS AND SEPTIC SHOCK
The clinical and haemodynamic phenotypes are defined by markers of perfusion (lactate and ScvO2) into various stages that have diagnostic, therapeutic and outcome implications (Fig. 1).
Normal lactate and low ScvO2
An early decrease in DO2 is accompanied by a low ScvO2. This occurs prior to Stage A (Fig. 1) and in non-ICU settings. Because this phase can frequently manifest before lactate production, it can go unrecognized because central venous or pulmonary artery catheter placement for measurement of ScvO2/SvO2 usually has not been performed. This haemodynamic picture is usually triggered by a hypotensive episode and more commonly reversed with early fluid therapy or other interventions to increase DO2 and/or decrease VO2. The incidence of patients admitted to the ICU with a normal lactate and low ScvO2 has been reported to be 33–37% [12▪▪]. The corresponding mortality is 15–23%, with the higher mortality associated with unresolved hypotension refractory to fluid therapy . This is the most ‘benign’ haemodynamic phenotype, with minimal interventions necessary if resolved at this stage.
Elevated lactate and low ScvO2 (Early)
Stage A in Fig. 1 is the DO2-dependent phase that frequently begins with normal vital signs, which is referred to as occult or cryptic shock (Fig. 1, Stage A) [3,5,14–16]. A critical decrease in DO2 is followed by an increase in the systemic oxygen extraction ratio (OER) or decreased ScvO2/SvO2 as a compensatory mechanism to maintain VO2[12▪▪,17]. Anaerobic metabolism ensues when the limit of this compensatory mechanism (OER >50%) is reached, leading to lactate production . In this critical DO2-dependent phase, lactate concentrations are inversely related to DO2 and ScvO2/SvO2 (Fig. 1, Stage A) .
This phase is also often present prior to or early upon admission to the ICU. Because of the cryptic nature of the severity of this illness, sudden cardiopulmonary organ failure (i.e. arrhythmias, respiratory failure, overt shock or cardiac arrest) may be seen in up to 20% of patients in this critical phase [4,19–25]. In the absence of lactate screening, many of these patients would otherwise be sent to general practice floors and succumb to these complications or death. The early detection of cryptic shock has been associated with a mortality reduction up to 10% [5,21,26▪▪,27,28▪▪,29▪▪].
Normal lactate and normal ScvO2
Stage B in Fig. 1 indicates adequate resuscitation to a DO2-independent phase (normal lactate and normal ScvO2/SvO2). Patients in this group typically have responded to interventions with an increased cardiac output and a normal OER. This state may be accompanied by a normal blood pressure or a low systemic vascular resistance necessitating low-dose vasopressor administration. An initially low ScvO2 that is corrected within 6 h (based on hypotension or a lactate > 4 mmol/l) carries a corresponding mortality reduction from 27.5 to 15% [12▪▪,29▪▪]. Interventions needed for continued haemodynamic optimization are minimal in this phase.
Elevated lactate and low ScvO2 (Late)
Stage C in Fig. 1 has been defined as pathological supply dependency, wherein even in the presence of an increased DO2, there is continued evidence of global tissue hypoxia (increased lactate and low ScvO2) [14,22,30,31]. These patients may exhibit variable cardiac outputs, vascular resistance and a low ScvO2[14,22,30–32]. The goals are still to improve DO2 (increase oxygen levels, haemoglobin or cardiac output) or decrease VO2.
Progressive hypoxaemia secondary to acute lung injury decreases DO2 and frequently accompanies sepsis. The compensatory increase in work of breathing can consume 20–40% of DO2 (compared with less than 5% in resting state) [33,34]. A persistently low ScvO2 can signal cardiopulmonary decompensation and the need for ventilator support [33–36]. Not only is mechanical ventilation associated with increased mortality, but this intervention also alters the haemodynamic phenotype. The introduction of ventilator support and sedation increases ScvO2 and diminishes the incidence of low ScvO2 upon ICU admission [37,38].
Myocardial dysfunction can be present in up to 15% of patients in septic shock [39–41]. This can be even more pronounced in patients with prior cardiovascular comorbidities. These patients will have an impaired ability to increase DO2 appropriately to meet systemic demands. Although these patients may receive life-saving mechanical ventilation, adverse heart–lung interactions may necessitate more cardiovascular manipulation. The combination of a low ScvO2, increased CVP and increased lactate is indicative of haemodynamically significant myocardial dysfunction . This haemodynamic phenotype is associated with increased mortality if unrecognized [42▪▪,43–48].
If ScvO2/SvO2 remains low for all 6 h of resuscitation, the mortality increases to 40% , and if present upon ICU admission, mortality is 51% [12▪▪]. ScvO2 is predictive of outcome 47 h after the onset of acute lung injury and its normalization is associated with a mortality reduction from 38 to 23% .
Elevated lactate and increased ScvO2
Stage D in Fig. 1 represents the impairment of OER (decreases VO2) secondary to microcirculatory defects or impaired cellular respiration (cytopathic tissue hypoxia). Patients in this stage have an elevated ScvO2 and increased lactate (impaired clearance), which are associated with high mortality [48,49]. The mortality of an elevated lactate and ScvO2 at least 70% initially and after 6 h is 33 and 31%, respectively. If this scenario is present upon ICU admission, the mortality approaches 40% [12▪▪]. When hypotension requiring vasopressors becomes an accompanying feature, the mortality of this stage increases from 46.1 to 60.3% [26▪▪,29▪▪,50]. Treatment of this phenotype remains difficult and is the subject of intense research.
Hypotension is an important element of cardiovascular insufficiency and generally potentiates the mortality of all the described phenotypes [13,29▪▪,51–53]. Cardiovascular insufficiency is the most lethal organ dysfunction within the first 24 h of onset in septic shock . However, although hypotension is considered an essential feature of shock, its impact on outcome can be variable [28▪▪,53,55–57]. Septic or vasoplegic shock is defined as a patient who is vasopressor dependent after presumed adequate fluid resuscitation. However, vasopressor dependency is a function of fluid responsiveness and the amount of volume given. There is variability in this definition when it is based on a 1 l versus 20–30 ml/kg fluid bolus.
Thus, the introduction of vasopressor therapy creates a vasoplegic phenotype, which may be a function of volume and clinician judgement. This also provides a confounding variable for the use of corticosteroids, which are recommended for this phase of septic shock. Patients who are hypotensive with near normal lactate levels have generally higher ScvO2, fewer organ failures and lower mortalities than patients who are hypotensive with elevated lactates [28▪▪,53,55–57]. There is outcome variability in patients who are vasopressor dependent to septic shock.
USING HAEMODYNAMIC PHENOTYPES TO INTERPRET RECENT SEPSIS INTERVENTION STUDIES
Comparing related clinical trials by haemodynamic phenotype can provide objective comparisons of enrolment characteristics, therapies received and the interpretation of reported outcomes. For example, sepsis studies heavily comprising patients with an increased lactate, low ScvO2, hypotension, mechanical ventilation and cardiopulmonary comorbidities represent some of the most lethal subgroups [12▪▪]. These patients require more interventions to optimize DO2 (i.e. oxygen, fluid, blood, inotropic therapy or mechanical ventilation). Although it is associated with high mortality, this phenotype can be reversed when treated early [12▪▪,48].
In a recent trial [58▪▪], patients were randomized to a haemoglobin of 7 or 9 g/dl. At enrollment, patients had near normal lactate and ScvO2 (tissue normoxia) (Table 1). Using the haemodynamic principles of perfusion to interpret this trial, we can conclude that, the physiologic need to augment DO2 with red blood cells was minimal, which is consistent with the study's conclusion of no outcome benefit [60,61▪].
Recent trials examining EGDT conclude no benefit of augmenting early resuscitation with ScvO2[7▪▪–9▪▪]. The conclusion recommending lactate clearance as a substitute for ScvO2 by Jones et al. was also derived from studies of similar haemodynamic phenotypes. The haemodynamic phenotypes of patients enrolled in these trials differ from those in the original trial of EGDT (Table 1). The results and conclusions of these trials apply to a different stage and illness severity based on haemodynamic phenotype (Table 1).
Irrespective of the haemodynamic phenotype, mortality is dependent upon the care provided . The use of other parameters such as lactate clearance, direct measurement of VO2 and microcirculatory indices may further improve upon the individual discrimination of the haemodynamic phenotype.
The haemodynamic phenotypes of severe sepsis and septic shock are a multidimensional interaction of oxygen extraction (ScvO2), perfusion (lactate) and blood pressure, which distinctly reflect mortality. This phenotypic characterization provides objective information to compare resuscitation studies and interpret the conclusions. This individual haemodynamic characterization decreases heterogeneity and improves the fidelity of enrolment characteristics. This may improve the clarity of results and conclusions in clinical outcome trials in severe sepsis and septic shock.
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Conflicts of interest
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- ▪ of special interest
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