Diastolic (Dys)Function in Sepsis D.J. Sturgess, T.H. Marwick, and B. Venkatesh

D.J. Sturgess, T.H. Marwick, and B. Venkatesh

Introduction

Sepsis is a clinical syndrome that results from the systemic response of the body to infection [1]. It is a serious clinical problem, accounting for substantial morbidity and mortality. The majority of these patients die of refractory hypotension and of cardiovascular collapse [2].

The hemodynamic consequences of sepsis are complex and wide ranging. These consequences can result from absolute or relative decrease in central blood volume [3], altered left ventricular (LV) [4, 5] and right ventricular (RV) function [6], and severe peripheral vasodilation [7]. The etiology of these cardiovascular abnormali- ties is complex but appears to be mediated by a circulating factor(s) [8].

Research regarding the cardiovascular manifestations of sepsis has tended to focus upon the evaluation of systolic performance. However, diastolic dysfunction is increasingly appreciated as a contributor to morbidity and mortality in other clinical settings [9]. Diastolic dysfunction can impact adversely on ventricular fill- ing. However, the impact of sepsis upon diastolic function is incompletely under- stood.

The principal aim of this chapter is to review current methods of assessing dia- stolic function in the critically ill patient and examine the evidence regarding the impact of severe sepsis and septic shock upon ventricular diastolic function.

Definition of Diastole

The challenge of conceptually dividing diastolic from systolic ventricular function

is highlighted by the number of definitions in the cardiac literature. The tradi-

tional definition of diastole refers to the period of the cardiac cycle from the

end of ventricular ejection until the onset of ventricular tension development dur-

ing the subsequent beat [10]. An alternative defines systole by the myocyte con-

traction-relaxation cycle and diastole refers to the remainder of the cardiac cycle

[11]. However, since the traditional definition is more widely used clinically, it

will be accepted here. Thus, diastole normally consists of isovolumetric relaxa-

tion, early diastolic rapid filling, diastasis (slow filling), atrial contraction (see

Figure 1).

Fig. 1. Diastolic filling of the left ventricle. Left ventricular (LV), left atrial (LA) and aortic (Ao) pressures are represented on the same axes. Under classic definitions the cardiac cycle is divided into systole and four phases of diastole: isovolumetric relaxation (IVR), rapid filling (RF), diastasis or slow filling (SF) and atrial contraction (AC). An alternative approach of dividing the cardiac cycle into contraction, relaxation and fill- ing is also presented, along with a number of determinants of diastolic function which are indicated by arrows. From [21] with permission.

Evaluation of Diastolic Function

No single index reliably differentiates normal from abnormal diastolic function.

Therefore, comprehensive evaluation of diastolic function relies upon measurement of a number of indices (Table 1). Although diastolic function is a complex interplay of numerous components, the most clinically relevant determinants of ventricular filling include ventricular relaxation, stiffness, and filling pressures. These determi- nants may be assessed either at cardiac catheterization or by echocardiography.

Ventricular relaxation is the result of a series of energy-consuming steps that result in a decline in myocardial tension [12]. It consists of the isovolumetric relaxa- tion and early diastolic filling periods [13]. Classically, relaxation has been described by invasive measures such as the maximum rate of pressure decline (-dP/dt) and the time constant of relaxation (tau or S ) [11].

Non-invasive measures, such as those performed during echocardiography, are

more readily performed in the intensive care unit (ICU). These include Doppler

evaluation of mitral valve inflow such as isovolumetric relaxation time (IVRT), peak

E wave velocity, E/A ratio, E/time velocity integral (VTI), and the E-wave decelera-

Table 1. Abbreviations and description of commonly used indices of diastolic function.

Abbreviation Description

-dP/dt Maximum rate of pressure decline during the ventricular relaxation phase.

S or tau Time constant of relaxation. The value of S is calculated as the inverse gradient of the linear relationship between the natural log LV diastolic pressure versus time. Thus, it is the time taken for LV diastolic pressure to fall to approximately two-thirds of its origi- nal value. A higher value of S is consistent with slowing of the relaxation phase.

IVRT Isovolumetric relaxation time.

E E wave velocity. The peak rate of LV filling in early diastole as measured by pulsed wave Doppler of the mitral valve inflow.

E/A E wave to A wave ratio. The ratio of the peak rate of LV filling in early diastole (E) to that during atrial contraction (A).

E/VTI The ratio of peak E wave velocity to E wave velocity time integral (VTI). This variable measures peak filling rate normalized to mitral stroke volume. VTI refers to the area under the curve of Doppler velocity versus time and is a measure of flow during that period.

DT E wave deceleration time.

E’ Peak velocity of the mitral annulus in early diastole as measured by tissue Doppler.

E/E’ The use of E’ to adjust the E velocity for the effects of relaxation, thus yielding an esti- mate of ventricular filling pressure

Vp Propagation velocity of early diastolic flow into the LV as measured using color M-mode echocardiography (color flow propagation).

E/Vp The use of Vp to adjust the E velocity for the effects of relaxation, thus yielding an estimate of ventricular filling pressure

dV/dP Change in cavity pressure for a given change in ventricular volume (stiffness). Indices of ventricular stiffness often incorporate cardiac dimensions as surrogates of ventricular volume.

dP/dV Compliance (the reciprocal of stiffness).

E/LVEDV Normalized peak filling rate. The ratio of E to LV end diastolic volume.

S The systolic (S wave) component of pulmonary vein flow as measured by pulsed wave Doppler. Note that atrial filling from the pulmonary veins normally occurs throughout the cardiac cycle.

D The diastolic (D wave) component of pulmonary vein flow.

durAr The duration of flow reversal into the pulmonary veins during atrial contraction.

tion time. However, these variables tend to be influenced by a number of inter- related properties, including heart rate, filling pressure, ventricular systolic function, and ventricular stiffness [14].

Novel echocardiographic techniques include tissue Doppler imaging (TDI) and

color flow propagation. TDI is an echocardiographic technique that directly mea-

sures myocardial velocities [15]. E’ (pronounced ‘E prime’) correlates with invasively

measured S [16]. Propagation velocity (Vp) has also been shown to correlate with S

[17]. These new techniques are promising, in that they are potentially less preload

dependent than other echocardiographic approaches [9].

Ventricular stiffness, a term used to describe the passive viscoelastic properties of the ventricular chamber, is determined by the material properties of the myocar- dium (myocardial stiffness), the extent of myocardial relaxation, ventricular geome- try (including shape and wall thickness), and extracardiac factors [18]. These extra- cardiac factors include pericardial restraint, ventricular interaction and intrathoracic pressure.

One method of evaluating stiffness uses invasive pressure-volume loops. Exami- nation of the relationship between diastolic pressure and volume allows determina- tion of the change in cavity pressure for a given change in ventricular volume (dV/

dP) [19].

The relationship between passive ventricular volume and pressure is curvilinear, with increasing ventricular stiffness (reduced compliance) at higher ventricular vol- umes [19]. In order to accurately describe the shape and position of the passive pressure-volume curve, it is crucial to obtain data through a wide range of passive diastolic pressures and volumes and to account for transmural (rather than intraven- tricular) pressure [18]. This is impractical at the bedside of critically ill patients.

Certain echocardiographic variables, such as mitral valve inflow and pulmonary venous flow are influenced by ventricular stiffness, but do not directly quantify it.

Ventricular filling pressures are often estimated and used in the management of critically ill patients [20]. Measurements of ventricular filling pressures include ven- tricular end diastolic pressure and atrial pressures. Direct assessment of LV filling pressures requires left heart catheterization, which is infrequently performed in the ICU. Left atrial pressure is more commonly estimated as pulmonary artery occlu- sion pressure (PAOP) from an indwelling pulmonary artery (Swan-Ganz) catheter.

Right sided pressures are often assessed in the ICU with central venous or pulmo- nary artery catheters.

There are a number of echocardiographic variables that offer information regard- ing ventricular filling pressures. The mitral valve inflow velocity profile and pulmo- nary venous flow provide an assessment of ventricular filling pressures. Well-charac- terized patterns of mitral valve inflow have been related to invasive measures of dia- stolic function [21]. Doppler evaluation of pulmonary venous flow appears to com- plement information derived from assessment of mitral valve inflow [9]. Increased left atrial pressures are associated with reversal of flow into the pulmonary veins during atrial contraction. This reversal of flow tends to increase in velocity and duration relative to mitral A wave flow duration with worsening diastolic properties [9]. Another indicator of elevated left atrial pressure is increased left atrial volume [9]. E velocity is dependent upon filling pressure and ventricular relaxation. The use of the E/Vp ratio is one method of adjusting the E velocity for the effects of relaxa- tion, thus yielding an estimate of ventricular filling pressure [9]. Another estimate of LV filling pressure uses E’ to adjust for the effects of relaxation, yielding the E/E’

ratio. E/E’ has been shown to be an estimate of LV filling pressure in a variety of clinical settings including hypertrophic cardiomyopathy [22], sinus tachycardia [23], atrial fibrillation [24], post-cardiac transplant [25], and critical illness [26, 27].

Diastolic (dys)Function in Sepsis

Parker et al. highlighted the clinical significance of diastolic dysfunction in sepsis as

early as 1984, when they demonstrated an association between ventricular stiffness

and outcome in patients with septic shock [28]. It has not been possible to deter-

mine the exact prevalence of abnormal diastolic function in sepsis. This is largely because of differences in study methodology and the lack of consensus regarding the characterization of abnormal diastolic function. Each of these limitations reflects the complexity of evaluating diastolic function. Nonetheless, evidence suggests that sep- tic shock is commonly associated with diastolic dysfunction and that this represents a spectrum that includes isolated diastolic dysfunction, as well as combined diastolic and systolic impairment [29].

Data from animal models

Even under experimental conditions, data regarding diastolic function in sepsis appears inconsistent. For instance, although many animal models of sepsis have demonstrated decreased diastolic compliance [30, 31], others have revealed increased diastolic compliance [32, 33]. The different findings may result from dif- ferences in fluid administration. The impact of fluid resuscitation was highlighted by Zhong et al. who studied endotoxemic guinea pigs [34]. LV diastolic compliance fol- lowing endotoxin administration was decreased in the absence of fluid resuscitation, but increased in animals that received generous crystalloid resuscitation. This effect appeared to be modulated by a mechanism independent of ventricular tissue hydra- tion.

Human volunteers

Endotoxemia in humans has been associated with increased LV compliance. Suffre- dini et al studied the effects of endotoxin in healthy volunteers [35]. Following endo- toxin administration and volume loading, LV ejection fraction (LVEF) decreased, while LV end-diastolic and end-systolic indices increased. Filling pressures before and after fluid loading (including central venous pressure (CVP) and PAOP) were not significantly different between endotoxin and control groups. However, by five hours following intervention, the increase in PAOP was associated with an 18 % increase in LV end-diastolic volume (LVEDV) in the endotoxin group compared to a 0.6 % decrease in the control group.

Critically ill patients

As already mentioned, there is significant overlap between different determinants of diastolic function. This is particularly significant because different methods for eval- uating diastolic function can provide information that is relevant to a number of inter-related processes. However, in order to aid conceptualization, an attempt will be made to discuss the impact of sepsis upon diastolic function in terms of ventricu- lar relaxation, stiffness, and filling pressures.

Human data on diastolic dysfunction primarily based on evaluation of ventricular relaxation

Although there are scant data regarding the impact of sepsis upon ventricular relax- ation, current evidence is consistent with delayed relaxation. Jafri et al. [36]

observed that Doppler parameters of LV filling were abnormal in a cohort of septic

patients with or without shock. Diastolic filling variables and heart rate were similar

in septic patients with or without shock. Compared with controls, septic patients

demonstrated an abnormal pattern of diastolic filling as evidenced by increase in

peak atrial velocity, decreased E/A ratio, increased atrial filling fraction and prolon- gation of atrial filling period as a function of the diastolic filling period. This is con- sistent with delayed relaxation and decreased LV end diastolic compliance.

Poelart et al. [29] studied 31 ventilated patients with persistently vasopressor- dependent ( 8 48 hours) septic shock. Invasive hemodynamics were obtained con- comitantly with transesophageal echocardiography (TEE). Measurements included LV end-systolic and end-diastolic areas, early and late filling parameters and systolic and diastolic filling characteristics of the right upper pulmonary vein. Each Doppler measurement was characterized by maximal flow velocity and VTI. Post-hoc analy- sis of Doppler flow characteristics supported the concept that septic shock can be associated with a continuum of LV pathophysiology, ranging from apparently nor- mal, through isolated diastolic dysfunction, to combined systolic and diastolic dys- function. The small numbers of patients in each of these subsets, potential con- founding variables (such as age, atrial contractile function, and loading conditions) and the post-hoc separation prevented any further conclusions about diastolic func- tion.

Munt et al. [5] studied LV diastolic filling patterns in 24 septic patients. Trans- thoracic pulsed wave Doppler echocardiography was used to measure peak filling rate normalized to mitral stroke volume (E/VTI). E/A ratio and deceleration time were chosen as secondary variables. Although patients with a history of cardiac dis- ease were excluded from the study, the absence of a control group makes it difficult to know whether sepsis induced an abnormality of LV relaxation in non-survivors, or whether there was preexisting diastolic dysfunction in this subgroup. Further- more, no account was made for the potential impact of systolic function upon dia- stolic filling.

Human data on diastolic dysfunction primarily based on evaluation of left ventricular stiffness

A landmark paper by Parker et al. [28] reported combined hemodynamic and radionuclide cineangiographic findings in 20 patients with septic shock. All patients were initially resuscitated with intravenous fluids to a PAOP of 12 – 15 mm Hg, then vasoactive agents were added as required. A control group of 32 critically ill patients who were not shocked and had negative blood cultures demonstrated normal LVEF; however, no ventricular volume data were reported for the controls.

Survivors (n = 13) demonstrated initially high mean LV volumes (LV end-systolic and end-diastolic volume indexes) that recovered to normal values over the next 7 – 10 days. In contrast, non-survivors (n = 7) had normal mean LV volumes that were unaltered with time. The same group of investigators subsequently reported similar results from a study of 54 patients with blood culture positive septic shock [37]. Fourteen of the patients had been included in the previous report [28]. Data regarding LV volumes and pressures in patients with septic shock are presented in Table 2.

A study by Ognibene et al. [38] combined hemodynamic measurements and

radionuclide angiography before and after volume infusion in 56 patients within 24

hours of admission to the ICU. Three groups were defined: control group, sepsis

without shock group, and septic shock group. The pre-volume infusion PAOP was

significantly higher in septic shock patients compared to controls. Similarly, there

was a trend toward higher pre-volume infusion left ventricular end-diastolic volume

index (LVEDVI) in the septic shock group. However, this may have been due to pre-

enrollment aggressive fluid resuscitation in patients with septic shock.

Table 2. Left ventricular end diastolic volume index (LVEDVI) and pulmonary artery occlusion pressure (PAOP) in patients with septic shock. TEE – transesophageal echocardiography; TTE transthoracic echocardi- ography; NS – not studied

Reference Year Investigation Sample Size LVEDVI (mL/m

) PAOP (mmHg) Parker et al [28] 1984 hemodynamic

and radionuclide

13 (survivors) 159 „ 29 13.7 „ 1.6 7 (non-survivors) 81 „ 9 10.6 „ 1.5 Ognibene et al [38] 1988 hemodynamic

and radionuclide

21 109 „ 7.2 9.6 „ 0.5

Schneider et al [39] 1988 hemodynamic and radionuclide

18 95 „ 5.8 10.0 „ 0.9

Parker et al [37] 1989 hemodynamic and radionuclide

33 (survivors) 122 „ 8 11.7 „ 0.8 21 (non-survivors) 99 „ 9 12.8 „ 1.0 Parker et al [40] 1990 hemodynamic

and radionuclide

22 (survivors) 145 13.7

17 (non-survivors) 124 14

Jardin et al [41] 1994 Hemodynamic and TTE

32 66 „ 18 13 „ 3

Jardin et al [42] 1999 TTE 34 (survivors) 75.3 „ 20.1 NS

56 (non-survivors) 64.9 „ 25 NS Vieillard-Baron et al

[43]

2001 TEE 40 61 „ 17 NS

Human data on diastolic dysfunction primarily based on evaluation of right ventricular stiffness

There are conflicting data regarding the impact of sepsis upon RV diastolic function.

It is difficult to determine the relative contributions of fluid management, increased pulmonary vascular resistance (potentially resulting from acute lung injury [ALI]

and acute respiratory distress syndrome [ARDS] associated with sepsis) and septic cardiomyopathy.

In addition to their previous work, Parker et al. [40] have performed serial hemo- dynamic and radionuclide angiographic studies on 39 patients with blood culture positive septic shock. Septic shock was demonstrated as a biventricular phenome- non. This was characterized by depression of both ventricular ejection fractions and simultaneous dilation of both ventricles. Survivors (n = 22) initially demonstrated severe abnormalities, but both ventricles returned toward normal during recovery.

Non-survivors demonstrated less severe abnormalities initially; however, these abnormalities did not significantly improve on subsequent evaluation. Changes in RVEDVI followed the same direction as changes in LVEDVI in the majority (n = 28) of patients. Data regarding RV volumes and pressures in patients with septic shock are presented in Table 3.

Vieillard-Baron et al. [43] documented minor RV dilatation (as defined by

RVEDA-LVEDA ratio) in 13 out of 40 patients with septic shock, whereas RV size

was normal in 27 patients. Another study by Vieillard-Baron et al. [44] recently eval-

uated 83 TEE examinations performed on 30 patients with vasopressor dependent

Table 3. Right ventricular end diastolic volume index (RVEDVI) and central venous pressure (CVP) in patients with septic shock.

Reference Year Investigation Sample Size RVEDVI (mL/m

) CVP (mmHg) Kimchi et al [6] 1984 hemodynamic

and radionuclide

25 98.2 „ 48 11.2 „ 4.6

Schneider et al [39] 1988 hemodynamic and radionuclide

18 114 „ 8.5 8.1 „ 0.08

Parker et al [40] 1990 hemodynamic and radionuclide

22 (survivors) 124 9.5

17 (non-survivors) 120 9.8

septic shock. Amongst their findings, the diastolic size of the RV was judged normal in 70 examinations and moderately dilated in the remaining thirteen. No patient exhibited major dilation at any time.

Human data on diastolic dysfunction primarily based on evaluation of filling pressures Filling pressures are often used as therapeutic goals in the resuscitation of septic patients. Therefore, there are limited clinical data regarding the direct impact of sep- sis upon filling pressures. A well described finding is that patients with sepsis dem- onstrate dissociation between filling pressures and EDV [6, 45].

Prognostic Significance of Diastolic Function

As already noted, Parker et al. [28] described an association between diastolic func- tion and mortality in patients with septic shock. It was proposed that non-survivors did not demonstrate LV dilation and, therefore, were unable to maintain stroke vol- ume and cardiac output [46]. The prognostic significance of diastolic function has also been demonstrated in echocardiographic studies. For instance, Munt et al. [5]

studied associations between mortality and LV diastolic filling patterns in 24 septic patients. All examinations were performed in hemodynamically stable patients within 24 hrs of the diagnosis of sepsis. In a multivariate analysis, only E wave decel- eration time and APACHE (Acute Physiology and Chronic Health Evaluation) II score were independent predictors of mortality.

Our group recently studied mortality in a cohort of 94 critically ill patients (including thirty with sepsis) who had transthoracic echocardiography supple- mented by tissue Doppler assessment of E/E’ [47]. No association was demonstrated between tissue Doppler variables and outcome. However, LV volumes demonstrated significant associations with hospital mortality (LVESV hazard ratio 2.3 [p = 0.039];

LVEDV hazard ratio 2.2 [p = 0.031]. Multivariate analysis demonstrated LVESV and APACHE III as independent predictors of mortality in this cohort.

Controversies and Difficulties in Assessing Diastolic Function

Accurate evaluation of diastolic function in severe sepsis and septic shock is difficult

for a number of reasons. To begin with, sepsis potentialy affects loading conditions

and contractility of the ventricle. In turn, many indices of diastolic function are

affected by these alterations in loading and contractility. Due to the interdependence of many diastolic processes and the influence of systolic function, comprehensive assessment is necessary to prevent incorrect conclusions.

Most available methods for evaluating diastolic function have important limita- tions. This has resulted in a lack of consensus regarding reference standards. For instance, it has been proposed that the combination of hemodynamic and cineangio- graphic data to calculate ventricular volumes may artefactually overestimate ventric- ular volumes [43]. On the other hand, two-dimensional echocardiography can under- estimate ventricular volumes [48]. Also, many of the invasive techniques that have contributed to the understanding of diastolic function in cardiac patients are imprac- tical or inappropriate in the ICU environment. Novel non-invasive techniques, such as tissue Doppler, color flow propagation, and three-dimensional echocardiography promise to contribute to our understanding of diastolic function in patients with severe sepsis and septic shock. Furthermore, it is yet to be determined whether non- invasive estimates of filling pressures (such as E/E’ or E/Vp) will provide useful ther- apeutic or prognostic information in septic patients or whether they can be used in the diagnosis of ARDS (instead of invasive measurements of filling pressures).

Most studies of septic patients are necessarily performed after initiation of hemo- dynamic support, including active fluid management. Valid control groups are diffi- cult to construct, in that it is unlikely that controls have been exposed to comparable therapies or interventions. As a result, it is difficult to differentiate the relative con- tributions of septic processes and resuscitation to observed pathophysiology. Addi- tional difficulties arise in attempting to quantify the impact of illness severity or pre-existing cardiac disease.

Based upon current evidence, it is possible to make a limited number of conclu- sions regarding the impact of sepsis upon diastolic function. First, sepsis potentially affects the diastolic function of both ventricles. Second, the effect of sepsis upon dia- stolic function constitutes a spectrum of pathophysiology ranging from insignificant to severe dysfunction. This heterogeneity contributes to difficulty in defining robust therapeutic targets. The reliability of CVP and PAOP as surrogates of preload has been questioned in this respect.

Comprehensive evaluation of diastolic function is challenging in the setting of critical illness. In this regard, the increasing availability of safe, non-invasive bedside techniques such as echocardiography will facilitate further research. Further research is warranted and it is hoped that the resulting developments will contribute to improved outcomes from severe sepsis and septic shock.

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