Installation of pleural effusion decreased preload and markers of global circulation. These changes were effectively restored with both fluid loading and infusion of norepinephrine.
Fluid loading
Moderate amounts of fluid loading (20 mL/kg) restored LVEDA (Fig. 2) and normalised MAP, CO and pulse pressure variation. As systemic blood pressure was quickly restored, this treatment clearly involves a risk of misdiagnosis. Hence, PLE mimics hypovolaemic or distributive shock both in its clinical appearance and the effects of fluid loading. This may hamper diagnosis of PLE or falsely reduce the perceived clinical significance of a known PLE. However, the immediate rise in CVP to supranormal values (Table 2 (2a)) following fluid loading testified to the volume overload induced by fluid loading, potentially subjecting recipients to the harmful effects of compromised organ microcirculation [21, 22].
Norepinephrine infusion
Relatively low infusion rates of norepinephrine restored LVEDA, CO, MAP and LV afterload (Fig. 2), hence nullifying the haemodynamic effects of PLE. In parallel to fluid loading, haemodynamic restoration was easily accomplished with a first-line treatment for hypotension, although still not treating the underlying cause.
First, α1-stimulation contracts peripheral, systemic vasculature, and the resulting increase in LV afterload may to some extend impede LV ejection and subsequently increase LVEDA [23]. Second, stimulation of myocardial β1-receptors enhances contractility and maintains heart rate [24]. Third, the biphasic effect of norepinephrine may be explained by its receptor affinity. First, the splanchnic and hepatic vessel beds act as a reservoir of blood (unstressed volume), and stimulation of α1, α2 and β2-receptors in these vessel beds, and in turn increases the stressed blood volume, venous return and consequently LVEDA [25, 26].
Norepinephrine increased LVEDA from 9.3 ± 1.2 to 10.5 ± 1.3 cm2 from installation of pleural effusion to a norepinephrine dose of 0.1 μg/kg/min despite an approximate 10% increase in HR. LV fractional area change was constant. As CO increased by 39% (1.8 ± 0.3 to 2.5 ± 1.0 L/min) whereas MAP increased by a comparable 30% (57 ± 9 to 74 ± 19 mmHg, see Fig. 2b), systemic vascular resistance must have changed minimally (MAP = CO × systemic vascular resistance). Therefore, the effect on LVEDA was primarily mediated by an increase in venous return. At high doses of norepinephrine (> 0.1 μg/kg/min), LVEDA decreased; we attribute this to myocardial β1-receptor stimulation as LV fractional area change increased concomitantly.
Measures of inferior vena cava
The marked decrease in LV preload and doubling of CVP after installation of PLE were not mirrored in measures of IVC dimensions (Table 1). Extensive fluid loading and an accompanying substantial increase in CVP did not affect the respiratory variation of the IVC, whereas the expiratory diameter of the IVC increased. However, the increase of 2 mm was negligible and close to practical measurement error [27]. Hence, our findings do not support IVC measurements as reliable indices of CVP in the presence of PLE, although these are related [28, 29]. Likewise, the initial increase and subsequent levelling out in CO caused by fluid loading was not reflected in changes in IVC respiratory variations, de-emphasising IVC dynamics as a measure of preload responsiveness when PLE is present [30, 31].
Installation of pleural effusion
This animal model confirmed the haemodynamic effects of PLE including an increase in CVP and concomitant decreases in arterial blood pressure, PaO2 and CO [4, 5, 7, 16] (Table 1). LV fractional area change showed an increasing trend, but this was not a consequence of a higher inotropic state, but instead due to a reduced preload and a decrease in LV transmural pressure as LV end-diastolic pressure increased.
Together with the decreases in MAP and CO, the increases in LV end-diastolic pressure and CVP testify to the pathophysiological effect of pleural effusion. As described in a previous study [6], pleural effusion likely decreased biventricular transmural pressures and, hence, effective filling pressures and ventricular volumes. PaO2 was reduced markedly with pleural effusion, but did not reach sub-normal levels so we find it unlikely that PaO2 levels influenced haemodynamic parameters.
PLE did not lead to changes in pulse pressure variation, though an increase was expected. However, a study with a comparable PLE intervention also detected only slight increases in pulse pressure variation [8]. While not addressing pulse pressure variations’ fluid responsiveness prediction abilities in this study and merely addressing physiology, we speculate that the significant PLE-induced changes in lung mechanics [8] may reduce pressure transmission to the pleural space during ventilation and, as such, may reduce the effective preload changes responsible for pulse pressure variation. Therefore, pulse pressure variation should probably be interpreted with caution when PLE is present. Apart from the effect of PLE, pulse pressure variation behaved as expected by declining in the fluid group and not changing in the two other groups.
Evacuation of pleural effusion
Evacuation of PLE altered most endpoints in the control group significantly or with a convincing trend (Table 2 (2b)). These effects were less obvious in the fluid loading group and in the norepinephrine group as numerical changes were virtually absent.
PaO2 increased markedly in all groups after evacuation regardless of intervention. Altogether, these observations favour early detection and drainage of PLE [3], as fluid load or infusion of norepinephrine have considerable side effects.
Clinical implications
This study confirms the profound effects pleural effusion may elicit on key haemodynamic variables. The decrease in arterial pressure and CO together with a rise in CVP, seen with pleural effusion, is synonymous with cardiac failure or pulmonary embolism to many clinicians and, seen together, emphasises the potential benefits of ultrasonographic visualisation of the heart and lungs.
Nevertheless, both fluid loading and infusion of norepinephrine effectively reserved the haemodynamic changes of pleural effusion. This underscores the value of these treatments as first-line options, but also reveals a risk of misdiagnosis, as physicians may attribute PLE-induced hypotension to hypovolaemia or vasodilatation, when either fluid- or vasopressor therapy prove effective.
Limitations
This study was conducted in an experimental model of young and healthy pigs, precluding direct extrapolation to patients with PLE, who often suffer from significant comorbidities. Additionally, PLE was induced rapidly, whereas patients often accumulate PLE slowly. The haemodynamic implications of the latter have not been described. The protocol comprised persistent and large amounts of fluid and norepinephrine, which might not resemble clinical practise. This was chosen as to evaluate the effect, or the lack of it, during overtreatment.
Also, the amount of pleural fluid installed was substantial when considering the size of the piglets. This amount was chosen from a previous study to ensure a haemodynamic effect of pleural effusion in physiologically intact animals [7]. The relationship between pleural effusion volume and haemodynamic effect in critically ill humans has not been described systematically.