Our results show an association between elevated CVP and impairment of microcirculatory blood flow in the early phase of human sepsis. At the same time, MAP and perfusion pressure did not differ significantly between both CVP groups. Moreover, in the short time frame of our analysis, we observed a significant rise in MFI in combination with a reduction in CVP, despite a decrease in MAP and perfusion pressure. These observations are compatible with our hypothesis that the ‘classical’ perfusion pressure, defined as MAP minus CVP, may not reflect the true driving pressure over the microcirculation. In this respect, two factors should be taken into consideration: 1) inflow pressure of the microcirculation may significantly differ from MAP as a result of post-arteriolar pressure drop and 2) the microcirculation may be considered as a low pressure compartment, with hydrostatic pressures slightly above CVP. However, diffusion distance seems to be unaffected, as reflected by the absence of a significant difference in TVD and PVD between CVP groups as well as over time. This may be explained by the fact that upregulation of the number of perfused capillaries, to compensate for a reduction in convective oxygen transport, may occur outside the timeframe of our observations .
Data on the effect of elevated venous pressure on microcirculatory blood flow are limited: SDF imaging of renal blood flow in pigs showed a decrease in renal MFI in intra-abdominal hypertension, which is a model for venous outflow obstruction . In an experimental setting, aiming for a CVP < 10 mmHg by intravenous administration of nitroglycerin in gastric tube reconstruction in pigs resulted in a higher microvascular blood flow as measured by laser Doppler flowmetry in comparison to controls, without being influenced by increases in MAP . The same group reported an increase in microvascular blood flow after topical administration of nitroglycerin in gastric tube reconstruction in humans, being compatible with the hypothesis that venous outflow obstruction results in impairment of microvascular flow . Several studies report impairment of microvascular perfusion in small increases in venous pressure by venous congestion plethysmography in humans [21, 22].
It is conceivable that raising CVP under specific circumstances may be beneficial to tissue perfusion . However, several studies point towards an ambiguous role of CVP in resuscitation of critically ill patients. Not only CVP failed as a useful measure for the assessment of preload and fluid responsiveness , a CVP > 12 mmHg was also associated with a higher mortality in this specific patient group in the early phase of resuscitation . Our data add to the understanding that taking elevated CVP levels as a general endpoint will not automatically result in improved organ perfusion. Therefore, it is conceivable that CVP guided resuscitation as advocated by for instance Surviving Sepsis Campaign (SSC) guidelines might have an undesirable effect on microcirculatory perfusion .
Our study has several limitations. Due to the post hoc design of the study, we were limited in the ability to explore the complex relationship between venous pressure and microcirculatory blood flow. Therefore, it is of utmost importance to stress that our finding is merely hypothesis generating. Imbalances between the two CVP groups in inotrope use, lactate levels and SvO2 may both be explained as confounders, exaggerating the observed differences in microcirculatory perfusion. Extravascular pressures such as intra-abdominal pressure and positive end expiratory pressure (PEEP) settings may also have influenced CVP. PEEP level did not differ significantly between groups, nor did it change over time. In this study, data on intra-abdominal pressure are lacking. However, correction for these potential confounders in multivariate analysis did not eliminate the observed differences in microvascular perfusion between CVP groups. Moreover, the potential confounding factors may also serve as additional markers of impaired organ perfusion, underlining the importance of the observed differences between the groups.
SDF imaging of the sublingual microcirculation was performed, but venous pressure was not measured at this level. It is imaginable that venous pressure in the superior vena cava is not representative for venous pressure at the sublingual site and that this might have influenced the association between venous pressure and the sublingual microcirculation.
We are also aware of the fact that microcirculatory blood flow is determined by other factors than inflow and outflow pressures alone. Not only may there be a further pressure drop within the capillary and venular compartment, it is also of note that microcirculatory flow regulation is not a static process. In reality, vasomotion is the constant opening and closing of capillaries under influence of downstream hypoxic signals . However, in the clinical setting, this complexity of microcirculatory flow is a complete black box. In previous papers, authors have tried to establish a clear relationship between the input signal (i.e. arterial pressure) and the microcirculation and were unable to do so .
Our data were limited to a short time frame in the early course of sepsis resuscitation. Therefore, extrapolation of our findings to a larger time window is difficult. It was decided to limit the evaluation of SDF and CVP data to the measurements obtained at 0 and 30 minutes, because we observed a tendency towards progression of MFI towards 3 in the majority of patients during the 24 hour study period in the original data set . Due to this regression to the mean phenomenon, it was expected that the a priori probability for detecting an association between CVP and microcirculation was highest in the early phase after initial sepsis resuscitation.