Sublingual microcirculatory changes during high-volume hemofiltration in hyperdynamic septic shock patients

High-volume hemofiltration (HVHF) is a potential rescue therapy in patients with severe septic shock, and some clinical studies suggest that HVHF can decrease vasopressor requirements and improve lactate clearance [1, 2]. Therefore, HVHF may have a place in refractory septic shock by contributing to the stability of systemic hemodynamics and eventually improving systemic perfusion. However, studies supporting HVHF are rather small and non-randomized, and this prevents investigators from drawing a more definitive conclusion about its real impact on clinically relevant outcomes. Indeed, decreases in vasopressor requirements and lactate levels may not necessarily reflect a real improvement in perfusion. In the past, therapies such as steroids and nitric oxide synthase inhibitors have been shown to increase vascular tone without any significant benefit in terms of perfusion or survival [3, 4]. In addition, it is now well accepted that hyperlactatemia may be explained by mechanisms not related to hypoperfusion [5]. Clearly, it would be desirable to assess the impact of HVHF on perfusion determinants (particularly, on microcirculation) more directly.

The development of optical techniques such as orthogonal polarized spectral imaging and, more recently, side dark field videomicroscopy (SDF) has made it possible to visualize microcircirculation at the bedside. Microcirculation is known to be markedly compromised during septic shock and these disturbances are considered to play a central role in multiple organ failure. By means of these novel techniques, the impact of conventional therapies on microcirculation is starting to be unraveled [6‐9].

There is very limited information concerning the potential effects of HVHF on microcirculation during septic shock. Only one previous experimental study has addressed this subject [10], but unfortunately, the model induced only non-severe microcirculatory derangements, making the results difficult to interpret. Beneficial effects of HVHF have been related to non-specific removal of mediators, which could potentially contribute to the reversion of microcirculatory disturbances induced by sepsis. However, the most evident clinical effect of HVHF is an increase in arterial pressure, and this occurs as a result of an increased systemic vascular resistance, and not of an increase in cardiac output, at least in hyperdynamic patients [2]. Therefore, it is critical to determine whether this increase in vascular resistance is associated with a detrimental effect on microcirculatory flow. We performed a prospective observational pilot study to assess changes in sublingual microcirculation during HVHF in patients with severe hyperdynamic septic shock.

Our local ethics committee approved the study, and informed consent was obtained from the patients or their relatives. All septic shock patients in our institution are managed with a norepinephrine-based, perfusion-oriented management algorithm. Septic patients presenting a circulatory dysfunction at the emergency department or the pre-intensive care unit (pre-ICU) are subjected to vigorous fluid resuscitation followed by central venous catheter insertion and basal measurements of lactate (Radiometer ABL 735; Radiometer, Brønshøj, Denmark) and central venous oxygen saturation (ScvO₂). Patients who develop persistent hypotension or hyperlactatemia are transferred promptly to the ICU. The algorithm involves early aggressive source control and fluid loading followed by norepinephrine, which is adjusted to keep a mean arterial pressure (MAP) of at least 65 mm Hg. Fluid resuscitation is guided by pulse pressure variation (if the patient is already on mechanical ventilation) or by central venous pressure. Pulse pressure variation (ΔPP) is calculated as ΔPP = 100 × (PP_max - PP_min)/[(PP_max - PP_min)/2]. If after fluid optimization norepinephrine is greater than 0.3 μg/kg per min, patients are characterized as having severe septic shock. At this stage, all patients must have a pulmonary artery catheter in place and be sedated and connected to mechanical ventilation. Mechanical ventilation and sedation are managed in accordance with current protective strategies [11]. Dobutamine is indicated as an inotrope for patients with low cardiac index (CI) (less than 2.5 L/min per m²) or low ScvO₂ or mixed venous oxygen saturation (SmvO₂) values (less than 60%) not responsive to other measures and with an MAP of greater than 65 mm Hg. HVHF is indicated for patients who fail to respond to all preceding management steps, including source control and fluid optimization guided by ΔPP [2, 12].

Specific inclusion criteria for this study were septic shock according to the 1992 ACCP-SCCM (American College of Chest Physicians/Society of Critical Care Medicine) consensus [13], norepinephrine requirements of at least 0.3 μg/kg per min to maintain an MAP of greater than 65 mm Hg for at least 1 hour before deciding HVHF, progressive hyperlactatemia (greater than 2.4 mmol/L and an increase in lactate levels during 4 hours of full resuscitation), and a CI of at least 3 L/min per m². Patients without full commitment for resuscitation or with active bleeding or an undrained source of surgical sepsis were excluded.

All patients had a pulmonary artery catheter in place and were mechanically ventilated following current guidelines [11], with fentanyl/midazolam sedation targeted to a Sedation-Agitation Scale (SAS) score of less than 3. No patient received steroids, vasopressin, or drotrecogin alpha either before or during the hemofiltration procedure. Blood transfusions were indicated before the procedure if the hemoglobin value was less than 8 g/dL.

Twelve consecutive patients with severe hyperdynamic septic shock (seven men and five women, 57.9 ± 13.2 years old) were recruited between March 2007 and March 2009. Baseline characteristics are presented in Table 1. The more common sources were abdominal in five and pulmonary in two. All patients started HVHF less than 6 hours after meeting the inclusion criteria. One patient had a baseline norepinephrine requirement of 0.28 μg/kg per minute, but he had met the norepinephrine inclusion criteria during the screening period (specifically, a norepinephrine dose of greater than 0.3 μg/kg per minute for more than 1 hour with a ΔPP of less than 10%). Baseline assessment was performed just before the start of HVHF. Only two patients were receiving dobutamine for at least 2 hours before the start of HVHF, and its dose was not changed during the procedure (patients 1 and 6). All patients survived until the end of the study period, but five patients died at day 28 (42%). No technical problems with the procedure were observed and no change of hemofilter was required in any patient.

In the present study, we found no deterioration of sublingual microcirculation during HVHF, despite an increase in systemic vascular resistance in patients with severe hyperdynamic septic shock. Furthermore, microcirculatory flow index significantly improved during HVHF, whereas PPV showed the same trend, which did not reach statistical significance. These effects seem to be more marked in patients with more impaired basal microcirculation.

Several experimental and clinical studies have suggested that HVHF can be an effective rescue therapy in refractory septic shock, stabilizing hemodynamics, decreasing vasopressor requirements, and improving lactate clearance [1, 2, 15]. This is the first study that explores the effects of HVHF on microcirculation in patients with septic shock. We observed an increase in sublingual microcirculatory blood flow during HVHF. Interestingly, this increase occurred despite an increase in SVRI and a trend to decreased cardiac output. One of the theories proposed to explain microcirculatory alterations in sepsis is the presence of shunt. The observation of increasing microcirculatory blood flow paralleled by increasing vascular resistance and decreasing cardiac output may be explained by a reversal of shunt.

The underlying mechanisms involved in the changes observed on hemodynamics and microcirculation are unclear. HVHF may remove some inflammatory mediators involved in the hemodynamic collapse of refractory septic shock from the blood compartment or the extravascular space [16]. Owing to its broad theoretical physiologic effects, HVHF could potentially influence several microcirculatory parameters and improve microcirculatory derangements in septic shock. However, because of the uncontrolled design of our study, we cannot rule out that changes observed on hemodynamics and microcirculation were not related to HVHF. The changes might correspond to the natural evolution of septic shock after initial resuscitation, as shown by Sakr and colleagues [17], or occur as the result of other cointerventions such as ongoing fluids or a strict hemodynamic management.

There has been controversy about the role of systemic hemodynamic variables on microcirculation [18, 19]. Theoretically, arterial pressure could influence microcirculatory flow if autoregulation is altered, or norepinephrine could induce a decrease in microcirculatory flow secondary to vasoconstriction. Trzeciak and colleagues [19] found a positive correlation between MAP and sublingual microcirculatory blood flow in septic shock patients during the early phase of resuscitation. However, two elegant physiologic studies performed in septic shock patients have shown that arterial pressure changes induced by changing norepinephrine doses do not influence sublingual MFI across a large range of arterial pressures and norepinephrine doses [20, 21]. In the present study, MAP increased from 67.5 ± 4.6 mm Hg at baseline to 74.5 ± 6.8 mm Hg at 12 hours of HVHF, but we found no significant correlation between changes in MAP and changes in MFI during the 12-hour HVHF. We also looked for correlations between changes in other systemic hemodynamic variables and changes in sublingual microcirculation during HVHF and found no significant correlation. Therefore, our data do not support the possibility that the increase in MFI observed was induced by changes in systemic hemodynamics.

Previously, an elegant experimental study compared the effects of standard hemofiltration versus HVHF in a porcine model of hyperdynamic sepsis [10]. Although HVHF was associated with an improvement in global hemodynamics, no beneficial effect on microcirculatory flow, hepatosplanchnic hemodynamics, cellular energetics, endothelial injury, or systemic inflammation could be observed. Unfortunately, the model induced only mild to moderate disturbances in hemodynamics and microcirculatory flow and therefore the condition did not represent severe septic shock.

Until now, only a few uncontrolled small studies have evaluated the hemodynamic effects of HVHF in patients with septic shock. Honore and colleagues [1] showed that HVHF responders improved cardiac output and systemic hemodynamics in a series of patients with hypodynamic septic shock. In our previous report involving only patients with hyperdynamic septic shock [2], we found that MAP increased mainly because of an increase in SVRI. However, an improvement in MAP at the expense of an increase in SVRI may not necessarily be beneficial in terms of microcirculatory flow [21], perfusion parameters [22], or survival [4]. The non-selective nitric oxide synthase inhibitor 546C88 induced a strong pressor effect in patients with septic shock, but unfortunately this effect was associated with higher incidences of pulmonary hypertension, systemic arterial hypertension, and heart failure; a decreased cardiac output; and a higher mortality [4]. Therefore, our results may be relevant since they suggest that the potential beneficial hemodynamic effect of HVHF is not at the expense of microcirculatory flow.

It is rather surprising that only 4 of 12 patients exhibiting severe septic shock presented the low MFI of less than 2. This observation is consistent with recent data from Dubin and colleagues [20] and Jhanji and colleagues [21], who found mean basal MFI values of 2.1 ± 0.7 and 2.3 ± 0.4, respectively. In fact, in the former study, only 4 of 22 patients with septic shock exhibited an MFI of less than 2. This is in sharp contrast with the data of Trzeciak and colleagues [19], who reported MFI values of less than 1.5 early after emergency room or ICU admission. It appears that MFI values, resembling what happens with ScvO₂, are very low in pre-resuscitated patients but may improve after aggressive resuscitation, except in refractory patients who are dying.

We found a negative correlation between the severity of basal microcirculatory derangements and their change after a 12-hour HVHF session. Similar observations have been reported by other authors when studying the effect of different interventions on microcirculatory dysfunction in septic patients. Dubin and colleagues [20] assessed the effects of increasing MAP over microcirculatory dysfunction and found that changes in perfused capillary density correlate inversely with basal values. Sakr and colleagues [17] showed that changes in capillary perfusion after red blood cell transfusion correlate negatively with baseline capillary perfusion. At this moment, we have no clear explanation for these findings, but it appears that different interventions aimed at improving microcirculatory flow may be more effective in patients with more severe basal derangements.

The present study has several limitations. First, it includes a small number of patients. In our current septic shock management algorithm, HVHF is a rescue therapy. As reported elsewhere [12], the strict application of our protocol has led to an improvement in outcome, and therefore only 20% of septic shock patients are eligible for this intervention. Since only hyperdynamic septic shock patients with norepinephrine requirements of at least 0.3 μg/kg per minute and progressive hyperlactatemia were included in this study, we recruited only 1 patient every 45 days. This fact precluded the inclusion of a larger number of patients. Second, we did not include a control group. This limitation is shared by several studies addressing the impact of conventional therapies on microcirculation [6‐8, 23]. In our case, this was an observational pilot study and therefore a control group was not considered. However, we acknowledge the advantage of having a control group for future studies. In fact, the only randomized controlled trial involving microcirculatory dysfunction, which compared nitroglycerin versus placebo in patients with septic shock, found that MFI improved over time in both groups in the setting of a strict-background common-resuscitation protocol [9]. Third, our study protocol considered microcirculatory reassessment only after completing the standard 12-hour HVHF procedure, and thus we could have missed earlier effects. We selected a 12-hour design for two reasons: (a) the first couple of hours after starting HVHF are characteristically unstable, and patients are subjected to frequent fluid challenges or vasopressor titration that preclude a clear interpretation of microcirculatory changes; and (b) we were interested in evaluating the full effect of a 12-hour pulse HVHF session. Finally, it is still unclear whether the sublingual microcirculation is representative of other organs [24, 25], so additional studies are necessary to assess the impact of HVHF over other microvascular beds.

The use of HVHF as a rescue therapy in patients with severe hyperdynamic septic shock is not associated with deterioration of sublingual microcirculation, despite the increase in systemic vascular resistance. For the clinician, this suggests that the arterial pressure and SVRI increases that are usually observed during HVHF are not at the expense of microcirculation. Furthermore, patients with the lowest values of sublingual microcirculatory blood flow seem to improve in this respect during HVHF. However, randomized controlled studies with HVHF in septic shock are required to confirm and better define the physiologic effects of HVHF on hemodynamics and perfusion.