Does the optimization of cardiac output by fluid loading increase splanchnic blood flow?

S. G. Sakka, K. Reinhart and A. Meier-Hellmann

Department of Anaesthesiology and Intensive Care Medicine, Friedrich-Schiller-University of Jena, Bachstrasse 18, D-07740 Jena, Germany*Corresponding author

Accepted for publication: November 20, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We studied the effects of increasing cardiac output by fluid loading on splanchnic blood flow in patients with haemodynamically stabilized septic shock. Eight patients (five female, 39–86 yr) were assessed using a transpulmonary thermo-dye-dilution technique for the measurement of cardiac index (CI) intrathoracic blood volume (ITBV) as a marker of cardiac preload and total blood volume (TBV). Splanchnic blood flow was measured by the steady state indocyanine-green technique using a hepatic venous catheter. Gastric mucosal blood flow was estimated by regional carbon dioxide tension (PRCO2). Hydroxyethyl starch was infused to increase cardiac output while mean arterial pressure was kept constant. In parallel, mean norepinephrine dosage could be reduced from 0.59 to 0.33 µg kg–1 min–1. Mean (SD) TBV index increased from 2549 (365) to 3125 (447) ml m–2, as did ITBV index from 888 (167) to 1075 (266) ml m–2 and CI from 3.6 (1.0) to 4.6 (1.0) litre min–1 m–2. Despite marked individual differences, splanchnic blood flow did not change significantly neither absolutely (from 1.09 (0.96) to 1.19 (0.91) litre min–1 m–2) nor fractionally as part of CI (from 28.4 (19.5) to 24.9 (16.3)%). Gastric mucosal PRCO2 increased from 7.7 (2.6) to 8.3 (3.1) kPa. The PCO2-gap, the difference between regional and end-tidal PCO2, increased slightly from 3.2 (2.7) to 3.4 (3.1) kPa. Thus, an increase in cardiac output as a result of fluid loading is not necessarily associated with an increase in splanchnic blood flow in patients with stabilized septic shock.

Br J Anaesth 2001; 86: 657–62

Keywords: complications, septic shock; heart, cardiac output; sympathetic nervous system, norepinephrine; heart, splanchnic blood flow; monitoring, indicator dilution technique; carbon dioxide, partial pressure


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Adequate fluid resuscitation is of primary importance in all critically ill patients. During fluid resuscitation of patients with sepsis or septic shock, optimization of global haemodynamics is generally established by a sufficient cardiac preload to gain an optimal cardiac output. Vasopressors should only be used after adequate fluid resuscitation, and then only in the lowest doses necessary.1 Any increase in cardiac preload which is associated with an increase in cardiac output may enable reduction of vasopressor support. However, it has not yet been established whether an optimization of cardiac preload by fluid loading will actually improve regional blood flow, especially in the splanchnic region.

Partitioning of blood flow to various regional vascular beds is still an important issue in sepsis.24 It is now well known that global parameters do not necessarily reflect regional oxygenation and perfusion. Consequently, guidance of fluid resuscitation by indicators of regional blood flow, especially to those areas that are involved in the outcome from sepsis, has been proposed.1 Thus, we designed the present study to investigate whether an increase in cardiac output via fluid loading during a decrease in norepinephrine infusion (maintaining mean arterial pressure constant) could improve splanchnic blood flow and oxygenation in patients with septic shock.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We prospectively studied eight patients (five female, 39–86 yr) with abdominal sepsis and septic shock as defined according to the criteria of the ACCP-SCCM consensus conference.5 Patient characteristics are shown in Table 1. Patients were sedated with fentanyl (0.4–0.6 mg h–1) and droperidol (5.0–7.5 mg h–1). If necessary, midazolam up to 9 mg h–1 was administered. In each patient, doses of sedative remained unchanged during the study period. All patients were mechanically ventilated using a pressure controlled mode (Evita 4®, Draeger Werke, Luebeck, Germany) and positive end-expiratory pressure (PEEP) was adjusted individually according to blood gas monitoring (PaO2 >9 kPa, PaCO2 <6.5 kPa). Airway pressures remained unchanged throughout the study. PEEP was between 5 and 12 (mean 9 (SD 2)) cm H2O and inspiratory peak pressure 18–35 (mean 28 (5)) cm H2O. In this study, dobutamine dosages were kept constant (range 0.0–11.4, mean 3.7, median 3.6 µg kg–1 min–1) and only the vasopressor was reduced to keep mean arterial pressure constant. No other vasopressors were used in this study. In our ICU, we keep mean arterial pressure above 75 mm Hg in septic patients to ensure adequate organ perfusion.


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Table 1 Patient characteristics. NOR (baseline)=norepinephrine dosage at baseline; NOR (2 h)=norepinephrine dosage after fluid loading; SAPS II=Simplified Acute Physiology Score II; SOFA=Sepsis-related Organ Failure Assessment
 
For haemodynamic monitoring in each patient, a 4-French gauge flexible catheter with an integrated thermistor and fibreoptic (Pulsiocath® 4F, PV 2024L, Pulsion Medical Systems, Munich, Germany) was advanced into the infradiaphragmatic aorta via the femoral artery. Transpulmonary thermodilution cardiac output, intrathoracic blood volume (ITBV), extravascular lung water (EVLW), and total blood volume (TBV) were calculated using a computer system (COLD-Z021®, Pulsion Medical Systems, Munich, Germany). In this transpulmonary thermo-dye-dilution technique, two specific indicators are injected simultaneously into the central circulation and detected in the aorta.6 Each bolus injection used cooled (0–6°C) indocyanine-green (ICG) (Pulsion Medical Systems, Munich, Germany) in a concentration of 2 mg ml–1 (15 ml per bolus). As cardiac output is one determinant for the calculation of ITBV and EVLW, cardiac output results from the double-indicator injection were verified by single transpulmonary thermodilution, for example each bolus of cooled ICG was followed by two injections of cooled saline. All bolus injections were manual and not ventilator-triggered.

Arterial and hepatic venous blood gas samples were analysed immediately for measurement of oxygen and carbon dioxide tensions, pH, haematocrit, haemoglobin concentration, haemoglobin oxygen saturation, glucose and lactate concentrations (Radiometer System 625®, Copenhagen, Denmark).

A hepatic venous catheter (7.5 French gauge five-lumen pulmonary artery catheter, Edwards Swan Ganz®, CCO/SvO2, Model 744H 7.5 F, Baxter Healthcare Corporation, Irvine, CA, USA) was inserted from the right internal jugular vein under fluoroscopic control for continuous measurement of oxygen saturation (SvO2) and assessment of splanchnic blood flow. The correct hepatic venous position of the catheter was verified before and after each study by x-ray.

Pressures were measured with patients in the horizontal position and connected to the ventilator. Besides continuous monitoring of arterial and liver venous arterial pressures, haemodynamic monitoring included measurement of central venous pressure, ITBV index (ITBVI), TBV index (TBVI), and transpulmonary thermodilution cardiac index (CI).

Splanchnic blood flow was evaluated by the steady state ICG (Pulsion Medical Systems, Germany) dye technique. Plasma ICG concentrations were measured spectrophotometrically at a wavelength of 805 nm. Hepatic ICG extraction (E) was calculated as described by Uusaro and colleagues.7 Gastric mucosal PRCO2 was measured with a 16-French guage tonometric probe (Trip® NGS catheter, Tonometrics Division, Helsinki, Finland). No patient received enteral nutrition or antacids during the study period. Furthermore, neither H2-inhibitors nor proton pump inhibitors were given during the study. Because of a Boerhaave syndrome in patient 5, PRCO2 was not obtained in this patient. After conversion of arterial oxygen-partial pressure from [kPa] to [mm Hg], systemic oxygen delivery (DO2I) was calculated as DO2I=(haemoglobin concentration xoxygen saturationx1.36+oxygen partial pressurex 0.0031)xCI. Systemic oxygen consumption (VO2I was measured using a metabolic cart (Deltatrac II®, Datex-Engstroem, Helsinki, Finland). In patient 1, no calorimetric data could be obtained because of technical problems.

After an initial ICG bolus of 30 mg, a continuous ICG infusion was started (37.5 mg h–1). After 20, 25, and 30 min of infusion, arterial and hepatic venous blood samples were taken to confirm steady-state ICG concentrations. After 30 min of ICG infusion, baseline haemodynamic measurements were made. Then, fluid resuscitation was started by the infusion of 200 kD hydroxyethylstarch 10% (HAES 10 steril®, Fresenius AG, Bad Homburg, Germany) at a rate of 10 ml kg–1 over 90 min. To maintain haemoglobin concentration above 10 g dl–1, each patient received 1 unit (300 (30) ml) of packed red blood cells during the study period. The norepinephrine dosage was reduced in each patient and was adjusted individually to keep mean arterial pressure constant. The study period was 2 h.

All results are expressed as mean and standard deviation (SD). For inter-individual comparison, values were normalized by body surface area according to DuBois. Changes between time points were compared using the non-parametric Wilcoxon signed rank test. Statistical significance was considered at P<0.05. Associations between measurements are demonstrated using scattergrams and Pearson correlation coefficients (r). For the statistical analysis, we used SigmaStat® for Windows (version 1.0) which was installed on a Compaq® Armada 1590DT computer with a Pentium processor and Microsoft Windows® 95 system.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Mean (SD) Simplified Acute Physiology (SAPS II) Score8 was 48 (9) and Sepsis-related Organ Failure Assessment (SOFA) score9 was 13 (1). Global and regional splanchnic haemodynamic and oxygenation variables are summarized in Tables 2 and 3. On average, 756 (281) ml of hydroxyethylstarch were infused, which led to a significant increase in TBV. Haemoglobin concentration decreased significantly from 11.9 (1.0) to 10.5 (0.9) g dl–1 and haematocrit from 36.8 (3.6) to 32.6 (3.3)%. As we maintained mean arterial pressure constant, mean norepinephrine dosage was reduced during fluid loading (from 0.59 to 0.33 µg kg–1 min–1). Over all eight patients, mean heart rate decreased from 103 (12) to 97 (14) beats min–1. CI increased from 3.6 (1.0) to 4.6 (1.0) litre min–1 m–2 and stroke volume index increased significantly from 58 (12) to 77 (9) ml m–2. ITBVI increased from 888 (167) to 1075 (266) ml m–2 and central venous pressure from 9 (3) to 12 (4) mm Hg. Total blood volume index increased significantly from 2549 (365) to 3125 (447) ml m–2. Absolute splanchnic blood flow did not change significantly (from 1.09 (0.96) to 1.19 (0.91) litre min–1 m–2), nor did fractional splanchnic perfusion as part of CI (from 28.4 (19.5) to 24.9 (16.3%)). Interestingly, the individual data showed that in some patients absolute and fractional splanchnic blood flow even decreased (Figs 1 and 2). Splanchnic blood flow increased most in patients with the greatest increase in CI, r=0.84 (P=0.009) (Fig. 3).


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Table 2 Global haemodynamic and oxygen transport variables (n=8). PaO2=arterial oxygen tension; FIO2=inspiratory oxygen fraction. Values for norepinephrine dosages at baseline and after 2 h are presented as mean (median) and 25th–75th percentiles. Differences are presented as mean (SD) [median] and range. P-values are derived from Wilcoxon signed rank test. *Indicates significance (P < 0.05)
 


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Fig 1 CI and absolute splanchnic blood flow in eight patients undergoing fluid loading associated with an increase in cardiac output during constant mean arterial pressure. QSPL=splanchnic blood flow.

 


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Fig 2 CI and fractional splanchnic blood flow as part of CI in eight patients undergoing fluid loading associated with an increase in cardiac output during constant mean arterial pressure. QSPL=splanchnic blood flow; CI = Cardiac index.

 


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Fig 3 Changes in cardiac index and in splanchnic blood flow in eight patients undergoing fluid loading associated with an increase in cardiac output during constant mean arterial pressure. QSPL=splanchnic blood flow; CI=cardiac index.

 
As we used pressure-controlled ventilation, minute volume significantly decreased from 8.5 (0.9) to 7.9 (1.1) litre min–1 while end-expiratory CO2-tension increased non-significantly from 4.6 (0.7) to 5.0 (0.8) kPa. The difference between regional and end-tidal PCO2 (PCO2-gap) increased slightly from 3.2 (2.7) to 3.4 (3.1) kPa. Steady-state conditions were confirmed by coefficients of variation for ICG concentrations of 4.6 (2.2) and 4.4 (2.4)% for all arterial and hepatic venous samples, respectively.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
These data demonstrate that, in patients with haemodynamically stabilized septic shock, an increase in cardiac output because of fluid loading associated with reduced vasopressor support—a strategy that has been suggested in recently published recommendations in the treatment of sepsis1—does not necessarily lead to an increase in splanchnic blood flow. Moreover, we demonstrated that the response to fluid loading and reduction in vasopressor support is very variable. Indeed splanchnic perfusion was increased with increasing CI in some patients, but in others it was not. More detailed analysis of this non-uniform response showed that splanchnic blood flow increased most in patients with the greatest increase in CI.

Another reason for the heterogeneous effects of fluid loading in our study might also have been that fluid loading did not really increase cardiac preload and consequently cardiac output in all patients. As clearly demonstrated in Figure 1, an increase in cardiac output was observed in every patient. Furthermore, the ratio between ITBV and TBV remained unchanged (35 (4) and 34 (5) %), indicating that fluid loading increased ITBV proportionally. The techniques that we used in this study for the measurement of cardiac preload and cardiac output are well validated. For the measurement of cardiac output we used transpulmonary thermodilution, which has been extensively validated against reference techniques; for example, pulmonary artery thermodilution and Fick principle derived values.1016 Furthermore, the transpulmonary double-indicator dilution technique allows the measurement of the ITBV, which has been found to be an appropriate or even better indicator of cardiac preload in critically ill patients when compared with cardiac filling pressures.1719

As PEEP itself may affect splanchnic blood flow and hepatic function2022 we maintained airway pressures constant. Droperidol may have influenced splanchnic blood flow, but in our study, droperidol doses remained stable.

Of course, in our study we cannot separate the effects of the two different therapeutic interventions, i.e. fluid loading and reduction in norepinephrine, on splanchnic blood flow. On the other hand, the aim of our study was to mimic clinical practice. In the clinical setting, when perfusion pressure increases after fluid loading, norepinephrine support is normally reduced.

The effects on norepinephrine on splanchnic blood flow cannot be assessed in our study. However, the combination of fluid loading with a reduction in vasopressor support did not always increase splanchnic blood flow. Norepinephrine has been shown to increase splanchnic vascular resistance and, thus, decrease splanchnic blood flow in animal and human studies during non-septic conditions.23 24 Thus, one could speculate that decreasing vasopressor support should be associated with an increase in splanchnic blood flow. On the other hand, Bersten and colleagues24 demonstrated that a redistribution of blood flow with norepinephrine infusion, away from the kidneys, liver and pancreas, was not observable in septic animals. Moreover, a beneficial effect of norepinephrine on splanchnic oxygenation, by increasing mean arterial pressure in septic patients, was shown by Marik and colleagues25 who compared norepinephrine and high-dose dopamine as vasopressors. In their study, dopamine increased mean arterial pressure largely by increasing CI whereas norepinephrine increased mean arterial pressure by increasing systemic vascular resistance while maintaining CI. Although oxygen delivery and oxygen consumption increased in both groups of patients, gastric mucosal pH (pHi)—an indicator of microcirculatory perfusion—increased significantly in those patients treated with norepinephrine whereas pHi decreased significantly in those patients receiving dopamine.

Thus, norepinephrine seems to have potential beneficial effects on splanchnic blood flow in patients with sepsis. By maintaining mean arterial pressure constant while reducing norepinephrine in the present study, we controlled for perfusion pressure alone as the cause of these effects. However, some patients showed a decrease in splanchnic blood flow after optimization of CI.

Variation in responses of septic patients to vasoactive substances has been reported previously.26 27 In these studies, the effects of norepinephrine and low-dose dopamine on splanchnic blood flow were found to be unpredictable.

In conclusion, we have shown that an increase in cardiac output as a result of fluid loading while keeping mean arterial pressure constant is not necessarily associated with an increase in regional blood flow. Further studies are necessary to better understand this varying response of splanchnic perfusion.


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Table 3 Regional splanchnic haemodynamic and oxygen transport variables (n=8). Differences are presented as mean (SD) [median] and range. P-values are derived from Wilcoxon signed rank test. *Indicates significance (P < 0.05). PRCO2=gastric mucosal CO2 tension, PE'CO2=end-expiratory CO2 tension
 

    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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