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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In 36 hemodynamically stable septic patients, we explored whether changes in gastric mucosal-arterial PCO2 gradient (PCO2gap) induced by a short-term dobutamine infusion may reveal hepatosplanchnic hypoperfusion. Hepatosplanchnic blood flow (HSBF) was determined by the continuous indocyanine green infusion technique and gastric mucosal PCO2 (PgCO2) by saline tonometry. In each patient, hemodynamic measurements, blood samples, and PgCO2 determinations were performed three times: first at baseline (DOB 0), second during a dobutamine infusion at a dose of 5 µg/kg/min (DOB 5), and third at a dose of 10 µg/kg/min (DOB 10). The results were analyzed by Wilcoxon's matched-pairs signed rank test and are presented as medians with ranges. The PCO2gap decreased preferentially in groups of patients with inadequate hepatosplanchnic perfusion, i.e., with a low fractional HSBF (HSBF/CI), defined as the ratio of the HSBF to the simultaneous cardiac index, or a high gradient between the mixed venous blood and the suprahepatic blood O2 saturations (DSvhO2). In the 11 patients with a DSvhO2 above 20% at baseline, PCO2gap decreased from 12.1 (6.3 to 19.5) mm Hg at DOB 0 to 6.2 (2.5 to 19.3) mm Hg at DOB 5 (p < 0.001 versus DOB 0), and to 4.2 (0.1 to 35.9) mm Hg at DOB 10 (p < 0.05 versus DOB 5), whereas in the 25 patients with a DSvhO2 below 20% at baseline, PCO2gap did not change significantly. At no time was the PCO2gap correlated with HSBF/CI or DSvhO2. We conclude that although the PCO2gap does not correlate well with global indexes of gut oxygenation, such a simple dobutamine infusion test could identify patients with inadequate hepatosplanchnic perfusion.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During sepsis, regional hypoperfusion may be present in the hepatosplanchnic region (1, 2) even when global hemodynamic and oxygen-derived variables appear adequate (3). Because gut hypoperfusion has been incriminated in the development of multiple organ failure in these patients (6, 7), it may be important to dispose of a clinical surrogate marker of splanchnic hypoperfusion. Venous suprahepatic catheterization allows estimation of hepatosplanchnic blood flow (HSBF) by the continuous indocyanine green (ICG) infusion technique (8) and monitoring of suprahepatic venous blood O2 saturation (9), which may better reflect the balance between hepatosplanchnic O2 supply and demand. However, this technique is highly invasive and can be used only for limited periods of time.
On the other hand, gastric tonometry (10, 11) has been proposed as a much less invasive but very sensitive method to assess the adequacy of gut perfusion. Many studies have shown that gastric intramucosal pH (pHi) or gastric intramucosal carbon dioxide tension (PCO2) are reliable prognostic indicators in critically ill patients (4, 5, 12, 13). A multicentric study by Gutierrez and colleagues (14) suggested that pHi-guided therapy may improve outcome in patients with a normal pHi on admission.
Tonometry-derived parameters, including pHi or mucosal-arterial PCO2 difference, are generally considered as an index of gut perfusion (11, 15), although a number of factors can influence them. In particular, factors other than changes in mucosal blood flow such as mucosal intracellular acidosis directly caused by cellular alterations may influence gastric tonometry measurements (16). There are also a number of methodologic limitations that may limit their interpretation.
The present study postulated that mucosal-arterial PCO2
difference can represent a surrogate marker to assess hepatosplanchnic O2 supply, provided that several measurements
are obtained during an acute increase in HSBF. Various catecholamines could be used for this purpose, but we thought
dobutamine would represent the best candidate. Despite its
dopaminergic effects resulting in an increase in hepatosplanchnic blood flow, dopamine usually does not change, or
decrease, pHi (17). Even dopexamine, with predominant dopaminergic and 
2-adrenergic activity, does not consistently improve splanchnic oxygenation (21) or pHi (24). Epinephrine usually decreases splanchnic perfusion (27), and
norepinephrine yields conflicting results (19). Among the various adrenergic agents available today, dobutamine has been
found to most consistently decrease mucosal-arterial PCO2 difference and increase gastric mucosal blood flow (3, 18, 28).
We therefore analyzed, in patients with severe sepsis, the effects of a short-term dobutamine infusion on the mucosal-arterial PCO2 difference and the HSBF to determine if the adequacy of gut perfusion can be easily assessed by gastric tonometry in these patients.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Population
After approval by the Ethics Committee of Erasme University Hospital and after informed consent obtained from the patient's nearest relative, 36 patients (28 male and 8 female; 58 ± 16 yr of age) with severe sepsis or septic shock were included in the study. Severe sepsis was defined by the presence of fever or hypothermia (rectal temperature > 38° C or < 36° C), leukocytosis or leukopenia (white blood cell count > 12,000/mm3 or < 4,000/mm3), associated with signs of hypofusion (lactic acidosis, oliguria, or acute alteration of mental status) or sepsis-induced hypotension (systolic arterial pressure < 90 mm Hg or a fall of more than 40 mm Hg from the baseline) in the presence of a clinically and bacteriologically documented infection. Septic shock was defined as severe sepsis with sepsis-induced hypotension, persisting despite adequate fluid resuscitation and requiring the administration of vasopressor agents. Patients with liver cirrhosis, hepatocellular deficiency secondary to (sub)fulminant hepatitis or liver metastases were not considered. Each patient was hemodynamically stable during the study, and vasoactive drugs and fluid infusion rates were not modified for at least 2 h before the start of the study. Seventeen patients were treated with dopamine at a median rate of 6.6 µg/kg/min (range, 2 to 20 µg/kg/min). Each patient was mechanically ventilated, sedated with midazolam and morphine, and paralyzed with pancuronium. Each patient was invasively monitored with a pulmonary artery catheter (Swan-Ganz catheter 7F; Baxter Healthcare, Irvine, CA) and an arterial catheter. Each patient had been treated with an H2-receptor blocker, ranitidine, and had received no enteral feeding for at least 6 h.
Study Maneuver and Measurements
In each patient, a nasogastric tonometry catheter (TRIP, NGS catheter; Tonometrics, Helsinki, Finland) was inserted and its correct position controlled radiographically. After insertion of a venous introducer (cc-350B-8.5F; Baxter Healthcare) in the right jugular vein, a multipurpose catheter (5F; Cook, Bjaerskov, Denmark) was inserted into the right suprahepatic vein under fluoroscopic guidance.
Systemic and regional hemodynamic measurements, blood samples, and gastric mucosal PCO2 determinations were performed at baseline (DOB 0), during a dobutamine infusion at a dose of 5 µg/kg/ min for 30 min (DOB 5), and at a dose of 10 µg/kg/min during the next 30 min (DOB 10).
Thermodilution cardiac output was measured (COM 2; Baxter Healthcare) by successive injections of boluses of 10 ml cold (< 8° C) 5% dextrose in water, via a closed system (CO-set system; Baxter Healthcare). Each bolus injection was initiated at end-inspiration. To obtain each cardiac output value, at least three values within 5% of each other were averaged. Cardiac index (CI) was calculated by dividing the cardiac output by the patient's body surface area.
HSBF was determined by the ICG continuous infusion technique as described by Uusaro and colleagues (8). An intravenous bolus of 12 mg of ICG (Pulsion, Munich, Germany) was followed by a continuous infusion of 1 mg/min for 30 min (corresponding to the 30-min equilibration time for the gastric saline tonometry, see below). After 20, 25, and 30 min of ICG infusion, 3 ml arterial and hepatic venous blood samples were taken simultaneously to determine the plasma ICG levels by spectrophotometry (Uvikon 930; Kontron, Bâle, Switzerland), using a standard curve obtained by dilution of a known quantity of ICG in a control serum. According to Uusaro and colleagues, the measurement of the HSBF by this technique has a variation coefficient of 7 ± 1% (8). According to the Fick principle, HSBF was calculated as follows:
HSBF (ml/min) = ICG administration rate (mg/min)/(Ca 
Chv) × (1 Hct) where Ca and Chv are the systemic arterial and suprahepatic venous indocyanine green blood concentration (mg/ml), respectively, and Hct the hematocrit of the blood sample. HSBF was indexed to the patient's body surface area. Fractional HSBF (HSBF/CI)
was determined as the ratio (in %) of HSBF to the simultaneous cardiac index.
To determine gastric mucosal PCO2, the gastric tonometry catheter was prepared according to the manufacturer's instructions and filled with 2.5 ml of saline solution. After an equilibration time of 30 min, 1 ml of dead-space volume was aspirated from the catheter and discarded. The remaining saline solution was then aspirated and analyzed for PCO2 (ABL 500; Radiometer, Copenhagen, Denmark). The gastric mucosal PCO2 was then obtained by multiplying the measured saline PCO2 by 1.24, the time equilibration factor determined by the manufacturer for an equilibration time of 30 min. The mucosal-arterial PCO2 difference (PCO2gap) was calculated as the difference between gastric mucosal PCO2 and arterial blood PCO2.
Blood samples were simultaneously taken from the arterial catheter, the suprahepatic venous catheter, and the distal lumen of the pulmonary artery catheter for blood gas analysis (ABL 500; Radiometer). Hemoglobin saturations were measured by a co-oximeter (OSM-3 Hemoximeter; Radiometer).
At baseline and after 30 min of infusion of 5 µg/kg/min of dobutamine, hepatosplanchnic oxygen consumption (
O2) and delivery (DO2) were calculated using standard formulas, and the slope of the
hepatosplanchnic O2/DO2 relation (Mes O2/DO2 slope) was determined for each patient.
Inadequate Hepatosplanchnic Perfusion
The adequacy of hepatosplanchnic perfusion was assessed according
to three prospectively defined criteria: (1) an HSBF/CI ratio below or
above 20%; (2) a difference between mixed venous blood suprahepatic blood O2 saturations (DSvhO2) above or below 20%; (3) a Mes
O2/DO2 slope above or below 15%.
Statistics
The results are given as medians with ranges and analyzed by Wilcoxon's matched-pairs signed rank test. A p value less than 0.05 was accepted as statistically significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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During the dobutamine infusion, CI increased significantly and dose dependently (Table 1). HSBF simultaneously increased, HSBF/CI remaining unchanged (Table 1). PCO2gap decreased significantly from 10.8 to 7.0 mm Hg at DOB 5 (p < 0.001), but it did not decrease further at DOB 10 (Table 2 and Figure 1).
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At baseline, 18 of the 36 patients had an HSBF/CI below
20%. In these patients, PCO2gap decreased significantly and
dose dependently from 11.7 to 6.3 mm Hg at DOB 5 (p < 0.001) and to 5.6 mm Hg at DOB 10 (p < 0.001 versus DOB 0;
p < 0.05 versus DOB 5) (Table 2 and Figure 1). In the 11 patients with a DSvhO2 above 20%, PCO2gap decreased significantly from 12.1 to 6.2 mm Hg at DOB 5 (p < 0.001) and to 4.2 mm Hg at DOB 10 (p < 0.001 versus DOB 0; p < 0.05 versus
DOB 5) (Table 2 and Figure 1). In the 16 patients with a Mes
O2/DO2 slope above 15%, PCO2gap also decreased significantly (Table 2). In the other groups of patients, PCO2gap did
not change. Individual changes in PCO2gap during the dobutamine infusion for groups of patients with a baseline HSBF/
CI above and below 20% are shown in Figure 2.
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At baseline, there was no significant correlation between PCO2gap and HSBF/CI (r = 0.18; data not shown) or DSvhO2 (Figure 3). The changes in PCO2gap during the dobutamine infusion were not correlated with the PCO2gap values. Even baseline PCO2gap values above or below 10 mm Hg did not predict the response to dobutamine (Table 2 and Figure 4).
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Baseline PCO2gap and changes in PCO2gap during the dobutamine infusion were similar in the 17 dopamine-treated and the other patients (Table 2).
A receiver operating characteristics (ROC) curve was constructed in order to define the best cutoff value of change in PCO2gap during the dobutamine infusion for the detection of patients with a baseline DSvhO2 above 20%. This value was found to be around 5 mm Hg (Figure 5).
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A positive dobutamine test, as defined by a decrease in
PCO2gap of more than 5 mm Hg during an infusion of 10 µg/
kg/min of dobutamine, was found in 12 patients (Dob test + group). In the other 24 patients, PCO2gap decreased by less
than 5 mm Hg, did not change or increase (DOB test group). At baseline, there was no significant difference in systemic hemodynamic parameters between these two groups, but
the DSvhO2 was remarkably higher in the Dob test + group
than in the Dob test group (27.0 ± 8.5% versus 8.9 ± 6.4%,
p < 0.01). Ten of the 11 patients with DSvhO2 above 20% had
a Dob test + and 23 of the 25 patients with a DSvhO2 below
20% had a Dob test (Figure 3). All patients with a positive dobutamine test had an HSBF/CI below 20% (Figure 6). Significant changes in PCO2gap occurred only in patients with a
baseline HSBF/CI below 20%. In this group, PCO2gap changes
were correlated with baseline HSBF/CI (r = 0.80; p < 0.05)
(Figure 6). A positive dobutamine test could detect patients
with a DSvhO2 above 20% with a sensitivity of 83% and a
specificity of 96% (Figure 3) (positive predictive value, 91%;
negative predictive value, 92%; proportion of correct classification, 92%). The median value for the Mes O2/DO2 slopes was significantly higher in the Dob test + group than in the
Dob test group (53.9% versus 12.6%; p < 0.05). The patients
with a baseline HSBF/CI below 20% and those with a baseline
DSvhO2 above 20% (i.e., the patients who showed a decrease
in PCO2gap during the dobutamine infusion) had a significantly
higher hepatosplanchnic O2/DO2 slope than the others (i.e.,
the patients who showed no change in PCO2gap during the
dobutamine infusion) (Table 3).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of our study were that even though PCO2gap
per se is not correlated with HSBF or oxygen supply, changes in PCO2gap during a short-term dobutamine infusion can reveal an alteration in hepatosplanchnic perfusion. Specifically,
dobutamine infusion decreases the PCO2gap, particularly in patients with a low HSBF/CI, a DSvhO2 above 20% or a Mes
O2/DO2 slope above 15% at baseline.
Dobutamine has been shown to improve both splanchnic
oxygenation and gastric pHi in septic animals (31) and in
septic patients (3, 18, 28, 29). Some of these studies (3, 18, 28, 29) indicated that dobutamine increase pHi (or decreased
PCO2gap) in patients with low pHi (or high PCO2gap), but not
in those with normal pHi (or normal PCO2gap). In our study,
even when it was very high (> 10 mm Hg), the baseline
PCO2gap failed to predict the response to the dobutamine infusion. However, the PCO2gap decreased, particularly in patients
with a low HSBF/CI and/or indexes of an imbalance between
hepatosplanchnic oxygen supply and demand as reflected by a
DSvhO2 above 20%. The Mes O2/DO2 slopes were significantly higher in the group of patients with a positive dobutamine infusion test. Because HSBF increased in all patients,
the decrease in PCO2gap found in these latter patients could be
the result of a redistribution of blood flow toward the mucosa,
resulting in a simultaneous increase in hepatosplanchnic O2.
Inevitably, some patients with severe sepsis do require vasopressors, and dopamine has sometimes been found to increase the gastric mucosal-arterial PCO2 difference (18). However, the effects of dobutamine on PCO2gap were similar in dopamine- and non-dopamine-treated patients groups.
A cutoff value of 5 mm Hg for the dobutamine test seems to represent a reasonable change in PCO2gap and also represents more than twice the precision of the saline tonometry technique in the determination of the ambient PCO2 that we have previously estimated at 1.9 mm Hg (34). The best discriminant value of this cutoff point was confirmed on a ROC-curve analysis (Figure 5).
We used three prospectively defined criteria to define inadequate hepatosplanchnic perfusion: the HSBF/CI ratio, the
DSvhO2, and the Mes O2/DO2 slope. For the HSBF/CI ratio, a
cutoff value of 20% seemed reasonable since the normal value
is around 25% (35). For the DSvhO2, the cutoff value of 20%
was chosen for two reasons. First, DSvhO2 values, calculated from
individual data of SvO2 and ShO2 reported by Dahn and coworkers (36) in nonseptic patients, were usually close to zero
and had a standard deviation of 8.9%, so that a cutoff value of
more than twice this value was reasonable. Second, in a previous study including 44 septic patients (2), virtually every patient (14 of the 15) with a DSvhO2 above 20% had a sharp
hepatosplanchnic O2/DO2 slope (above 15%) compatible with
a regional O2/DO2 dependency. The vast majority of patients
(11 of 12) with a DSvhO2 below 10% had a hepatosplanchnic
O2/DO2 slope below 15%, suggesting no regional O2/DO2
dependency. The patients with a DSvhO2 between 10 and 20%
had a variable response. For the Mes O2/DO2 slope, we selected
a cutoff value of 15% because in our previous study (2), the
septic patients with no hepatosplanchnic O2/DO2 covariance
had a Mes O2/DO2 slope of 10.4 ± 5.1%.
Of these three parameters of hepatosplanchnic perfusion, we selected the DSvhO2 to divide the patient population during the dobutamine test because DSvhO2 probably represents the best clinical index of the adequacy of the O2 supply and demand balance in the hepatosplanchnic area in septic patients (36). Indeed, in these patients, splanchnic blood flow usually increases in proportion to cardiac output (HSBF/CI is stable), but splanchnic oxygen consumption increases to a greater extent than whole-body oxygen consumption (39), so that even when hepatosplanchnic blood flow is increased, an increase in DSvhO2 may reflect an imbalance between O2 supply and demand in this region (36, 38).
The lack of correlation between PCO2gap values and HSBF or DSvhO2 can be explained by several mechanisms that are not mutually exclusive. One is that the PCO2gap reflects merely the oxygen supply to the gastric mucosa, whereas the HSBF and the DSvhO2 are global indexes of oxygen supply to the liver and the three layers of the gut (mucosa, muscularis, and serosa). The gut mucosa can behave differently from the two other layers of the gut in septic patients. Several studies (16, 40) have demonstrated the presence of flow redistribution between the mucosal and muscular layers of the gut during sepsis, leading to a decreased local CO2 clearance in hypoperfused mucosal regions. Moreover, the particular countercurrent vascular anatomy of the gut villi renders the tip of the villus very vulnerable to hypoxia (41). Mucosal acidosis may also be the result of direct metabolic alterations caused by sepsis even in the absence of regional hypoperfusion (16). The decrease in the PCO2gap in patients with hepatosplanchnic hypoperfusion argues for a prevalent role of mucosal blood flow rather than metabolic cellular alterations in the genesis of gastric intramucosal acidosis.
Although a single PCO2gap value in septic patients brings limited information, changes in PCO2gap during a dobutamine infusion appear to be clinically relevant. Early identification of gut ischemia may be an important step to prevent the development of multiple organ dysfunction and its associated mortality (5, 7, 12, 13). The present study has outlined a simple, noninvasive test to detect hepatosplanchnic hypoperfusion. This may serve as a useful test for further studies.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Jean-Louis Vincent, Dept. of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. E-mail: jlvincen{at}resulb.ulb.ac.be
(Received in original form July 7, 1998 and in revised form February 18, 1999).
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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