Effects of Dobutamine on Gastric Mucosal Perfusion and Hepatic Metabolism in Patients with Septic Shock LUC-MARIE JOLY, MEHRAN MONCHI, ALAIN CARIOU, JEAN-DANIEL CHICHE, FLORENCE BELLENFANT, FABRICE BRUNET, and JEAN-FRANÇOIS DHAINAUT Medical Intensive Care Unit, Cochin Port Royal University Hospital, Paris, France
We prospectively evaluated the effects of dobutamine on gastric mucosal perfusion and hepatocytic clearance in patients with septic shock. After resuscitation with volume expansion and norepinephrine (12 patients) as needed, 14 hemodynamically stable patients (median age: 60 yr, median SAPS II score: 47) were given an infusion of 7.5 mg/kg/min dobutamine for 1 h. Gastric mucosal perfusion and hepatocytic clearance were assessed with tonometry and indocyanine green (ICG) elimination, respectively. All measurements were made before dobutamine infusion, after 1 h of dobutamine infusion, and 1 h after the infusion ended. Cardiac output (thermodilution technique) increased with dobutamine from a baseline median level of 4.0 L/min/m2 (range: 1.7 to 7.4 L/min/m2) to 5.0 L/min/m2 (range: 3.5 to 8.9 L/min/m2) (p 5 0.004) and returned to baseline levels after dobutamine infusion ended. The gastric–arterial PCO2 difference decreased from a baseline median level of 13 mm Hg (range: 5 to 54 mm Hg) to 7 mm Hg (range: 5 to 48 mm Hg) (p 5 0.005). ICG elimination was low in all patients at baseline (median plasma disappearance rate: 12.2%; range: 7.6 to 16.2%) and did not change significantly during or after dobutamine infusion. In summary, dobutamine increases gastric mucosal perfusion but does not alter hepatocytic clearance in patients with septic shock. The absence of a beneficial effect of dobutamine on hepatocytic clearance may be related to profound alterations in hepatocellular metabolism during septic shock. Joly L-M, Monchi M, Cariou A, Chiche J-D, Bellenfant F, Brunet F, Dhainaut J-F. Effects of dobutamine on gastric mucosal perfusion AM J RESPIR CRIT CARE MED 1999;160:1983–1986. and hepatic metabolism in patients with septic shock.
The multiple organ dysfunction syndrome (MODS) is a major therapeutic challenge for intensive care physicians treating critically ill patients. The mortality rate in MODS still exceeds 50% despite recent improvements in supportive treatment in the intensive care unit (1). Over the past 20 yr, extensive research has been devoted to better understanding the pathophysiology of sepsis and MODS. Investigative efforts have highlighted the pivotal role of the gut–liver axis in triggering and perpetuating the inflammatory reaction that results in MODS (2). Abnormal perfusion of gut mucosa (3) and liver (4, 5) can persist after resuscitation from septic shock, leading to increased gut-wall permeability and hepatic dysfunction. Increased gut-wall permeability can result in the portal release of bacterial products and endotoxin, which stimulate the immunoinflammatory cascade after activation of Küpffer cells in the liver. Hepatic dysfunction resulting from abnormal perfusion of the liver contributes to the altered immune homeostasis that characterizes MODS (6). Because systemic hemodynamics measurements provide a poor estimate of splanchnic blood flow (7), specific tools are required to assess the adequacy of tissue perfusion and oxygenation during resuscitation from septic shock. Gastric tonom-
etry, which detects mucosal acidosis (8), and the indocyanine green (ICG) elimination technique, which reveals hepatic perfusion and metabolism (9, 10), have been proposed as methods for studying splanchnic microcirculation. These tools have allowed detection of splanchnic hypoperfusion even in the absence of altered systemic hemodynamics (3, 5, 11). The effect of vasoactive agents on organ blood flow distribution is difficult to investigate in clinical practice (11–17). In septic patients, the concurrent effects of dobutamine on gastric mucosal and hepatic perfusion have not been extensively investigated. In this prospective study, we used gastric mucosal PCO2 and ICG elimination measurements to evaluate the concurrent effects of dobutamine on gastric mucosal perfusion and hepatocytic clearance in patients with septic shock.
METHODS Patients After approval by our local ethics committee, and with informed consent from relatives, we studied patients presenting with septic shock according to the Bone criteria and requiring invasive hemodynamic monitoring (18). The study was done within 36 h after each patient’s admission in the ICU. Exclusion criteria were shock of other etiology, organ transplantation, severe burns, and liver cirrhosis.
(Received in original form August 26, 1997 and in revised form May 6, 1999) Supported in part by Lilly France.
Clinical Management
Correspondence and requests for reprints should be addressed to Pr. J. F. Dhainaut, Hôpital Cochin, Réanimation Médicale, 27 rue du Faubourg Saint Jacques 75679 Paris, France. E-mail:
[email protected] Am J Respir Crit Care Med Vol 160. pp 1983–1986, 1999 Internet address: www.atsjournals.org
All patients required sedation (fentanyl and midazolam infusions) and mechanical ventilation. Ventilatory parameters were not altered during the study period. Patients were fasted during the study period and did not receive histamine-2 receptor antagonists or antiacid treatment. If present, hypovolemia was corrected with fluid infusion be-
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TABLE 1 PATIENT CHARACTERISTICS Patient No.
Age/ Sex
Preexisting Disease
Etiology of Septic Shock
1 2 3 4 5 6 7 8 9
50/M 75/F 72/M 50/F 83/F 26/M 65/M 42/M 56/M
COPD Sjögren’s syndrome Monoclonal gammapathy Myeloma Diabetus mellitus Sickle cell disease Amiodarone pneumonia Chronic osteomyelitis Severe psychosis
Pneumonia Nosocomial pneumonia Pneumonia Unknown Pyelonephritis Pneumonia Nosocomial pneumonia Bone abcess Fecal peritonitis
10 11
74/M 77/M
Coronary disease, COPD Colectasia
12 13 14
52/F 46/M 88/M
Breast cancer Bacterial meningitis Prosthetic-hip infection
Terciary peritonitis Fecal peritonitis 1 septicemia Catheter sepsis Nosocomial pneumonia Peritonitis
Bacteriologic Data
SAPS II Score
Outcome (d )
NE (mg/h)
Lactate (mmol/L)
40 57 55 36 65 78 34 53 61
S (22) D (8) D (17) D (4) D (3) S (11) D (20) S (15) D (16)
0.3 0.5 0.3 0.1 0.2 0 0.15 0.8 0
11.7 4 3.1 1.3 4.1 3.2 3.5 4.6 1.7
25 43
D (18) D (37)
0.5 0.5
3.1 1.9
39 41 52
S (43) D (23) D (12)
0.8 0.9 2
3.8 2.4 5.2
Anaerobes Pseudomonas aeruginosa Pneumococcus Escherichia coli Pneumococcus MSSA, Stenotrophomonas maltophilia MRSA GNB Candida Candida Escherichia coli, Enterobacter cloacae MSSA Pseudomonas aeruginosa Pseudomonas aeruginosa, C. glabrata
Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease; D 5 died; GNB 5 gram-negative bacillus; MRSA 5 methicillin-resistant Staphylococcus aureus; MSSA 5 methicillin-sensitive Staphylococcus aureus; NE 5 norepinephrine; S 5 survived; SAPS 5 Simplified Acute Physiology Score.
fore the study intervention, in order to keep the pulmonary artery occlusion pressure above 12 mm Hg. Norepinephrine (NE) infusion was started if systolic arterial pressure remained lower than 80 mm Hg despite optimization of preload. Other catecholamines were not permitted during the study period. Demographic characteristics, microbiologic data, and Simplified Acute Physiology Score (SAPS) II score at admission were recorded.
Gastric Intramucosal PCO2 Measurements A gastric tonometer (Tonometrics, Inc., Hopkinton, MA) was inserted in the stomach and its position was confirmed radiographically. The balloon was filled with 2.5 ml of normal saline and an equilibration period of 1 h was allowed before sampling. At the time of measurement, normal saline was anaerobically aspirated and the first milliliter was rejected. The rest of the sample was immediately analyzed for PCO2 with a blood gas analyzer (Model AL 510; Radiometer, Copenhagen, Denmark) while the balloon was refilled for the next measurements. Arterial blood gases were measured simultaneously. Gastric PCO2 was corrected with adjustment for the duration of the equilibration period to obtain the steady-state adjusted PCO2. The gastric– arterial PCO2 difference was considered the best parameter with which to detect gastric intramucosal acidosis (19).
Hemodynamic and ICG Elimination Measurements A fiberoptic catheter was inserted into a femoral artery, connected to a computer, and calibrated according to the manufacturer’s recommendations (Cold System; Pulsion Medical Systems, Munich, Germany). A 10-ml ICG bolus (concentration 2%, temperature 0 to 58 C) was injected into the superior vena cava. Cardiac output (CO) was determined by thermodilution and the ICG concentration was measured for 240 s after the bolus injection. A computerized algorithm allowed calculation of the plasma disappearance rate of ICG (PDRICG) as follows: PDRICG 5 100 ? Ln2/t1/2ICG, where PDRICG indicates the percentage of ICG that disappears each minute from the blood as a result of hepatic elimination.
p , 0.05 indicated statistical significance. For each parameter, baseline values were compared with values obtained during and after dobutamine infusion.
RESULTS Fourteen patients presenting with septic shock were included in the study. Characteristics of the patients are presented in Table 1. The median age of the patients was 60 yr (range: 26 to 88 yr). The patients’ median SAPS II score was 47 (range: 25 to 78). Four patients survived and were discharged from the hospital. No patient had biologic features of acute liver failure. The patients’ mean arterial blood lactate concentration was 3.8 mmol/ L (range: 1.3 to 11.7 mmol/L). Twelve patients received NE at a mean infusion rate of 0.6 mg/h (range: 0.2 to 2 mg/h). Dobutamine infusion was well tolerated except for Patient 6, who developed transient atrial fibrillation at the end of the infusion. The gastric–arterial PCO2 difference was not obtained for Patient 4 because of technical failure of the blood gas analyzer. Hemodynamic parameters are presented in Table 2. Dobutamine infusion increased CO from a baseline median level of 4.0 L/min/m2 (range: 1.7 to 7.4 L/min/m2) to 5.0 L/min/m2 (range: 3.5 to 8.9 L/min/m2) (p 5 0.004). CO returned to baseline levels after the infusion ended (Figure 1). To assess changes in splanchnic blood flow in response to dobutamine, we concurrently measured the gastric–arterial PCO2 difference and ICG elimination. The gastric–arterial PCO2 difference decreased with dobutamine from a baseline median level of 13 mm Hg (range: 5 to 54 mm Hg) to 7 mm Hg (range: 5 to 48 mm Hg) (p 5 TABLE 2 HEMODYNAMIC PARAMETERS: MEDIAN AND RANGE
Protocol Following an initial stabilization period, systemic hemodynamics, CO, gastric–arterial PCO2 difference, and PDRICG were measured before and after a 1-h dobutamine infusion (7.5 mg/kg/min). Measurements were repeated 1 h after discontinuation of the dobutamine infusion. No change in the NE infusion rate was allowed during the study period.
Statistics Statistical analysis was done with nonparametric statistical tests. The results are expressed as median and ranges. Comparisons were made by using Wilcoxon’s signed ranks paired difference test. A value of
HR, beats/min Pas, mm Hg Ppas, mm Hg Ppao, mm Hg CO, L/min/m2 Lactate, mmol/L
Baseline
Dobutamine
95 (62–137) 71 (48–79) 35 (23–43) 14 (12–20) 4.0 (1.7–7.4) 3.1 (1.3–11.7)
117 (85–149) 69 (46–94) 32 (23–45) 12 (10–20) 4.95 (3.5–8.9)
After Dobutamine 102 (62–138) 69 (45–94) 33 (25–42) 14 (12–20) 4.35 (1.7–7.1)
* p , 0.05 versus baseline. Definition of abbreviations: CO 5 cardiac output; HR 5 heart rate; Pas 5 mean systemic arterial pressure; Ppao 5 pulmonary arterial occlusion pressure; Ppas 5 systolic pulmonary arterial pressure.
Joly, Monchi, Cariou, et al.: Effects of Dobutamine in Septic Shock
Figure 1. CO before (baseline), during, and 1 h after dobutamine infusion. Each line represents an individual patient. Patients 6 and 9 did not receive NE.
0.005), and reached 10 mm Hg (range: 4 to 42 mm Hg) after the infusion ended (p 5 0.03 versus baseline) (Figure 2). Baseline ICG elimination was low in all patients (median plasma disappearance rate: 12.2%; range: 7.6 to 16.2%), and did not change significantly during and after dobutamine infusion (Figure 3).
DISCUSSION In this study, dobutamine administration in patients with septic shock significantly increased CO, produced a modest improvement in gastric mucosal perfusion, and had no measurable effect on hepatocytic clearance. Comparison with previously reported studies and careful interpretation of these data mandate a systematic appraisal of the methods used to assess splanchnic perfusion. The present investigation confirms other findings of an improvement in gastric mucosal perfusion after dobutamine administration in patients with septic shock (19–23). Dobutamine has also been shown to improve gastric mucosal blood flow at the microvascular level, as measured with a laser-Doppler technique (21, 24). Our results are based on the assumption that measurement of gastric intramucosal acidosis can be interpreted as an index of gastric mucosal perfusion. Indeed, the level of gastric acidosis as measured from the gastric–arterial PCO2 difference appears to be more a accurate marker of
Figure 2. Gastric–arterial PCO2 difference before (baseline), during, and 1 h after dobutamine infusion. Each line represents an individual patient. Patients 6 and 9 did not receive NE.
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abnormal splanchnic perfusion than the previously used pHi (25–27). An improvement in gastric mucosal perfusion has also been observed with dopexamine, a b2-agonist, in patients with severe sepsis (14, 15). The mechanism of both dobutamine and dopexamine seems to involve a b2-receptor-mediated redistribution of blood flow from the muscularis to the mucosa. In our patients with septic shock, we did not find any measurable change in hepatocytic clearance after dobutamine infusion. We used the ICG elimination technique to asses hepatic perfusion. This approach relies on the assumption that hepatic elimination of ICG is flow-dependent. ICG is a dye that dilutes in blood only. After a single bolus injection, ICG is secreted in unaltered form into the bile by the liver. Of the injected amount of dye, close to 100% is recovered in the bile fluid. Assuming that hepatic elimination of dye is not saturated (i.e., low doses of ICG in subjects with normal hepatocellular dye captation), elimination is flow-dependent, and variations in the plasma ICG disappearance rate directly reflect variations in hepatic blood flow. Conversely, impairment of hepatocellular dye captation or saturation of hepatic dye elimination capability limits the usefulness of this technique for assessing hepatic blood flow. In these cases, the plasma ICG disappearance rate becomes mainly dependent on hepatocellular metabolism. Alternation of hepatocellular metabolism has been observed during hemorrhagic and septic shock in animal models (4, 5, 28) as well as in humans (11, 29). Thus, decreased hepatic blood flow, as well as impaired hepatic metabolism leading to reduced captation of ICG may account for the low baseline values of ICG elimination measured in our patients with septic shock. We did not find any change in ICG elimination after a 7.5 mg/kg/min dobutamine infusion. These results are consistent with the findings of De Backer and coworkers in a study of hepatic hemodynamics and metabolism in septic patients (11). In their study, dobutamine resulted in a small increase in ICG clearance when used at a low dose (5 mg/kg/min), but failed to improve ICG clearance at a higher dose (10 mg/kg/min). These data suggest that dobutamine has no clinically relevant effect on hepatocytic clearance. Several mechanisms may explain the lack of effect of dobutamine on hepatocytic clearance in our study. First, dobutamine may fail to increase total hepatic blood flow. Second, dobutamine may increase hepatic blood flow, but profound alterations of cellular metabolism may impede the captation of ICG, which then becomes flow-independent. Wang and col-
Figure 3. Plasma ICG disappearance before (baseline), during, and 1 h after dobutamine infusion. Each line represents an individual patient. Patients 6 and 9 did not receive NE.
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leagues tested the latter hypothesis and measured hepatic blood flow in a rat model of severe sepsis induced by cecal ligation and puncture (4). Whereas both CO and hepatic blood flow (assessed through electromanometry) increased, hepatocellular captation of the dye (assessed from the maximal rate of ICG clearance) decreased within 2 h after cecal ligation. In a subsequent study, fluid resuscitation failed to restore hepatocytic clearance despite increased hepatic blood flow (5). Third, administration of NE prior to dobutamine infusion in many patients enrolled in our study may have modified the effect of dobutamine on hepatocytic clearance. In these patients, NE infusion was clinically indicated to maintain the hemodynamic stability necessary to investigate the effects of dobutamine. In addition, experimental and clinical studies have revealed either no change or an improvement in hepatic hemodynamics and hepatocellular function after treatment with NE (13, 30, 31). It therefore seems unlikely that NE adversely modified the effects of dobutamine on hepatocytic clearance in our study. Additionally improvement in hepatocellular function in response to catecholamines may be time-dependent. Like Smithies and associates, we assessed changes in splanchnic perfusion after a 1-h dobutamine challenge (14). In contrast, others reported significant effects of prolonged administration of various catecholamines on splanchnic perfusion (13, 32). A 1-h infusion time may have been too short to observe changes in ICG elimination by hepatocytes. In summary, we used tonometry and the ICG elimination technique to investigate the effect of dobutamine on splanchnic perfusion in patients with septic shock. Our study confirms that dobutamine improves systemic hemodynamics and moderately increases gastric mucosal perfusion in septic shock. The absence of a beneficial effect of dobutamine on hepatocytic clearance in septic shock may be related to profound alterations of hepatocellular metabolism. Acknowledgment : The authors are very grateful to Michael Pinsky, M.D., of the Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, for helpful discussion in preparing this manuscript.
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