Anesthesiology 2004; 100:1188–97 © 2004 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Effects of Dopamine, Dobutamine, and Dopexamine on Microcirculatory Blood Flow in the Gastrointestinal Tract during Sepsis and Anesthesia Luzius B. Hiltebrand, M.D.,* Vladimir Krejci, M.D.,* Gisli H. Sigurdsson, M.D., Ph.D.† Background: Insufficient blood flow to the splanchnic organs failure.1–4 The concept that oxygen consumption in the is believed to be an important contributory factor for the devel- hepatosplanchnic region may be dependent on oxygen opment of organ failure after septic shock. It has been sug- delivery in sepsis has recently been confirmed.5 There- gested that increasing systemic flow also may improve splanch- fore, increasing systemic flow, which may also improve nic blood flow in septic patients. The aim of this study was to Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/5/1188/354544/0000542-200405000-00022.pdf by guest on 24 September 2021 compare the effects of three commonly used inotropic agents, splanchnic blood flow, is one of the current therapeutic dopamine, dobutamine, and dopexamine, on systemic (cardiac goals in perioperative treatment of high-risk patients and index), regional (superior mesenteric artery), and local (micro- in intensive care medicine.6–11 This concept is based on circulatory) blood flow during septic shock in pigs. the assumption that the gastrointestinal mucosa receives Methods: Eight pigs were intravenously anesthetized, me- chanically ventilated, and exposed to sepsis induced by fecal its share of increased systemic and regional oxygen de- peritonitis. Cardiac index was measured with thermodilution, livery. However, a recent study from our institution has superior mesenteric artery flow was measured with ultrasound shown that under septic conditions, distribution of mi- transit time flowmetry, and microcirculatory blood flow was crocirculatory blood flow in the abdominal organs is continuously measured with a six-channel laser Doppler flow- highly heterogeneous and cannot be predicted from metry in the gastric, jejunal, and colon mucosa as well as in the 12 kidney, pancreas, and jejunal muscularis. Each animal received, systemic or regional perfusion. There was little corre- in a random-order, crossover design, the three test drugs, one at lation between changes in systemic flow and in micro- a time: 5 and 10 ␮g·kg؊1 · min؊1 dopamine, 5 and 10 ␮g· circulatory flow in the splanchnic organs, including the ؊1 ؊1 ؊1 ؊1 kg · min dobutamine, and 1 and 2 ␮g·kg · min dopex- gastrointestinal mucosa. amine. Administration of each drug at each dose continued for In clinical practice, usually the first step to increase 30 min and was followed by a 40- to 60-min recovery period. A new baseline was taken before the next drug was administered. systemic and splanchnic oxygen delivery in patients in Results: All three drugs significantly increased cardiac index; septic shock includes adequate fluid volume resuscita- dopamine by 18%, dobutamine by 48%, and dopexamine by tion. If that is insufficient, it is usually followed by ad- 35%, compared with baseline (P < 0.001 for each). At the same ministration of inotropic agents such as dopamine, do- time, superior mesenteric artery flow increased by 33% (P < butamine, or dopexamine. However, the scientific 0.01) with dopamine and 13% (P < 0.01) with dopexamine, whereas it did not change with dobutamine. Microcirculatory background for the choice of a particular inotropic agent blood flow did not change significantly in any of the organs for this purpose is still poorly established, and many studied with any of the drugs tested. factors regarding their effects on regional and local Conclusion: All the inotropic agents markedly increased car- blood flow, particularly in the splanchnic region, remain diac output in this sepsis model. However, increased systemic unknown. flow did not reach the microcirculation in the gastrointestinal tract. This may in part explain why some of the clinical trials, in To our knowledge, there is no previous comparative which systemic oxygen delivery was deliberately increased by dynamic study that investigates the differential effects of administration of inotropic drugs, have failed to improve sur- dopamine, dobutamine, and dopexamine on the vival in critically ill patients. splanchnic microcirculation. Therefore, we tested these drugs in a clinically relevant septic pig model. The aims IT is now widely recognized that rapid resuscitation of of the study were (1) to correlate changes in systemic, splanchnic perfusion is an important factor for success- regional, and local blood flow for each tested drug dur- ful outcome of severely ill and injured patients. Insuffi- ing normodynamic sepsis and (2) to compare the effects cient blood flow to the gastrointestinal tract during sep- of these agents on microcirculatory blood flow in differ- sis may provoke gut mucosa barrier dysfunction, ent abdominal organs. Considering the results of our resulting in bacterial translocation and multiple organ previous study,12 we assumed that there would be no correlation between changes in cardiac output (CO) and * Consultant, Department of Anesthesia, University of Berne, Inselspital. changes in microcirculatory blood flow in the gastroin- † Professor and Chairman Department of Anesthesia and Intensive Care Medi- testinal tract by any of the drugs tested. cine, Landspitali University Hospital, Reykjavik, Iceland. Received from the Department of Anesthesia, Experimental Laboratory, Ex- perimental Surgical Institute, University of Berne, Inselspital, Berne, Switzerland. Submitted for publication August 13, 2003. Accepted for publication December Materials and Methods 7, 2003. Supported by the Research Fund of the Department of Anesthesia, University of Berne, Inselspital, Berne, Switzerland. This study was performed according to the National Address reprint requests to Dr. Sigurdsson: Department of Anesthesia and Institutes of Health guidelines for the use of experimen- Intensive Care, Landspitali University Hospital, Hringbraut, IS 101 Reykjavik, Iceland. Address electronic mail to: [email protected]. Individual article reprints tal animals. The protocol was approved by the Animal may be purchased through the Journal Web site, www.anesthesiology.org. Ethics Committee of Canton, Berne, Switzerland. Eight Anesthesiology, V 100, No 5, May 2004 1188 INOTROPIC DRUGS AND THE MICROCIRCULATION IN SEPSIS 1189 min), during Hypodynamic Septic 0 ؍ Table 1. Systemic, Regional, and Microcirculatory Data before Induction of Septic Shock (t (min 300 ؍ min), and after Administration of Intravenous Fluids (t 240 ؍ Shock (t t ϭ 0 min t ϭ 240 min t ϭ 300 min Heart rate, beats/min 118 Ϯ 29 185 Ϯ 60* 162 Ϯ 47 MAP, mmHg 100 Ϯ 10 54 Ϯ 10† 78 Ϯ 17† CI, ml ⅐ kgϪ1 ⅐ minϪ1 169 Ϯ 46 75 Ϯ 18† 144 Ϯ 36§ SVRI, mmHg ⅐ kgϪ1 ⅐ minϪ1 599 Ϯ 239 681 Ϯ 124 544 Ϯ 123 PVRI, mmHg ⅐ kgϪ1 ⅐ minϪ1 95 Ϯ 27 226 Ϯ 67† 159 Ϯ 69 CVP, mmHg 6.8 Ϯ 3.0 4.5 Ϯ 1.9† 5.6 Ϯ 2.0 PAP, mmHg 21.0 Ϯ 4.6 20 Ϯ 2.1 26.3 Ϯ 6.8 PCWP, mmHg 5.5 Ϯ 2.1 4.0 Ϯ 1.4 5.3 Ϯ 1.0 Ϫ1 Ϫ1 SMAI, ml ⅐ kg ⅐ min 28.5 Ϯ 11.4 14.9 Ϯ 4.5† 23.4 Ϯ 5.7‡ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/5/1188/354544/0000542-200405000-00022.pdf by guest on 24 September 2021 Ϯ Ϯ Ϯ SvO2,% 67.8 5.8 41.6 12.4† 59.0 4.6§ Ϯ Ϯ Ϯ SmO2,% 77.0 9.3 53.6 11.93† 70.9 6.8§ MBF gastric mucosa 100 Ϯ 0 (266 Ϯ 36) 78 Ϯ 5† 94 Ϯ 5§ MBF jejunal mucosa 100 Ϯ 0 (338 Ϯ 82) 94 Ϯ 21 112 Ϯ 30 MBF jejunal muscularis 100 Ϯ 0 (1,215 Ϯ 258) 47 Ϯ 17† 60 Ϯ 18† MBF colonic mucosa 100 Ϯ 0 (492 Ϯ 99) 96 Ϯ 35 119 Ϯ 22 MBF pancreas 100 Ϯ 0 (272 Ϯ 174) 46 Ϯ 18† 67 Ϯ 27† MBF kidney 100 Ϯ 0 (584 Ϯ 238) 67 Ϯ 18* 89 Ϯ 27 Data are presented as mean Ϯ SD. Peritonitis/sepsis was induced at t ϭ 0; at t ϭ 240 min, intravenous fluids were administered to convert hypodynamic septic shock to normodynamic sepsis. t ϭ 300 min was after fluid administration. All microcirculatory blood flows were set at 100% at t ϭ 0, i.e., before induction of generalized peritonitis. The real laser Doppler readings in perfusion units are shown in parentheses. * P Ͻ 0.05, † P Ͻ 0.01 compared with baseline. ‡ P Ͻ 0.05, § P Ͻ 0.01 compared with 240 min of peritonitis. CI ϭ cardiac index; CVP ϭ central venous pressure; MAP ϭ mean arterial blood pressure; MBF colonic mucosa ϭ microcirculatory blood flow in the colonic mucosa; MBF gastric mucosa ϭ microcirculatory blood flow in the gastric mucosa; MBF jejunal mucosa ϭ microcirculatory blood flow in the jejunal mucosa; MBF jejunal muscularis ϭ microcirculatory blood flow in the muscularis of the jejunum; MBF kidney ϭ microcirculatory blood flow in the cortex of the kidney; MBF pancreas ϭ microcirculatory blood flow in the pancreas; PAP ϭ mean pulmonary artery pressure; PCWP ϭ mean pulmonary artery occlusion pressure; PVRI ϭ ϭ ϭ ϭ pulmonary vascular resistance index; SMAI superior mesenteric artery flow index; SmO2 mesenteric venous oxygen saturation; SvO2 mixed venous oxygen saturation; SVRI ϭ systemic vascular resistance index. domestic pigs (weight, 20–25 kg) were fasted overnight advanced through the right heart into the pulmonary but were allowed free access to water. The pigs were artery. sedated with intramuscular ketamine (20 mg/kg) and With the pig in the supine position, a midline laparot- xylazinum (2 mg/kg). Anesthesia was induced with in- omy was performed. The spleen was removed to avoid travenous metomidate (5 mg/kg) and azaperone (2 mg/ autotransfusion during shock, and a catheter was in- kg).