Low potential of dobutamine and to block intestinal peristalsis as compared with other catecholamines

Sonja Fruhwald, MD; Stefan Scheidl; Wolfgang Toller, MD; Thomas Petnehazy; Peter Holzer, PhD; Helfried Metzler, MD; Heinz F. Hammer, MD

Objective: Catecholamines are frequently used in critically ill Measurements and Main Results: Low concentrations of each patients to restore stable hemodynamics and to improve organ catecholamine, except epinephrine, caused a decrease in the perfusion. One effect of short-term or long-term administration of pressure threshold, which reflects a stimulatory effect on peri- catecholamines may be inhibition of propulsive motility in the stalsis. Higher catecholamine concentrations caused a concen- intestine. We therefore analyzed the effect of dopexamine, dobut- tration-related increase in the threshold, cumulating in a com- amine, and on ileal peristalsis and compared their plete block of peristalsis. The rank order of inhibitory potency was action with that of epinephrine and , which have epinephrine > norepinephrine > dopamine > dobutamine ϳ long been known to suppress intestinal peristalsis. dopexamine. Dobutamine and dopexamine were about 500-fold Design: In vitro study on excised guinea pig ileum segments. less active than epinephrine in suppressing peristalsis. Setting: Laboratory for experimental studies at the University. Conclusions: This study shows that dobutamine and dopex- Subjects: Isolated guinea pig ileum. amine have the least potential to block propulsive motility in the Interventions: Segments of ileum excised from guinea pigs intestine, whereas epinephrine demonstrates the most adverse were mounted in a tissue bath in Krebs-Henseleit solution and inhibitory effect. Because at low concentrations dobutamine and bubbled with 95% oxygen/5% CO2. Luminal perfusion with the dopexamine even stimulate peristalsis, these drugs appear to be same solution was performed at a rate of 0.35 mL/min. The bath superior compared with other catecholamines with regard to their temperature was kept at 36.5°C. Peristalsis was recorded via direct effects on intestinal motility. (Crit Care Med 2000; 28: changes in the intraluminal pressure. The drugs under investiga- 2893–2897) tion (dopamine, epinephrine, norepinephrine, dobutamine, and KEY WORDS: guinea pig; ileum; threshold; peristalsis; dopamine; dopexamine) were added to the tissue bath. epinephrine; norepinephrine; dobutamine; dopexamine; motility

atecholamines are frequently fects of catecholamines on cardiac output also inhibit peristalsis and, if so, how the used in critically ill patients and overall splanchnic circulation, cat- potency of such effects compares with with low cardiac output syn- echolamines do not necessarily improve that of epinephrine and norepinephrine. drome to improve global he- blood flow to the gastrointestinal mu- We therefore set out to compare the modynamicsC and/or regional perfusion. cosa. Dopamine, for instance, increases actions of catecholamines currently in Their effects on the human splanchnic splanchnic perfusion but causes a redis- clinical use on peristalsis in the isolated region may be divided into indirect ef- tribution of blood flow from the mucosa guinea pig ileum. The experimental fects, which result from beneficial or det- to the muscularis, which may lead to model, which uses a fluid-perfused seg- rimental impact on splanchnic perfusion, mucosal dysfunction, promote bacterial ment of ileum, allows a quantitative as- and direct effects on intestinal motility. translocation, and eventually give rise to sessment of direct drug effects on peri- Experimental and clinical research on the multiple organ failure (8, 9). stalsis independent of circulatory effect of catecholamines on the gastroin- A well-established action of the older changes (15, 16). To allow comparison of testinal tract currently focuses primarily catecholamines epinephrine and norepi- the potency of five catecholamines (epi- on their indirect effects because of nephrine on the gut, which may limit nephrine, norepinephrine, dopamine, do- changes in cardiac output and splanchnic their therapeutic usefulness, is the inhi- butamine, and dopexamine), concentra- perfusion (1–7). Despite the beneficial ef- bition of propulsive intestinal motility tion response curves were constructed for (10–13). This effect is primarily a result each drug. of inhibition of acetylcholine release from From the Departments of Anesthesiology and In- enteric neurons (11, 13, 14). New cat- MATERIALS AND METHODS tensive Care (Drs. Fruhwald, Toller, Metzler), Internal Medicine (Dr. Hammer, Mr. Scheidl, Mr. Petnehazy), echolamines, such as dobutamine and dopexamine, have been introduced into Animals and Assay Arrangement. Guinea and the Institute of Pharmacology (Dr. Holzer), Univer- pigs were obtained from the Central Research sity of Graz, Graz, Austria. clinical routine. They are used alone or in Institute for Laboratory Animal Breeding, Uni- Address requests for reprints to: Heinz F. Hammer, combination with traditional cat- MD, Associate Professor of Medicine, Medizinische versity of Vienna, Austria. The guinea pigs Universitaetsklinik, Auenbruggerplatz 15, A-8036 Graz, echolamines with the aim of improving were fasted overnight with free access to wa- Austria. E-mail: [email protected] regional hemodynamic effects (1, 6). It is ter. The animals were killed by decapitation Copyright © 2000 by Lippincott Williams & Wilkins not known whether these catecholamines and the ileum was excised. Before the guinea

Crit Care Med 2000 Vol. 28, No. 8 2893 Table 1. Composition of the Krebs-Henseleit so- amplifier, type 301, Hugo Sachs Electronics). tration-dependent rise of the pressure lution Contractions were recorded with a Multi-Pen threshold (Fig. 1B). At 100 nM, peristalsis Recorder (R-OX, Hugo Sachs Electronics). was completely abolished (Fig. 1C). Epi- Concentration The pressure curves of the mounted ileum nephrine was the only catecholamine Substance (mM) segments were characterized by a slow initial that did not decrease the threshold at rise of pressure to a threshold at which a lower concentrations (Fig. 2). NaCl 119 peristaltic contraction was triggered (Fig. 1A). KCl 4.75 Then the cycle started anew. An increase in At lower epinephrine concentrations, CaCl 2.5 2 the threshold represents an inhibitory effect, the frequency of peristaltic contractions MgSO4 1.5 increased (Fig. 1A), whereas at higher NaHCO 25 whereas a decrease in the threshold reflects a 3 action on peristalsis. concentrations peristaltic frequency was KH2PO4 1.2 Glucose 11 Data Analysis. Each segment served as its reduced (Fig. 1B). own control. Paired Student’s t-test was used Norepinephrine. Concentrations Ͻ5 for statistical analysis. A p of Ͻ .05 was con- nM did not alter peristaltic motility. Con- sidered to be significant. The recordings were centrations between 5 and 25 nM led to a pigs were killed, all procedures for care were analyzed for a shift in the pressure threshold significant reduction of the threshold required for triggering a contraction. The ef- executed in accordance with national and in- with a maximal effect at 10 nM. Higher fects of different catecholamine concentra- ternational guidelines for the care and use of concentrations resulted in an increase in laboratory animals. tions on peristaltic frequency were analyzed by After cleaning, the ileum was first equili- measuring the distance between two consec- the threshold and a complete blockade of ␮ brated in Krebs-Henseleit solution (Table 1) utive contractions. peristalsis at 1 M. The frequency of peri- ϳ staltic contractions was reduced at all and bubbled with 95% oxygen/5% CO2 for 1 hr. In a second step, segments of ileum with a RESULTS concentrations tested. length of 6 cm were taken and mounted in a Dopamine. There was no effect on small volume (22 mL) tissue bath (Mayflower, We tested five different catecho- peristalsis with dopamine concentrations Hugo Sachs Electronics, Freiburg, Germany) lamines in at least six different concen- Ͻ75 nM. A concentration of 100 nM led in Krebs-Henseleit solution, which was bub- trations. Analysis of the concentration re- to a significant reduction of the thresh- bled with 95% oxygen/5% CO . The tempera- 2 sponse curves for pressure threshold old. Concentrations up to 5 ␮M resulted ture of the tissue bath was kept at 36.5°C, showed significant qualitative and quan- in a small increase of the threshold, whereas the pH of the Krebs-Henseleit solu- tion was kept between 7.35–7.45. titative differences in the action of the whereas higher concentrations led to a Peristaltic contractions of the mounted il- different catecholamines on peristalsis. pronounced increase in the threshold, eum segment were elicited by luminal perfu- As shown in Figure 2, all catecholamines which resulted in a complete block of sion with Krebs-Henseleit solution at a rate of had a concentration-related increase in peristalsis at 50 ␮M. The frequency of 0.35 mL/min using a REGLO-Digital MS-4/6– pressure thresholds, cumulating in a peristaltic contractions increased at do- 100 roller pump (Ismatec, Germany) against complete block of peristaltic activity. Epi- pamine concentrations between 10 and an aboral pressure of 5 cm H2O. The peristaltic nephrine was the most effective inhibitor 25 nM. Higher concentrations of the drug nature of the contractions was confirmed vi- of peristalsis; significantly lower concen- reduced peristaltic frequency. sually. Peristaltic contractions resulted in trations increased the pressure threshold Dobutamine. Dobutamine added to complete emptying of the segment. In total, as compared with the other cat- the tissue bath at concentrations Ͻ1 ␮M 70% to 80% of the ileum segments developed repetitive peristaltic contractions and could be echolamines. Dopexamine and dobut- did not influence peristaltic motility (Fig. used for our experiments. Segments that did amine were the least potent inhibitors; 3A). Concentrations between 1 and 10 not show regular contractions were discarded. higher concentrations were necessary to ␮M caused a significant reduction of the After a 15-min control period, the test drug show an effect on the pressure threshold. threshold. At bath concentrations of 15 to was added to the organ bath and a 15-min test The highest concentrations of each cate- 25 ␮M, the drug caused a moderate con- period was recorded. For each test drug and cholamine used in the study resulted in a centration-related increase in the thresh- test concentration, a new segment was used. block of peristalsis. The concentration old. A concentration of 30 ␮M dobut- Test Drugs. The drugs used in the study that led to this block of peristalsis was amine led to a marked rise in the were dobutamine (Dobutrex, Eli Lilly, India- significantly lower for epinephrine and threshold, and at 50 ␮M, a complete napolis, IN), dopamine (Dopamin, Fresenius, norepinephrine as compared with the block of peristalsis was seen (Fig. 3B, C). Austria), dopexamine (Dopacard, Fisons plc, Pharmaceutical Division, UK), epinephrine other catecholamines (Fig. 2). Figure 2 The peristaltic frequency was reduced by (Suprarenin, Hoechst, Austria), and norepi- also shows that all substances, except epi- dobutamine at all concentrations tested. nephrine (Arterenol, Hoechst, Austria). Each nephrine, caused a small, but significant, Dopexamine. Dopexamine concentra- test substance was first examined at a concen- reduction in the pressure threshold in tions up to 1 ␮M did not alter peristaltic tration of 1 nM. In the following experiments, their lower concentration ranges. motility. Concentrations between 1 ␮M the concentration was increased to evaluate Effects of Different Catecholamines. and 20 ␮M lowered the peristaltic pres- the effect of different catecholamine concen- Table 2 summarizes concentrations of sure threshold. At 30 ␮M, no change in trations on intestinal motility. The drugs were maximum threshold reduction, half- the threshold was found, whereas higher administered into the bath to the serosal sur- maximum catecholamine concentrations concentrations of the drug caused a face of the ileum, in volumes not exceeding and maximal inhibitory concentrations marked increase in the threshold, and 50 1% of the bath volume. ␮ Data Recording. Intraluminal pressure was (block of peristalsis). M dopexamine completely suppressed Ͻ measured at the oral end of the segment with Epinephrine. Concentrations 5nM peristalsis. All concentrations caused an a very low range differential pressure trans- did not change the peristaltic activity of initial increase in the peristaltic fre- ducer (Validyne DP 45-XX, Hugo Sachs Elec- the ileum segment. Higher concentra- quency, whereas after a few minutes a tronics) and an amplifier (2-channel bridge tions of epinephrine resulted in a concen- decrease of frequency was found.

2894 Crit Care Med 2000 Vol. 28, No. 8 Figure 2. Concentration response curves of the effect of different catecholamines on the pressure threshold of peristalsis. The effect of catecholamines on threshold is shown as the difference between thresholds before and after administration of the test substance (⌬threshold). Mean Ϯ SEM from six experiments performed at each concentration. Positive ⌬ threshold values represent inhibition of peristalsis and negative values represent stimulation of peristalsis. *significant values as compared with baseline.

Table 2. Relevant catecholamine concentrations

Maximum Half-Maximum Figure 1. Effects of epinephrine on peristalsis in Threshold Catecholamine Block of guinea pig ileum. The figures show original pres- Catecholamine Reduction Concentration Peristalsis sure recordings before and after administration (s) of epinephrine. Note the pressure threshold Epinephrine 0.065 0.1 (T) at which peristaltic contractions were elic- Norepinephrine 0.01 0.250 1 ited. At 25 nM, the peristaltic frequency was in- Dopamine 0.1 25 50 Dobutamine 10 39 50 creased. At 50 nM, the threshold increased mark- Dopexamine 20 40 50 edly and the frequency decreased. At 100 nM, peristalsis was completely blocked, an effect that All concentrations given in ␮M. was irreversible during the test period (15 mins).

other catecholamines on peristaltic mo- Another difference relates to the DISCUSSION tility have not been tested. The low inhib- steepness of the concentration-response ␤ itory potency of dobutamine ( 1-adreno- curves for peristaltic inhibition. The ␤ Our results demonstrate that cat- ceptor agonist) and dopexamine ( 2- curves for norepinephrine and dopamine echolamines that are currently used in adrenoceptor agonist and dopamine were flatter than those for the other critically ill patients because of their car- receptor agonist) is, however, consistent tested substances, which is likely to re- diovascular effects differ markedly in with the finding that ␣-adrenoceptor ago- flect the involvement of different recep- their inhibitory and stimulatory actions nists are more active in inhibiting acetyl- tors and/or mechanisms. on the peristaltic motility of guinea pig choline release from enteric neurons and There were also differences in the cat- ileum in vitro. Dobutamine and dopex- suppressing peristalsis than ␤-adrenocep- echolamine-induced changes of peristal- amine are ϳ500 times less potent in in- tor agonists (13, 17, 18). tic frequency. Epinephrine, dopamine, hibiting peristalsis than epinephrine, Other differences among the catecho- and dopexamine increased the frequency, which was the most active compound lamines concern the observation that at least at subinhibitory concentrations. among the catecholamines tested. The all substances, except epinephrine, de- The increase in pressure thresholds at rank order of inhibitory potency was as creased the peristaltic pressure threshold higher catecholamine concentrations was follows: epinephrine Ͼ norepinephrine Ͼ at low subinhibitory concentrations, associated with a reduction of frequency. dopamine Ͼ dobutamine ϳ dopexamine. which means that they facilitated peri- This was not evaluated further because The relative potency of epinephrine stalsis at this concentration range. The peristaltic frequency in vitro is a complex and norepinephrine corresponds with the relevance of this finding to propulsive variable dependent on infusion rate, in- potency reported by Mc Dougal and West motility in vivo remains to be deter- testinal compliance, peristaltic pressure (10). To our knowledge, the effects of the mined. threshold, and the efficiency of emptying.

Crit Care Med 2000 Vol. 28, No. 8 2895 Interpretation of frequency changes is the time that is needed for diffusion of therefore controversial (19). Further- the catecholamine to their receptors was obutamine and more, in contrast to changes in thresh- not a limiting factor of our preparation. dopexamine have olds, which were constant during the In addition, as shown in the Figures 1 whole observation period for each of the and 3, the catecholamine effect did not the least potential catecholamine concentrations tested, in- increase during the observation time, D fluences on peristaltic frequency were not which suggests that there was no diffu- to block peristalsis; at low constant. sion barrier which would have been over- The opposite effects of low and high come with time and which might possibly concentrations they even concentrations of four of the five tested have influenced the quantitative aspect of stimulate peristalsis. These catecholamines on motility are most the catecholamines. likely attributable to stimulation of dif- Although caution must be observed drugs appear to be superior to ferent receptors. Stimulation of different when our data from the guinea pig are receptors at different catecholamine dos- applied to intensive care patients, some other catecholamines with re- ages has been demonstrated for the effect comparisons may shed light on potential of dopamine on blood vessels. Low-dose clinical implications. Arterial plasma gard to their adverse effects dopamine (Յ3 ␮g/kg/min) has a vasodi- concentrations reach 23.9 nM in healthy on intestinal motility. latory effect because of a stimulation of volunteers after infusion of epinephrine receptors. Doses Ͼ5 ␮g/ at a rate of 0.2 ␮g⅐kgϪ1⅐minϪ1 (21). In kg/min cause a stimulation of ␣-recep- guinea pig ileum, comparable concentra- tors and a vasoconstriction. In the tions of epinephrine resulted in a stimu- present study, we have also observed lation of peristaltic frequency (Fig. 1A). dose-dependent switches of direct cate- There was no marked effect on the cholamine effects. Except in the case of threshold of peristalsis at this concentra- epinephrine, lower concentrations tion, but because the concentration- caused a reduction of the pressure response curve of epinephrine is very threshold, and therefore a stimulation of steep, only slightly higher concentrations intestinal contractility. already cause a considerable inhibition of The present observations concerning peristaltic contractility of the guinea pig the peristaltic pressure threshold indicate ileum (Fig. 2). Infusion of norepineph- that dobutamine and dopexamine have rine in humans at a rate of 0.2 ␮g⅐kgϪ1⅐ the least potential to block propulsive minϪ1 resulted in arterial plasma con- motility in the gut. This low potency in centrations up to 44.1 nM (21). In the suppressing intestinal propulsion favors guinea pig ileum, comparable concentra- the use of dobutamine and dopexamine in tions caused a marginal increase of the critically ill patients, although this rec- threshold. Because the concentration re- ommendation is only based on their ef- sponse curve of the effects of norepineph- fects on intestinal motility and does not rine on motility is flatter, the margin of take their effects on gut perfusion into safety for the therapeutic use of norepi- account. Milder disturbances of intestinal nephrine may be bigger as compared with motility are frequently seen in the inten- epinephrine. sive care setting. Serious abdominal com- Plasma concentrations of dobutamine plications are known to occur in 1.4% of at an infusion rate of 10 ␮g⅐kgϪ1⅐minϪ1 patients after and have a reach about 0.6 ␮M, and plasma concen- total mortality of 14.5% (20). Risk factors trations of dopexamine at an infusion rate for severe abdominal complications in of 4 ␮g⅐kgϪ1⅐minϪ1 reach 0.4 ␮M (22, cardiac surgery include advanced age, 23). As can be seen in Figure 2 these prolonged aortic cross-clamping time, concentrations have no effect on intesti- low cardiac output, and multiple organ nal motility. Higher concentrations failure. would stimulate motility, before at even In experimental studies of pharmaco- higher concentrations inhibition of mo- logic effects on intestinal motility, addi- tility would occur. From the point of ileal tion of a pharmacologic substance to the motility, our data therefore support the organ bath rather than through the mes- suggestion of Meier-Hellmann et al. (4) Figure 3. Effect of dobutamine on peristalsis in enteric vessels is commonly performed. and Levy et al. (1) that a combination of guinea pig isolated ileum. The figures show orig- Our data suggest that neither the timing norepinephrine and dobutamine may be inal pressure recordings before and after admin- nor quantitative aspects of the actions of preferable over an epinephrine mono- istration (s) of dobutamine. Note the pressure threshold (T). At 100 nM, there is no influence on catecholamines on the ileum are influ- therapy. This combination of drugs has peristaltic contractions. A concentration of 30 enced by a possible diffusion barrier. As also recently been suggested to be used in ␮M of dobutamine led to a marked increase in shown in Figures 1 and 3, the cat- septic patients, by the Task Force of the pressure thresholds, whereas at 50 ␮M, peristal- echolamines had an immediate effect on American College of Critical Care Medi- sis is completely blocked. peristaltic activity, which suggests that cine (24).

2896 Crit Care Med 2000 Vol. 28, No. 8 In conclusion, our in vitro study com- patients. In: Yearbook of Intensive Care stimulates and inhibits intestinal peristalsis pared the different effects of clinically and Emergency Medicine. Vincent JL (Ed). via distinct receptors. J Pharmacol Exp Ther used catecholamines on intestinal motil- Berlin, Springer-Verlag, 1997, pp 289–301 1995; 274:322–328 ity. We demonstrated that these cat- 7. Meier-Hellmann A, Sakka S, Reinhart K: As- 17. Holzer P, Lembeck F: Effect of neuropeptides echolamines differed profoundly in their pects in monitoring and treatment of gastro- on the efficiency of the peristaltic reflex. Naunyn Schmiedebergs Arch Pharmacol action on intestinal motility. Of the intestinal underperfusion in . Diagno- sis and therapy of gastrointestinal under- 1979; 307:257–264 tested substances, dobutamine and 18. Marcoli M, Lecchini S, De Ponti F, et al: dopexamine have the least potential to perfusion in sepsis. Anesthesiol Intensivmed Notfallmed Schmerzther 1998; 33 (Suppl 2): Subsensitivity of enteric cholinergic neu- block peristalsis; at low concentrations rones to ␣ -adrenoceptor agonists after 60–69 2 they even stimulate peristalsis. These chronic sympathetic denervation. Naunyn 8. Giraud GD, Mac Cannell KL: Decreased nu- drugs appear to be superior to other cat- Schmiedebergs Arch Pharmacol 1985; 329: trient blood flow during dopamine- and epi- 271–277 echolamines with regard to their adverse nephrine-induced intestinal vasodilatation. effects on intestinal motility. 19. Waterman SA, Tonini M, Costa M: The role of J Pharmacol Exp Ther 1984; 230:214–220 ascending excitatory and descending inhibi- 9. Carricio CJ, Meakins JL, Marshall JC, et al: tory pathways in peristalsis in the isolated Multiple-organ-failure syndrome. The gastro- guinea-pig small intestine. J Pharmacol intestinal tract: The “motor” of MOF. Arch REFERENCES 1994; 481:223–232 Surg 1986; 121:196–208 20. Simic O, Strathausen S, Geidel S, et al: Ab- 10. Mc Dougal MD, West GB: The inhibition of dominal complications after surgery 1. Levy B, Bollaert PE, Charpentier C, et al: the peristaltic reflex by sympathomimetic interventions. Zentralbl Chir 1997; 122: Comparison of norepinephrine and dobut- amines. Br J Pharmacol 1954; 9:131–137 893–897 amine to epinephrine for hemodynamics, 11. Doherty NS, Hancock AA: Role of alpha-2 21. Ensinger H, Weichel T, Lindner KH, et al: lactate metabolism, and gastric tonometric receptors in the control of diar- Relationship between arterial and peripheral variables in : A prospective ran- rhea and intestinal motility. J Pharmacol venous catecholamine plasma concentra- domized study. Intensive Care Med 1997; 23: Exp Ther 1983; 225:269–274 tions during infusion of noradrenaline and 282–287 12. Kazic T: Effect of adrenergic factors on in healthy volunteers. Eur J Clin 2. Leier CV: Regional blood flow responses to peristalsis and acetylcholine release. Eur Pharmacol 1992; 43:245–249 vasodilators and in congestive J Pharmacol 1971; 16:367–373 22. Leier CV, Unverferth DV, Kates RE: The . Am J Cardiol 1988; 62:86E–93E 13. Frigo GM, Lecchini S, Marcoli M, et al: relationship between plasma dobutamine 3. Bersten AD, Hersch M, Cheung H, et al: The concentrations and cardiovascular responses Changes in sensitivity to the inhibitory ef- effect of various sympathomimetics on re- in cardiac failure. Am J Med 1979; 66: fects of adrenergic agonists on intestinal mo- gional circulations in hyperdynamic sepsis. 238–242 tor activity after chronic sympathomimetic Surgery 1992; 112:549–561 23. Baker PR, Gardner JJ, Lockley WJS, et al: denervation. Naunyn Schmiedebergs Arch 4. Meier-Hellmann A, Reinhart K, Bredle DL, et Determination of dopexamine hydrochloride al: Epinephrine impairs splanchnic perfusion Pharmacol 1984; 325:145–152 in human blood by high-performance liquid in septic shock. Crit Care Med 1997; 25: 14. Paton WDM, Vizi ES: The inhibitory action of chromatography with electrochemical detec- 399–404 noradrenaline and adrenaline on acetylcho- tion. J Chromatogr B Biomed Appl 1995; 5. Meier-Hellmann A, Reinhart K: Effects of line output by guinea-pig ileum longitudinal 667:283–290 catecholamines on regional perfusion and muscle strip. Br J Pharmacol 1969; 35:10–28 24. Task Force of the American College of Crit- oxygenation in critically ill patients. Acta 15. Bu¨ lbring E, Crema A, Saxby OB: A method ical Care Medicine, Society of Critical Care Anaesthesiol Scand 1995; 107:239–248 for recording peristalsis in isolated intestine. Medicine: Practice parameters for hemody- 6. Martin C, Viviand X, Potie F: Use and misuse Br J Pharmacol 1958; 13:440–443 namic support of sepsis in adult patients in of catecholamines: Combination in septic 16. Holzer P, Scluet W, Maggi CA: Substance P sepsis. Crit Care Med 1999; 27:639–660

Crit Care Med 2000 Vol. 28, No. 8 2897