Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on gastric mucosa in septic shock.
CCM 1999 27.5 893-0.
n=12. Prospective controlled randomised crossover. epinephrine | norepinephrine | norepinephrine + dobutamine in random order. Target MAP of 70-80 mmHg.
Laser-Doppler probe for mucosal flow; gastric tonometry (pHi and gastro-arterial pCO2);
Both epinephrine (on its own) and norepinephrine + dobutamine increased gastric mucosal flow over norepinephrine alone. The ratio of gastric mucosal perfusion to systemic oxygen delivery was higher with norepinephrine + dobutamine than with Epi. There was no significant difference for pHi or gastro-arterial pH gradient between the different regimens. Note that in all groups, MAP was 74mmHg ?! NO BASELINE measurements are shown. Were the patients passing urine well?
References cited for 'gut motor of mods' are Fiddian-Green (CCM 1993 21S S103-7), Fink (CCM 1991 19 627-41) and Gutierrez (Lancet 1992 339 195-9). Cite Meier-HellmannM (CCM 1997 25 399-4) re merits of norepinephrine + dobutamine; and Neviere (AJRCCM 1996 154 1684-8) re alleged benefits of dobutamine on gastric perfusion. See also Gutierrez &c (AJRCCM 1994 150 324-9). A good reference for the effect of beta stimulation on mucosal blood flow is Shepherd &c (AJP 1984 247 G377-4).
Their discussion attributing higher gastric perfusion with epinephrine due to "greater improvement in CI" is incoherent.
A dobutamine test can disclose hepatosplanchnic hypoperfusion in
septic patients
AJRCCM 1999 160 839-5.
n=36, non-randomised, 'own controls'. 28M 8F. Patients were on dopamine
mean 6.6 µg/kg/min. PAC. PAc, gastric tonometry. {How was BSA calculated?}.
Hepatosplanchnic blood flow (HSBF) by ICG infusion. Monitoring of suprahepatic SvO2
(difference between this and mixed venous sat labelled 'DSvhO2').
With dobutamine 5 and 10 µ/kg/min, CI increased from 3.2 to 4.1 to 4.6 l/min/m 2 ;
HSBF from 0.59 to 0.77 to 0.82; and PCO2gap dropped from 10.8 to 7.0 to 7.4;
A decrease in PCO2gap over 5mmHg at 10µg/kg/min was considered positive
(n=12); if positive then DSvhO2 was greater (27% vs 9%) and HSBF/CI was
< 20%. Positive dobutamine test predicted DSvhO2 above 20% with sensitivity
of 83%, specificity 96%. {they do many sub-analyses}.
Quote
Fink (CCM 1991 19 627-41) and
Mythen (ICM 1994 20 203-9) to
support 'gut motor' hypothesis for sepsis. Quote Gutierrez (AJRCCM 1994 150 324-9),
Marik (Chest 1993 104 225-9) and Maynard &c (JAMA 1993 270 1203-0) to
support regional hypoperfusion in presence of adequate global haemodynamics.
Use of pHi monitoring to guide therapy (
Gutierrez Lancet 1992 339 195-9).
Quote
Levy (ICM 1997 23 282-7) that epinephrine decreases splanchnic perfusion.
How did the patients do?
Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock Int Care Med 1999 25 942-8.
n=24. Prospective randomised intervention. Shock, 'optimal' volume resuscitation, norepinephrine given to a MAP of 75mmHg {where does this recurring number originate?} and CI over 3.5 l/min/m 2 {how was BSA estimated?}, randomised to dobutamine 5µg/kg/min or dopexamine 1µg/kg/min.
No significant effect on MAP, DO2 or CI. There was no significant effect of either dobutamine or dopexamine on the gastric PCO2 gap. MAP was around 79-84 at various times in the various groups (mean), CI around 5 l/min/m 2 .
Refs 3..7 ( Silverman Chest 1992 102 184-8; Gutierrez AJRCCM 1994 150 324-9; Maynard Chest 1995 108 1648-4; Smithies CCM 1994 22 789-5; Neviere ARJCCM 1996 154 1684-8) are invoked to support use of beta agonists. Of interest: 'less thermogenic effect of dobutamine with stress' ( Uusaro CCM 1995 23 674-0); value of dobutamine and dopexamine for renal function (Duke CCM 1994 22 1919-5; Juste ICM 1998 24 564-8) A PCO2 gap over 25mmHg is said to be incompatible with aerobic gastric mucosal metabolism ( Schlichtig JAP 1994 76 2443-1). There is some (poor) correlation between decreased pHi and gastric mucosal perfusion, r=0.53 (Elizalde CCM 1998 26 827-2). Intramucosal oxygenation (HbiO2) may increase in response to dopexamine without a change in PCO2 gap (Temmesfeld-Wollbruck ICM 1997 23 423-7).
There are no controls given neither dobutamine or dopexamine.
Is it time to abandon the pHi concept?
Int J Int Care 1998 16-21. ('Spring' : ? Vol number)
Review
Cites Russell (ICM 1997 23 3-6) on questionable validity of pHi, as well as Boyd (Lancet 1993 341 142-6) and Benjamin (Crit Care Clin 1996 12 587-01;
CCM 1993 21S S257); see also Benjamin (CCM 1992 20 1181-3).
A good review of how pHi is meant to work {of course completely ignoring
the Stewart approach to acid-base}.
Studies relating pHi to survival include Gutierrez (Lancet 1992 339
195-9; CCM 1992 20 451-7),
Doglio (CCM 1991 19 1037-0), Ensinger (Anasthesiol Intensivmed
Notfallmed Schmerzther 1996 31 132-2),
Chang (Arch Surg 1996 131 728-1;
J Trauma 1997 42 577-4); See also Chang (J Trauma 1994 37 488-4) and Joynt (Anaesthesia 1997 52 726-2). Cites Meier-Hellman (CCM 1997 25 399-3)
and Levy (ICM 1997 23 282-7) on epinephrine v norepinephrine + dobutamine.
Notes the contrasting studies of Meier-Hellman (ICM 1996 22 1354-9) and
Ljunghdi (Shock 1997 7 131-8) that show lack of correlation between intestinal
blood flow and pHi or intestinal lactate production. Much speculation.
Dobutamine antagonizes epinephrine's biochemical and cardiotonic effects
Anesthesiology 1998 89 49-7.
Two sections. (i) n=10 healthy volunteers: lymphocyte cAMP response to graded concentrations of Epi, dobutamine or a combination of the two. Concentrations ranged from epinephrine 10 -9 to 10 -5 , and dobutamine 10 -8 to 10 -4 . (ii) n=8 patients undergoing elective aortocoronary bypass surgery with normal pre-operative left-ventricular function were given epinephrine 10, 20 and 40 ng/kg/min, and/or dobutamine 1.25, 2.5 and µg/kg/min.
Dobutamine caused a 40% increase in cAMP, epinephrine a 200% increase, and dobutamine antagonised the effect of Epi.
Isobolographic analysis (at a 10% increase in CI) showed that in the patients dobutamine antagonised the positive effect of adrenaline on cardiac index.
Despite the small sample size, this elegant study strongly suggests that dobutamine is a partial agonist at the beta-2 receptor, being ten times less potent than epinephrine. In the clinical section of the study, higher doses of dopamine combined with low-dose epinephrine had no more effect (presumably beta-1 + beta-2) on CI than lower doses. The authors provide a good discussion of the limitations of the study.
In the presence of adrenaline, dobutamine appears to add nothing in terms of either beta-1 or beta-2 stimulation.
The impact of antioxidant and splanchnic-directed therapy on persistent uncorrected gastric mucosal pH in the critically injured trauma patient.
J Trauma 1998 44.2 355-0
Historical controls n=7 versus 13 patients with haemodynamic instability and acidosis and persistently low pHi who received folate, mannitol and low-dose isoprenaline (isoproterenol).
Two of the controls and one of the 'splanchnic resuscitation' group died.
Quote Deitch (CCM 1993 4 131), Marshall (Am Surg 1993 218 111), Xu (CCM 1995 23 125), Moore (J Trauma 1994 37 881) &c in support of 'gut motor' hypothesis for MODS; and Marik (Chest 1993 104 225), Doglio (CCM 1991 19 1037), Maynard (JAMA 1993 270 1203), Ivatury (J Trauma 1995 39 128) and Kirton (Chest 1995 108S 104S) that failure of pHi correction correlates with poor outcome.
Failure of splanchnic resuscitation in the acutely injured trauma patient correlates with multiple organ system failure and length of stay in ICU
Chest 1998 113 1064-9.
n=19 consecutive critically ill trauma patients with systemic hypoperfusion (low pHa, high base deficit or lactate) - a small select subgroup; ; blinded pHi monitoring ; PAC; Hb kept >= 11g/dl; ANOVA; Fisher; Student;
If pHi was under 7.32 5/10 died; 1/9 of those with pHi >= 7.32 died (p = 0.07). If pHi was similarly low, 6/10 developed MOSF compared with 1/9.
"There is convincing evidence that systemic hemodynamic and oxygen transport variables fail to portray accurately the complex interaction between energy requirements and the energy supply at a tissue level [3-5], and that achieving supranormal cardiovascular oxygen transport and utilization indexes does not reliably confer improved outcome [6-9]"
Similar studies by Doglio (CCM 1991 19 1037-0) and Maynard (JAMA 1993 270 1203-0).
{In this small study 24 hour pHi attained significance. It is unfortunate that pHi at 6 hr and 72hr didn't. Might this have been chance?}
Neither dopamine nor dobutamine corrects mesenteric blood flow depression caused by positive end-expiratory pressure in a rat model of acute lung injury.
CCM 1998 26.11 1875-0.
n=?; Male rats; their ALI model was not convincing;
Stress the 'negative effect of PEEP'. {This is simplistic}. In rats PEEP selectively lowers splanchnic perfusion;
Note that (-) dobutamine is alpha agonist (+) is antagonist and also has beta effect (quote Goodman &c 'Pharmacological Basis of Therapeutics' 1990).
Table 1 confused me {presumably e.g. the Control / 20 PEEP didn't actually get any PEEP!}. How did they know that 'volume resuscitation' was sufficient?
Does hepato-splanchnic VO2/DO2 dependency exist in critically ill septic patients?
AJRCCM 1998 157 1219-25
n=42 patients with severe sepsis; ICG clearance; found DO2spla vs VO2spla in response to dobutamine infusion; Subgroup n=14 PEEP increased to 20cmH2O; M:F = 31:11; added dopamine n=23, norepinephrine n=3. One way ANOVA with Newman-Keuls. Linear regression for VO2/DO2 relationships; slopes then correlated with various parameters (+ Bonferroni). Post hoc separation into subgroups..
MAP was in range 75 +- 12 to 86 +- 18 (+- SD); CI increased from 3.13 / 3.31 to 4.62 with 10µg/kg/min of dobutamine; DO2 374 / 415 to 542 / 577; VO2 97 / 122 to 113 / 135; VO2spla 38 +- 37 / 45 +- 22 to 41 +- 44 / 59 +- 39; SvO2 70 / 66 to 74 / 71; and ShO2 68 +- 8 / 43 +- 14 to 72 +- 7 to 49 +- 15.
Basal hepatosplanchnic blood flow (HSBF) was 877 +- 859 ml/min/m 2 {One worries about an HSBF of 4.7 litres/min/m 2 , their maximum value ?!}. The authors dwell extensively on the slope of the change in VO2/DO2 ratios. {Presumably if patient A has a VO2/DO2 of 0.3 and after dobutamine infusion this changes to 0.4, the slope is (0.4 - 0.3)/0.3 ie the ratio has increased by 33%}. They first look at the systemic effect of dobutamine and determine a VO2/DO2 slope of 7.3 +- 8.8% {note the vast SD}. They note that the "increase in hepato-splanchnic blood flow was not dose-related for the whole group since a large interindividual variation was observed" and then go on to tedious manipulations involving slopes. These manipulations appear to have been decided upon sometime during the course of the study, as they then look at the effects of PEEP in 14 patients, and conclude based on the similarity of the slopes attributable to dobutamine and PEEP, that the covariance between dobutamine-induced VO2 and splanchnic DO2 is not due to a metabolic effect of the dobutamine.
Invoke Landow (Act An Sc 1994 38 626-39), Mythen (ICM 1994 20 203-9) and Fong (JCI 1990 85 1896-4) to support 'MOF motor'. Increased splanchnic O2 extraction in sepsis supported by Dahn (ICM 1988 14 373-8), Dahn (Surg 1987 101 69-80), Steffes (Arc Sur 1994 129 46-2), Reinelt (Anesthesiol 1997 86 818-4), Ruokonen (CCM 1991 19 1365-9) &c but the authors acknowledge that blood flow may be more important than O2 extraction. 'Limited thermogenic effect of dobutamine in the critically ill' supported by his work De Backer(ARRD 1994 150 95-0; CCM 1993 21 1658-4).
Randomized, prospective comparison of increased preload versus inotropes in the resuscitation of trauma patients: effects on cardiopulmonary function and visceral perfusion.
J Trauma 1998 44.1 ??_pp.
n=39 consecutive trauma patients carefully selected: low right ventricular ejection fraction (< 40%); 33 excluded before randomisation; pHi determined;
Patients were volume resuscitated to an RVED index of over 90ml/m 2 , and then if RVEF was low and systemic perfusion was inadequate, randomised to either more fluid (to an RVEDI of 120) or inotropes. Selection of inotropes was complex (dopamine +- epinephrine if MAP under 70mmHg) otherwise dobutamine. A resuscitation algorithm is given.
pHi was better in the fluid group than in the inotrope group. Subgroup analysis suggested that 'dopamine or epinephrine' lowered pHi but dobutamine (n=12) did not, but note that "dobutamine was begun in five other patients but because of persistent hypotension, it was changed to dopamine in three patients and epinephrine in two" which more or less blows this sub-analysis out of the water.
Of interest is the similar incidence of 'ARDS' and similar PaO2/FiO2 values in the two groups.
An intensivist's dilemma: support of the splanchnic circulation in critical illness.
CCM 1998 26.10 1637-8.
Editorial
Talks about the 'gut motor' referring to Fine (NEJM 1959 260 214-0; JExpMed 1960 112 793-0), and Dantzker (JAMA 1993 270 1247-8). Mentions the controversy over the value of pHi ( Fiddian-Green CCM 1993 21S s25-1; Gutierrez Lancet 1992 339 195-9; vs Boyd Lancet 1993 341 142-6). Refers to current review by Silva (p 1749). Notes Silva's conclusion that no definitve recommendations can be made, and that "gut-directed vasoactive support is largely ineffective", with reservations. Also comment on the possible unreliability of pHi compared with (say) pCO2 gradient. A brief and suitably vague editorial.
Effects of vasoactive drugs on gastric intramucosal pH.
CCM 1998 26 1749-8.
Review of literature from Medline 1980-97, and follow-ons.
Quotes Landow (CCM 1993 21 S84-1), Dantzker (CCM 1993 21 S40-3) and Fiddian-Green (CCM 1993 21 S25-1) in support of the hypothesis that patients who 'appear adequately resuscitated' may still have splanchnic ischaemia, invoking shunting of blood from the gastrointestinal tract {unreferenced} and the mucosal countercurrent mechanism to explain this ( Kamp Acta Phys Scand 1968 72 396-3). Low pHi and poor prognosis referenced (Friedman CCM 1995 23 1184-3; Maynard JAMA 1993 270 1203-0; Marik Clest 1993 104 225-9; Gutierrez Lancet 1992 339 195-9). See Schlichtig re supply dependency and pHi (JAP 1994 76 572-7). See also Vallet re high lactate output despite perfusion (JAP 1994 76 793-0) and Salzman (AJP 1994 266 G633-46) on non-haemodynamic toxicity of endotoxin.
This review examines both adrenergic and non-adrenergic agents. In respect of dobutamine which they regard as the 'agent of reference to improve myocardial function', they quote Sakio as a reference that dobutamine increases splanchnic blood flow, (Masui 1994 43 1304-9) but this was in dogs after mesenteric artery clamping; De Backer (ARRD 1994 149 A19) is referenced concerning endotoxic dogs, and Fink (Surgery 1991 110 154-61) is invoked to support the alleged superiority of dobutamine over hetastarch. Schmidt's work on rats supports the use of dobutamine to preserve villous blood flow; Neviere supports 'beneficial' effect of dobutamine + saline. See also Parviainen (BJA 1995 74 277-82).
Studies on septic humans are those of Meier-Hellmann (ref 22), Duranteau (AJRCCM 1996 153 A832), and De Backer (AJRCCM 1996 153 A125).
Effects on pHi were studied by Gutierrez (AJRCCM 1994 150 324-9), and Silverman (Chest 1992 102 184-8), and also Levy (ICM 1997 23 282-7), Creteur (ICM 1996 22 S310), Esen (Clin Int Care 1996 7 180-9), and Neviere (AJRCCM 1996 154 1684-8). In contrast Reinelt showed no improvement in pHi with pancreatitis and dobutamine (ICM 1996 22 S75).
Of note is that this review ignores literature that suggests liver injury associated with dobutamine infusion. In our opinion, a large but pedestrian review.
Inotropes and gut mucosal perfusion: a brake on the motor of multiple organ failure?
CCM 1997 25.8 1266-7.
Editorial
Notes adverse prognosis associated with low pHi ( Doglio CCM 1991 19 1037-0) Gutierrez Lancet 1992 339 195-9). Comment on Neviere p 1371 - speculate (but don't recommend) that maintenance of gut perfusion and pH might be used as end-points for inotrope administration in 'sepsis and other critical illnesses'.
Dobutamine improves gastrointestinal mucosal blood flow in a porcine model of endotoxic shock.
CCM 1997 25.8 1371-7.
n=12 pigs 30kg; saline resuscitation (0.3ml/kg/min) compared with saline and dobutamine 5µg/kg/min. Pigs were paralyzed, given ~1mg of midazolam per hour, and then had neck vessel cutdowns and laparotomies. No opiates were given. PAC; tonometry; laser doppler flow probe;
After 3 hr MAP went from 114 / 125 (control v dobutrex) to 77 / 75 mmHg; CO 100 / 102 to 97 / 125; SVR 1300 / 1200 to 900 / 800 dyn.s.cm -5 m -2 ; Gastric and ileal intramucosal pH and blood flow were lower in the controls than with dobutamine. The authors allege that pulmonary artery occlusion pressure and central venous pressure were maintained at their baseline values {which are not provided}.
Invoke Cain (Circ Shock 1992 38 173-81) for mucosal benefits of beta agonism; contrast their results with Revelly (CCM 1996 24 1345-1) who showed a substantial increase in mucosal flow in endotoxic shock. {Conclusion: in inadequately resuscitated hypotensive pigs, dobutamine may ameliorate gut mucosal hypoperfusion}.
.
Epinephrine impairs splanchnic perfusion in septic shock.
CCM 1997 25.3 399-4.
n=8 patients with septic shock; crossover: epinephrine vs dobutamine + norEpi;
no paralysis; PAC; ICG; Hb kept to 11g/dl; fluid optimised (HES) to LV stroke
work (!); Paired data compared using nonparametric Wilcoxon rank-sign.
5/8 died. MAP 89 +- 12 / 86 +- 14 (dobut+norepinephrine / Epi); PAOP 17 / 18;
CI 5.9 / 5.9; SVR 552 / 561; DO2 and VO2 were also similar;
Splanchnic blood flow was 2.8 +- 1.4 l/min/m 2 for Dobut+norepinephrine v
1.6 +- 0.6 for Epi! Splanchnic DO2 and VO2 were lower in the epinephrine group.
Lactate levels were higher and pHi was lower in the epinephrine group.
Note that Mackenzie &c (ICM 1991 17 36-9) support use of adrenaline;
likewise Moran (CCM 1993 21 70-7). Contrast this with lowered splanchnic
flow in normal sheep (
Bersten CCM 1994 22 994-1) and visceral blood pooling
(ref 10) induced by adrenaline;
Breslow (AJP 1987 252 H291-0) supports
similar effects in pig sepsis. Splanchnic flow is up in human sepsis
according to Fong (JCI 1990 85 1896-4) but demand is said to be even
greater (Dahn Surg 1987 101 69-80).
See also animal studies summarised by Kvietys (AJP 1982 243 G1-9), and note Antonsson (AJP 1990 259 G519-3) on correlation between pHi and
needle electrode.
See Nelson (JAP 1988 64 2410-9) and Cain (ref 35) in support of
both global and regional supply dependency in sepsis.
The major problem with this apparently well-designed and well-argued
study is its tiny size . In addition, the high lactate levels
seen with adrenaline infusion are not necessarily harmful.
Optimizing gastric mucosal perfusion: all catecholamines may not be created equal.
CCM 1997 25.10 1624-5.
Editorial
Supports PCO2 gap over pHi. Mentions Rudis' review (CCM 1996 24 525-37) of vasopressors and inotropes in sepsis, but main focus is Levy's look at dobutamine in gastric mucosal perfusion (CCM 1997 25 1649-4). Refers to studies of dopamine on splanchnic flow, and dopexamine, and notes studies showing lower splanchnic perfusion with epinephrine ( Meier-Hellman Act Anae Scand 1995 39 S107 239-8 {n=3}; Meier-Hellmann Adv Exp Med Biol 1994 345 701-7; Levy ICM 1997 23 282-7; Meier-Hellmann CCM 1997 25 399-4). Preferential redistribution towards the stomach by norepinephrine was shown by Marik (JAMA 1994 272 1354-7). Quotes Gutierrez (AJRCCM 1994 150 324-9) and Silverman (Chest 1992 102 184-8) in support of dobutamine improving gastric perfusion. The authors appear to like Levy's study.
Dobutamine improves the adequacy of gastric mucosal perfusion in epinephrine-treated septic shock
CCM 1997 25 1649-4.
n=20 consecutive patients with hyperdynamic septic shock; nonrandomised, no cross-over, no controls, unblinded. PAC, tonometry. Volume resuscitation to maximum CI or lowering of SaO2; epinephrine titrated to MAP > 75mmHg. {No explanation why 75 chosen}. Dobutamine 5µg/kg/min. Difference between two arbitrary groups based on PCO2 gap.
Epinephrine dose 0.7 +- 0.10 µg/kg/min; 9/20 died; In the seven patients with an increased PCO2 gap, pHi significantly decreased after the dobutamine was stopped at 2 hours. References Silverman (Chest 1992 102 184-8), Gutierrez (AJRCCM 1994 150 324-9), Maynard (Chest 1995 108 1648-4), Smithies (CCM 1994 22 789) and Neviere (AJRCCM 1996 154 1684-8) as support for use of beta agonists to improve splanchnic oxygenation.
Dobutamine and the oxygen uptake/supply relationship in sepsis: from global to regional - nothing is simple and easy
Int Care Med 1997 23 715-7
Editorial
Refers to prognostic value of dobutamine test (Vallet &c CCM 1995 23 415-6). {My interpretation: if you can still run away when I beat you with a big stick you'll do better} and challenges invoking mathematical coupling ( Phang AJRCCM 1994 150 318-3). Refers Ruokonen p732. Normal splanchnic flow (Qspl) and VO2spl are 0.75l/min/m 2 and 40ml/min/m 2 . Ruokonen found increased Qspl, and VO2spl, with increased O2 extraction as also found by Gump (Ann Surg 1970 171 321-8) and Wilmore (Ann Surg 1980 192 491-504). Note that in some patients Qspl decreased with dobutamine, which may worsen splanchnic O2 balance.
The effect of dobutamine infusion on splanchnic blood flow and oxygen transport in patients with acute pancreatitis
Int Care Med 1997 23 732-7
n=10 pancreatitis mainly due to alcohol; n=11 controls for elective abdominal surgery; convenience sampling; male;
Fluid resuscitation to baseline, then CI up 25(+)% with dobutamine (3 - 10 µg/kg/min) and remeasured. regional flow ICG; VO2 by Deltatrac indirect calorimetry; CO by thermodilution; No mention how surface area was estimated;
5/10 died; CI up from 3.9 (before dobutamine) to 4.9 (after dobutamine). VO2 up 10% on a DO2 up 29%. Splanchnic blood flow did not change overall in response to dobutamine with an increase in 5 and a decrease in 5. Fractional splanchnic flow decreased markedly in five patients. Note that in controls baseline MAP was 110; in patients baseline MAP was 88, increasing to 99 during dobutamine.
Commentary is insightful and appropriate.
n=79 critically ill trauma patients.
If pHi was >= 7.32 then 4/45 died, versus 11/34 with low pHi. Right ventricular end diastolic volume index was higher in those with normal pHi, at start and later. {What other measures of systemic acidosis were done?}
[abs]
n=18 patients with severe sepsis had monitoring of blood lactate and pHi over 5 days.
Lactate but not pHi distinguished survivors from non-survivors over time. "It is likely, based on the inability of gastric intramucosal pH to distinguish survivors from nonsurvivors until 48 h, that it is not possible to use this measurement to guide resuscitation in patients who are severely ill and who have gastric intramucosal acidosis. "
[abs, get]
Effects of a dobutamine-induced increase in splanchnic blood flow on hepatic metabolic activity in patients with septic shock.
Anesthesiol 1997 86.4 818-4.
Hypothesis 'dobutamine-induced increase in Qspl and DO2spl leads to increasd VO2spl associated with accelerated hepatic glucose production (HGP) in patients with septic shock'.
n=12; septic shock; Stabilized to MAP >= 70mmHg with fluid & norepinephrine over 24-36 hr; Then dobutamine to get CI up 20%. ICG; hepatic glucose production measured.
Qspl matched CI increase; no effect on VO2spl; HGP decreased. No delivery dependent VO2spl! They argue against Steffes CP (Arch Surg 1994 129 46-2). 'Effect of dopamine on splanchnic bed is non-preferential', quote Parviainen &c (BJA 1995 74 277-2) and Uusaro (ICM 1996 22 26-3) also Kainuma (Anesthesiol 1992 77 432-8);
Reasonable self-criticism. No controls, follow-up after dobutamine stopped, or outcomes!
The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients
AJRCCM 1996 154 1684-8
n=10 septic patients, selected to be off inotropes, had PAC, pHi and Doppler flowmetry of gastric mucosa at one site (1 mm 3 ), before and after dobutamine or dopamine 5µg/kg/min. Six ventilated controls (with [?] peptic ulcer disease). Albumin was infused to maintain PCWP. H2 blockers were given, justified by Fiddian-Green (1995 74 591-06) and Heard (CCM 1991 19 271-4).
MAP was 67 +- 12 at baseline, CI was high. Half the patients died. Urine output is not mentioned. Gastric mucosal blood flow and pHi increased, and pCO2 gap decreased after dobutamine with an opposite response to dopamine. Under half of the variation in intramucosal PCO2 gap was attributable to variation in mucosal blood flow.
Invoke Deitch (Arc Surg 1990 125 403-5) to support 'gut motor' hypothesis. Quote Gutierrez (AJRCCM 1994 150 324-9) on dobutamine's positive effect on pHi.
Dobutamine appears to increase mucosal perfusion and lower pCO2 gap in highly selected heterogeneous group of hypotensive patients with a subsequent poor outcome.
Dobutamine increases oxygen consumption during constant flow cardiopulmonary bypass
BJA 1996 76 5-8.
n=20 patients on CPB @ temperature 34C. (n=7 studied using laser Doppler flowmetry). Two interventions (i) up flow from 2.4 to 3.0 l/min/m 2 ; (ii) dobutamine 6µg/kg/min; Paired t-tests corrected for multiple comparisons {?}. Nonrandomised (for reasons explained).
VO2 did not increase with increased flow, but was up 11% with dobutamine infusion. "increases in VO2 during dobutamine may be flow- independent". Dobutamine failed to increase gastric microcirculatory blood flow (n=7).
Quote others who show catecholamines increase metabolic rate: (Blaak &c AJP 1993 264 E11-7; Ruttimann &c AJP 1989 257 E641-6; Abdul-Rasool &c CCM 1987 15 1044-0; Bhatt BJA 1992 69 298-3). {Good idea; well constructed & executed; the VO2 numbers don't look that impressive despite the statistical significance; changes in O2 saturation seem more impressive}.
Splanchnic oxygen transport after cardiac surgery: evidence for inadequate tissue perfusion after stabilization of hemodynamics
Int Care Med 1996 22 26-33
n=16; nonrandomised; no cross-over; intragroup Wilcoxon matched pair; intergroup ANOVA ('one dependent variable, grouping factor, one within-subject factor')
dobutamine 6µg/kg/min in n=10; indirect calorimetry (FiO2 < 0.6) & indocyanine green {ICG} & pHi by gastric tonometry.
CI up 3.2 to 4.4 {?SEM/SD} splanchnic blood flow up 0.68 to 0.91 (p < 0.05), femoral blood flow up 0.25 to 0.32 (p < 0.05).
pHi did not change in response to dobutamine, but trended slightly down in the 6 controls. O2 consumption increased with dobutamine. Changes in oxygen consumption and delivery parallelled one another. All patients bar one recovered uneventfully.
The authors make all sorts of unreasonable deductions from the above. They assume that the dobutamine is not increasing thermogenesis in the splanchnic bed. {Lots of use of "presumably", "suggesting", "is possible", "if one assumes", "may have been", "the tendency .. probably", ..} They don't stress that heart rate in the dobutamine group increased from 87 to 111 (p < 0.01). Is this good for a sick heart?
Regional effects of dobutamine in endotoxic shock
J Surg Res 1996 65 93-0
n=21 large dogs were anaesthetised and subject to endotoxin administration (2mg/kg) with fluid resuscitation & PAC, indirect calorimetry, regional (electromagnetic flow probe) blood flow determination, and gut tonometry. They were then randomised to control or dobutamine 5 or 10 µg/kg/min. {How was BSA calculated?}
Fluid resuscitation markedly improved CI (57 to 258 ml/kg/min, wide SD) with a further increase on dobutamine; DO2 followed this as did VO2, and mesenteric DO2. Mesenteric VO2 was unchanged, but pHi decreased in controls but not in the dobutamine groups. Renal DO2 and VO2 increased similarly in all groups but more urine was obtained in the dobutamine- treated groups. There was no significant difference in the effects of the two dobutamine infusion rates.
Mention various studies that showed mesenteric blood flow in septic shock to be down ( Gavin Surg 1994 115 310; Van Lambalgen J Crit Care 1991 6 61; Arvidsson Surg 1991 109 190; Barefield JAP 1992 72 272; Cain CCM 1991 19 1552; Fink CCM 1995 17 641), unchanged ( Breslow AJP 1987 252 H291) or up ( Lang AJP 1984 246 R331; Fink Surg 1991 110 154; Vallet JAP 1994 76 793). Refer to increased pHi with dobutamine ( Silverman Chest 1992 102 184; Gutierrez AJRCCM 1994 150 324), and studies in cardiac patients showing reduced ( Leier Circ 1978 58 466) or increased splanchnic blood flow (Ruokonen CCM 1993 21 1304).
A reasonably well-performed study.
Splanchnic blood flow is greater in septic shock treated with norepinephrine than in severe sepsis [sic]
ICM 1996 22 1354-9.
n=15 patients with 'septic shock' (MAP under 70 after fluid resuscitation), convenience-sampled and managed with norepinephrine were compared with n=13 patients who had 'severe sepsis' (but no 'septic shock') and were not managed with norepinephrine. No baseline values are reported for the septic shock group prior to starting norepinephrine.
13/28 patients died, 7/15 with 'septic shock', and 6/13 with 'severe sepsis'. Haemodynamics and oxygen transport and pHi were no different, comparing the two groups. Splanchnic blood flow in the shocked patients was nearly twice that in the severe sepsis group (2.2 v 1.3 l/min/m 2 ), but splanchnic PCO2 difference was similar in both groups, and normal, despite an abnormally low pHi.
Quote Fong(JCI 1990 85 1896-4) and Ruokonen (CCM 1993 21 1296-3) that splanchnic blood flow is up, and Giraud (J Ph Exp Ther 1984 230 214-0) and Nelson (JAP 1988 64 2410-9) that blood flow may be maldistributed and oxygen demand up in the splanchnic circulation. See also Imamura (Surg Gynecol Obstet 1975 141 27-4). See Van der Meer (CCM 1995 23 1217-26) who showed that despite normal mucosal oxygenation endotoxaemia causes ileal mucosal acidosis, and Lang (AJP 1984 246R 331-7) who showed good small bowel perfusion in the face of gastric hypoperfusion!
To me one merit of this study is that it shows that despite norepinephrine infusion, splanchnic blood flow was vastly greater in the 'sicker' patients (But note that a similar proportion died in both groups).
This is an assessment of right ventricular end diastolic volume index as a method of preload assessment in trauma patients!
{???}
[abs]
Effects of increased regional blood flow on splanchnic metabolism
ICM 1996 22 S75
n=12 patients with pancreatitis and hyperdynamic septic shock on norepinephrine to keep MAP over 70 mmHg. Dobutamine titrated to CI increase of 20%; ICG used to determine splanchnic flow, and hepatic glucose production (HGP) determined.
Increased splanchnic blood flow paralleled increasing CI; pHi was unchanged as was regional O2 uptake, and HGP dropped 30%. Despite the lack of controls they attribute the drop in HGP to the dobutamine and say that this is good.
Prognostic value of gastric mucosal PCO2 in septic patients
ICM 1996 22 S310 {#757}
A tiny article on continuous recirculation of air through a tonometer balloon to watch PrCO2 (gastric mucosal PCO2) in 12 stable septic patients at baseline, dobutamine infusion 5 and then 10 µg/kg/min, and then after discontinuation. 1/7 died if there was a drop in PCO2 gap after dobutmine, vs 4/5 if there wasn't.
Differential effects of dobutamine, dopamine, and noradrenaline on splanchnic haemodynamics and oxygenation in the pig.
Act anae Scand 1995 39 1088-96.
n = 9 healthy pigs were given dopamine 15 µg/kg/min, dobutamine 13 µg/kg/min and noradrenaline 0.4 µg/kg/min in random order, and flow measured using electromagnetic flow probes around hepatic artery, portal vein and SMA. PACs were inserted.
Dobutamine increased heart rate by 60% and dropped SVR by 50%. All catecholamines increased cardiac output. Dopamine increased small intestinal and hepatic blood flow, which where unchanged with dobutamine and decreased (with increased hepatic oxygen extraction) during noradrenaline infusion. In all cases small intestinal and total hepatic oxygen uptake was unchanged .
Reference Kainuma (Anesthesiol 1992 77 432-8) on the effect of dobutamine on liver blood flow during enflurane N2O anaesthesia, and give many references to the controversy about the effect of dopamine on splanchnic and liver blood flow.
This study appears well-constructed, and the authors' comments on its limitations appear appropriate. They speculate that dopamine might be good for improving splanchnic oxygenation.
.
[Document not found on PubMed]!
n=25 patients, 10 received dopamine, 10 dopexamine, 5 controls. pHi, hepatic metabolism of lignocaine to monoethylglycinexy-lidide (MEGX), and ICG measured.
Dopexamine improved pHi, ICG clearance, MEGX formation. This was not seen with dopamine or controls. Systemic variables were unchanged with dopexamine. The authors interpret this as a beneficial effect of dopexamine on splanchnic blood flow. {Get BPs etc}
[abs get]
Effects of catecholamines on regional perfusion and oxygenation in critically ill patients
Act Anaes Scand 1995 S107 239-8.
Review
They still plug supranormalization quoting Gilbert (ARRD 1986 134 873-8) and Kaufman (Chest 1984 84.3 337-0), but implicate regional poor perfusion in the high mortality of sepsis. They quote Deitch (Arc Sur 1987 122 185-0), Marshall (Arc Sur 1988 123 309-5) and Meakins to support the 'gut motor' hypothesis. Several references suggest increased gut bloodflow during sepsis ( Dahn Surg 1987 101 69-80; Lang AJP 1984 246R 331-7; Wang Arc Sur 1991 126 219-4); in the healthy, endotoxin doubles splanchnic bloodflow (Fong JCI 1990 85 1896-4). Their little table 1 is internally inconsistent {does dopamine magically decrease its dopaminergic agonist activity as the dose increases?}
Quote Silverman (Chest 1992 102 184-8) that dobutamine 5µg/kg/min increases low pHi; contrast Schneider (Cir Shock 1987 23 93-106) who found volume alone to work with no added benefit of dobutamine. Leier (AJC 1988 62 86E-3) found increased CO but decreased splanchnic perfusion with 7.5µg/kg/min in patients with heart failure. Mentions Hayes' study (NEJM 1994 330 1717-2) showing higher mortality with dobutamine supra-normalisation. Quotes Gutierrez (AJRCCM 1994 150 324-9) for beneficial effect on pHi.
In discussing norepinephrine they stress the importance of perfusion pressure. {A MAP in the 50's is clearly inadequate - but they don't address what is an adequate and what is an optimal perfusion pressure}. Note that Bersten (Surg 1992 112 549-61) found that in septic sheep (as contrasted with controls) norepinephrine did not redistribute blood away from the gut; Breslow similarly found that with a goal of MAP 75mmHg, norEpi, epinephrine or dopamine had no selective effect on regional blood flow. Marik (JAMA 1994 272 1354-7) showed norepinephrine improved pHi in septic patients while dopamine lowered it.
The authors (Adv Exp MB 1994 345 701-7) showed a sudden drop in ShvO2 with a switch from dobutamine to norepinephrine (in patients with septic shock). They do not try to explain why this differs from animal studies.
In animals various doses of epinephrine may improve (Greenway JPhys 1966 187 579-95) or lower intestinal perfusion (Haddy Gastroent 1967 52 444-1; Haddy Circ 1962 25 239-6; Pawlik JCI 1975 56 484-0). The authors found similar effects to norepinephrine on ShvO2. They state "Due to the lack of more information regarding epinephrine in the treatment of septic shock a conclusion is not yet possible".
Dopamine - they give no reference supporting the traditional assertion that dopamine receptor effect is clearly demarcated by dose. {Much discussion about merits/not of dopamine}.
Dopexamine - briefly discussed.
A good review that in 1999 appears slightly dated.
Gastric mucosal pH does not reflect changes in splanchnic blood flow after cardiac surgery
BJA 1995 74 149-4
n=14 patients after coronary artery bypass grafting: 8 given dopexamine, 6 controls. Not randomised. Oxygen consumption measured by indirect calorimetry, ICG for splanchnic flow, CO by PAC. H2-receptor blockers were not used, justified by Maynard (CCM 1994 22 A79) and Baigorri (ICM 1994 20.S2 S2).
Dopexamine administration was associated with increased splanchnic oxygen delivery and consumption, with a reduction in pHi. In controls, O2 delivery changed little, but consumption rose, with no significant change in pHi. There was no evidence of redistribution of CO towards the splanchnic circulation with dobutamine. Low pHi was frequent after uncomplicated cardiac surgery.
References other studies on dopexamine and splanchnic blood flow (Leier AJC 1988 62 94-9) and pHi (ref 27; Maynard ICM 1992 18.S2 S72; Smithies ICM 1992 18.S2 ?page). Quotes Leier (Circ 1978 58 466-75) that dobutamine has no effect on splanchnic flow in heart failure.
The authors suggest that dopexamine further interferes with gut microcirculation.
A big problem of small numbers, unexplained lack of randomisation.
Dobutamine-induced dissociation between changes in splanchnic blood flow and gastric intramucosal pH after cardiac surgery
BJA 1995 74 277-2.
n=22 patients post-CABG were randomly allocated to dobutamine (mean 4.4 µg/kg/min) or control (11 in each group), dobutamine being titrated to CI increase of 25% AND CI > 2 l/min/m 2 . In a separate group n=6 of patients with "low CI", dobutamine was given to all, with similar goals. PAC, ICG pHi, and indirect calorimetry used.
Splanchnic blood flow increased significantly with dobutamine, e.g. from 0.7 to 1.1 l/min/m 2 . In the low CI group, despite a similar increase in splanchnic blood flow, pHi dropped. Relative distribution of CO was unchanged.
Refer to their study of dobutamine +- nitroprusside on splanchnic blood flow ( Ruokonen CCM 1993 21 1304-1), and Webb's study which showed increased liver damage in pigs with experimental peritonitis after dobutamine infusion. (ICM 1991 17 487-3)
Several problems with this study including numbers, lack of randomisation in the tiny low CI group, and a tendency to draw conclusions that are difficult to support.
Goal-directed therapy with dopexamine, dobutamine and volume expansion: effects of systemic oxygen transport on hepatic ultrastructure in porcine sepsis
CCM 1995 23 1997-7
n=25 pigs: 5 groups of 5 had PAC, portal vein and hepatic artery flow probes, indirect calorimetry, and then dobutamine / dopexamine / colloid targeting a CI increase of 25%; with a control group and a sham group. Liver histology was examined 6hr after induction of peritonitis in all groups except the sham group.
There was no significant effect of any treatment on splanchnic DO2 or VO2. CO increased in the dobutamine vs the dopexamine & control groups. There was marked endothelial swelling in the septic controls, dobutamine and colloid groups, but significantly less swelling in the dopexamine group. Similarly, sinusoidal patency was diminished far less in the dopexamine group than in the other three groups.
Dopexamine appeared to protect against the liver damage that was seen in controls, with volume infusion, and with dobutamine.
Reference Gump (Ann Surg 1970 171 321-8) that sepsis augments splanchnic blood flow, and Dahn (Surgery 1987 101 69-80) that this increase may be inadequate. Contrasts Hayes (Chest 1993 21 1868-5) and Tuchschmidt (Chest 1992 102 216-0).
Appears rigorous, the question is how pertinent this is to humans.
n=27 patients were randomised to maintenance of pHi > 7.3 (11) or maintenance of oxygen delivery index and VO2 index (16), with no controls. Goals took up to 24 hours to achieve. One patient died in the first group, five died in the second.
{It is unclear from the study whether the pHi targeting was beneficial or the other approach deleterious. The numbers are also small.
[abs]
Variability in dobutamine pharmacokinetics in unstable critically ill surgical patients
Crit Care Med 1994 22.12 1926-2
In n=16 haemodynamically unstable adults on dobutamine for inotropic support (2 to 22 µg/kg/min) steady state blood dobutamine levels were measured. n=4 were on phenylephrine and n=6 on low-dose dopamine.
Dobutamine clearance was highly variable (19 to 120ml/kg/min) and steady state levels on 5 µg/kg/min varied between 25 and 350 ng/ml (14 fold). There was also marked intra-subject variability with time. Dobutamine pharmacokinetics best fitted a first order model.
Problems with the study include different sample numbers and timing for the various patients. The sample population was heterogeneous, with 'motor vehicle accidents', liver or renal transplant recipients, and patients with pancreatitis. Despite these limitations, an interesting study. The authors suggestion that in such patients, titration to effect is important is a sound and reasonable one.
Effect of dobutamine on oxygen consumption and gastric mucosal pH in septic patients.
AJRCCM 1994 150 324-9.
n=21 consecutive patients with sepsis and pHi under 7.32, good urine output following fluid resuscitation, and an MAP >= 60 mmHg; no control group; (prospective subgrouping according to lactate levels); Dobutamine infused at 5 then 10 µg/kg/min.
MAPs were in the range of 73 +-3 (high lactate group) to 89 +-7 mmHg {? SD or ? SEM}. We find no mention of urine output values. pHi increased with time and dobutamine. The initial pHi for the normal lactate group was lower than that for the high lactate group!
They mention (and possibly correctly derogate) the use of an 'oxygen flux test' (Bihari NEJM 1987 317 397-3; Vincent ARRD 1990 142 2-7) to show an oxygen deficit, as does Ronco (ARRD 1993 147 25-1). pHi may correlate with hypoxia (Grum JAP 1984 56 1065-9), and outcome (Fiddian-Green CCM 1987 15 153-6; Doglio CCM 1991 19 1037-0). They mention use of 'supranormalisation' based on pHi (Gutierrez Lancet 1992 339 195-9)
Controls would have been nice.
Laser doppler flowmetry, and tonometry, in pigs.
Mucosal acidosis whatever the cause (mechanical mesenteric ischaemia, hypoxia or hypercapnia) increased ileal mucosal permeability to fluorescein labelled dextran (MW 4000).
[abs]
In n=20 critically ill trauma patients, pHi and a host of other variables were measured.
Failure of pHi to correct was associated with death and organ dysfunction. Similar associations with mortality but not organ dysfunction were seen with base deficit.
[abs]
n=18 septic surgical patients had systemic and splanchnic VO2 and DO2 measured before and after blood transfusion. No controls.
With time and blood, DO2 rose 26% and VO2 9%, but splanchnic lactate uptake was unchanged. The authors cast doubt on the observed 'VO2/DO2' relationship because of the lactate observation, a fair comment. Remarkably frank.
[abs]
n=109; 9 responded to volume, 50 + 50 were randomly assigned to treatment or control groups. Goals were CI of 4.5 l/min/m 2 , DO2 600 ml/min/m 2 . Five to 200 µg/kg/min were required to achieve this goal.
Aggressive boosting of cardiac output using dobutamine was associated with a higher mortality. 34% of controls and 54% of the treatment group died. [abs].
A complex study in pigs who were initially either bled or given endotoxin, then resuscitated, and then (3 days later) had endotoxin infused into the portal vein.
They mainly reflect on the absence of a "priming" effect. {As arterial blood pressure decreased despite "aggressive fluid support" is is that surprising that splanchnic blood flow decreased?}
[abs, get the study]
n=20 consecutive ICU patients. Markers of metabolic acidosis correlated significantly (r > 0.6) with low pHi.
"A blood base deficit of -4.65 or less and an extracellular-fluid base deficit of -6.13 or less could estimate pHi below 7.32 (lower limit of normal range) with sensitivity of at least 77% and specificity of at least 96%."
[abs]
Gastric Tonometry in patients with sepsis.
Chest 1992 102 185-8
n=21 heterogeneous 'septic' patients with arterial line, PAC and gastric tonometry non-randomised and retrospectively analysed. 16 patients received packed cell infusions and then dobutamine; 19 patients in toto appear to have received packed cells; it is unclear where why the remaining two patients were included in the study, unless there were two patients who received packed cells and then dobutamine but had no measurements taken before and after packed cell administration. The patients appear to have been subdivided post-hoc into two subgroups - those with a normal pHi (MAP 87 +- 5 mmHg) and those with a low pHi (MAP 72 +- 6 mmHg): neither group had a significant MAP response to dobutamine, although CI increased. Urine output is not compared among these subgroups. No accurate chronology is obtainable from the supplied data as to the exact timing of dobutamine administration after packed cell administration, but of interest is the higher MAP in the low pHi + red cell transfusion group than in the low pHi + dobutamine group! A 'large majority' of the patients received ranitidine.
In the retrospectively selected subgroup with low pHi who then received dobutamine, pHi increased subsequent to this infusion, although from the nature of the study one cannot infer a causal relationship.
.
In 41 SICU patients, 33 developed infection in ICU - 16 pneumonia, 12 wound infection, 11 UTIs, 11 peritonitis, and 10 'bacteraemia'. The 'infecting organisms' were also isolated from the upper GIT.
They therefore say that the upper GIT was the source of the infection, and this justifies the "gut motor" hypothesis. Somewhat suspect. A rather sick ICU.
[abs]
n=30 critically ill patients, 15 developed MODS, 12 died.
pHi, arterial and venous pH were lower in those who died. VO2 and DO2 didn't help.
[abs]
The effect of various sympathomimetics on the regional circulations in hyperdynamic sepsis
Surgery 1992 112 549-61.
n=36 starved sheep on penicillin and gentamicin were rendered septic, baseline measurements were done. dobutamine / norepinephrine / dopamine / dopexamine / salbutamol / placebo were given by randomised blinded infusion to raise CI over 20% (except with placebo) in both non-septic and septic states. Regional perfusion was determined using radiolabelled microsphere injection. Analgesia given.
Before sepsis inotropes similarly redistributed flow towards the heart; with sepsis there was no redistribution away from small intestine and liver. Higher infusion rates were needed to achieve the same CI target in septic animals over non-septic ones. Pancreatic blood flow was diminished with sepsis, with or without inotrope infusion.
See also Bersten (ARRD 1990 141 1198-8) and Carter (JAP 1988 65 I:1782-8).
An adequate study.
n=51 patients with septic shock were randomised to 'normal' therapy (NT, n=25) or 'optimal' therapy (OT, n=26), that is a CI of 3.0 versus 6.0 l/min/m 2 .
Despite more patients dying in the OT group (not quite achieving significance) the authors use subanalysis to enthusiastically support the title of their paper - "Elevation of cardiac output and oxygen delivery improves outcome in septic shock"!! {We are stunned}.
[abs]
n=260 ICU patients with APACHE II scores of 15-25. pHi measured and randomised to controls (standard ICU management) or protocol (Rx to increase oxygen transport or decrease demand, IF pHi fell). In n=67, protocol was used.
The subgroup who had normal pHi on admission but then had protocol management had significantly increased survival over those who had normal pHi on admission and didn't receive the protocol. They do not explain why the subgroup who had a low pHi on admission and had protocol management had no improvement over those who had conventional management.
[abs]
Catecholamine-induced changes in vascular capacitance and sympathetic nerve activity in dogs.
Can J Physiol Pharmacol 1992 70 1021-1.
Venous blood flow from three compartments (splanchnic, renal and other) was monitored in n=18 healthy mongrel dogs on cardiopulmonary bypass to provide constant flow. Sympathetic efferent nerve activity (SENA) was monitored, and changes in blood volume were calculated. Dopamine, epinephrine and dobutamine were given in low and high doses, (each dog receiving only one agonist) at baseline and after baroreceptor deafferentation, and then again after hexamethonium injection. The authors pretty up their results by using +- SEM.
Dopamine and epinephrine decrease 'blood volume'(vascular capacitance) probably through splanchnic venoconstriction, this being very dependent on vascular tone and/or sympathetic nerve activity; dopamine increases renal blood flow while epinephrine decreases this. Dobutamine appeared to decrease vascular capacitance! Of great interest is that dopamine and epinephrine in high doses appears to profoundly reduce SENA, even after deafferentation!! This suppression was not seen with dobutamine.
Greenway's four-compartmental model (Pharm Rev 1982 33 213-51) is mentioned. The nature of the study doesn't allow the authors to conclude whether (say) decreases in splanchnic outflow were due to decreases in inflow, or pooling of blood in the splanchnic circulation. Note that ephedrine increases vascular capacitance - this may explain the peculiar response to epinephrine (See Baraka Anes Analg 1988 67 483-4).
Perhaps the most interesting observation from this study is the remarkable interaction between sympathetic outflow and response to catecholamines.
In patients undergoing liver resection, 3 µg/kg/min of dobutamine left hepatic arterial blood flow unchanged but increased portal venous flow, but hepatic oxygen uptake increased in proportion to increased oxygen delivery. Dobutamine stimulates hepatic oxygen use.
[abs]
In 18 pigs with septic shock (6), haemorrhagic shock (6) or controls (6), whole body, GIT and liver oxygen consumption and delivery were measured.
They found lower deliver of oxygen in both shocked states, but increased liver and GIT VO2 in sepsis. {Does this bear any relationship to adequately resuscitated humans??}
[abs]
In healthy volunteers, 20U/kg of endotoxin promoted TNF release from the 'splanchnic organs'.
[abs, get original]
In 16 out of 205 consecutive patients, the same bacterium that caused infection was found in the proximal GIT.
{So what? The bacteria were probably also on the anus, in the mouth, on the walls and indeed on the examiners' fingers}.
[abs, get]
Effect of vasopressors on organ blood flow during endotoxin shock in pigs
AJP 1987 252 H291-0
3 of 8 animals died acutely after administration of E coli endotoxin at 5 µg/kg/min for <= 40 minutes. There were 4 controls who received no endotoxin. The authors then did the rest of the study, using the five survivors + two added pigs as "group I" (no vasopressor); and groups II to IV (endotoxin + vasopressors, n=6 in each group), the vasopressors being norepinephrine, dopamine or phenylephrine; with a target MAP of 70-80 mmHg.
Baseline MAP was 119 mmHg, decreasing to 54 mmHg after endotoxin, with lowered flow to brain and kidney but not the bowel. Sensitivity of the vasculature to vasopressor infusion was markedly diminished; vasopressors did not affect the drop in kidney blood flow, nor the gut blood flow. There was no difference between norepinephrine, dopamine or phenylephrine on organ blood flow or regional vascular resistance.
Dopexamine preferentially increased renal and hepato-splanchnic blood flow in 12 patients with low-output heart failure, in the face of a mild reduction in systemic arterial pressure [abs].
Endotoxin was given to mice (IM or IP) -
it increased bacterial translocation into mesenteric lymph nodes.
[abs]
In n=12 'stable' patients with sepsis, splanchnic & whole body oxygen consumption and blood flow were measured. 28% of CO went to the splanchnic circulation, but 44% of the body's oxygen consumption was there, compared with 30% in n=7 'injured patients'. {What were the patients on ..}
[abs]
Dobutamine
Ann Int Med 1983 99 490-6
Strong beta1 and mild beta2 and alpha1 agonist; available from 1978. References Tuttle & Mills (Circ Res 1975 36 185-96) and references (2..11); radioligand binding is Williams (JCI 1981 67 1703-1); partial agonist alpha activity is Kenakin (J Ph Exp Th 1981 216 210-9) see also Ruffolo (J Ph Exp Th 1981 219 447-2). {Note: the partial agonist alpha activity may explain a lot: in patients on high doses of alpha agonists or with high intrinsic catecholamines, there may effectively be alpha antagonism with increased flow to the gut; the converse may hold with less alpha activity !}. The blunted positive chronotropic response (compared with inotropic) is not well understood. (-) isomer has more alpha, less beta effect than (+) and (+) may in fact cause alpha blockade!
Onset IV in 2 min, maximal at 10 min; mean plasma half-life with low output CCF is 2.37 +- 0.7 min; redistributed, and metabolised by COMT; inactive metabolites are renally eliminated. Vd is 0.2 +- 0.08 l/kg. Local tissue necrosis reported with dobutamine! "more positive chronotropy and ventricular dysrhythmias than dopamine". Tends to inhibit platelet function! Substantial vasopressor activity reported by Hess (Anaesthesist 1979 28 316-1) in some patients under anaesthesia!
An old review of some utility.
Vasoactive agents and splanchnic oxygen uptake
AJP 1982 243 G1-9.
Review
Massive discrepancies exist between the fifty or so studies to date as regards the effects of vasoactive agents on splanchnic oxygen uptake. In this good review, the authors propose a rational approach to standardising assessment of effects. The major mechanisms by which vasoactive agents alter splanchnic oxygen uptake are by either altering oxidative metabolism or by changing blood flow (including changes in 'capillary density'). They recommend (1) determine the relationship between flow and oxygen uptake in the absence of vasoactive drugs; (2) infuse the drugs locally under free-flow and constant-flow conditions; (3) estimate capillary exchange capacity under free-flow or constant-flow conditions; (4) estimate the effects of the drugs on oxygen uptake using differential respirometry; (5) employ the same drug dose in all procedures.
In 31 burn patients, hepatic (42) and renal (21) veins were catheterised 4-129 days post injury. ICG and PAH were used to determine blood flow. Only five studies were on patients who were "bacteraemic with complications".
Hmm.
[abs]
Renal and hepatic blood flow were not significantly altered in patients in cardiac failure on ~ 7 µg/kg/min of dobutamine for 24 hours. [abs]
In dogs superior mesenteric artery flow was measured using an electromagnetic flowmeter. Vasopressin lowered flow and oxygen consumption; adrenaline lowered flow but not consumption, but with beta blockade flow AND oxygen consumption were lowered substantially.
[abs]
Normal and septic pigs had measurement of portal and hepatic blood flow. In this old study they divided the pigs into two groups based on whether cardiac output increased or decreased.
If CO increased, total hepatic flow was preserved despite a 19% decrease in portal flow; with low CO, portal flow dropped similarly (23%) but hepatic arterial flow took the biggest hit (74%). {What were the blood pressures?}
[abs]
Extravascular shunting of oxygen in the small intestine of the cat
Act Phys Scand 1968 72 396-3
n=8 cats starved and anaesthetized had an intestinal loop isolated and denervated; oximetry was used to identify passage of oxygen-saturated blood and/or methaemoglobin-carrying red cells.
Oxygen appeared in the venous outflow 1-2 seconds earlier than methaemoglobinaemic cells, suggesting a 'countercurrent' shunting of oxygen occurs across the arteriovenous supply of the intestinal mucosa. This shunting seems to be abolished by intestinal vasodilatation (isopropylnoradrenaline), and by local sympathetic stimulation, the former perhaps due to wash-out, and the latter due to shunting of most flow away from the mucosa.
A 'classic' study that appears to have been well thought-out and executed. However, the importance of the counter-current mechanism has been subsequently questioned {cf. Levitt AJP 1980 239 G23-9}.
| Date of First Publication: 1999 | Date of Last Update: 2006/10/24 | Web page author: Click here |