Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal-arterial pCO2 gradient in abdominal aortic aneurysm surgery.

BACKGROUND: Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. METHODS: Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double-blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG-PDR) was used to estimate the total splanchnic blood flow. RESULTS: The immediate post-operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8-4.7) l/min/m(2) vs. 2.6(2.3-3.6) l/min/m(2); P<0.05] and the gastric mucosal-arterial pCO(2) gradient was lower in levosimendan-treated patients [0.9(0.6-1.2) kPa vs. 1.7(1.2-2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG-PDR, was comparable [29(21-29)% vs. 20(19-25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post-operative day. CONCLUSION: Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation.

The proportion of intensive care unit admissions related to alcohol use: a prospective cohort study.

BACKGROUND: Alcohol abuse is a risk factor for serious illnesses, and a history of chronic alcohol abuse adversely affects the outcome of critically ill patients. It is not known what proportion of intensive care unit (ICU) admissions is related to alcohol use. Therefore, we investigated the proportion of emergency admissions related to alcohol. METHODS: A prospective cohort study was conducted in a university hospital ICU. All adult patients (n = 893) who underwent emergency admission to our ICU during a period of 1 year were studied. RESULTS: The admitting physician determined whether there was a relationship between alcohol use and admission. ICU and hospital mortality and ICU length of stay (LOS) were recorded. The Therapeutic Intervention Scoring System (TISS) was used for ICU resource use estimation. There was a relationship between alcohol use and admission in 24% (215/893) of admissions and, in 156/893 admissions (17.5%), this seemed to be definite. ICU LOS was 1.2 days (0.7; 2.3) (median; interquartile range) for alcohol-related and 1.8 days (0.9; 3.6) for other admissions (P < 0.001). Patients with alcohol-related admissions consumed 17.8% of ICU patient-days and 18.7% of all accumulated TISS scores. ICU (8.8 vs. 10.5%, P = 0.603) and hospital (19.1 vs. 20.2%, P = 0.769) mortalities were no different between alcohol-related and other admissions. CONCLUSION: ICU admission is very often related to long-term chronic and/or occasional alcohol use.

Dobutamine compensates deleterious hemodynamic and metabolic effects of vasopressin in the splanchnic region in endotoxin shock.

BACKGROUND: Vasopressin is a potent vasopressor in septic shock, but it may impair splanchnic perfusion. We compared the effects of vasopressin alone and in combination with dobutamine on systemic and splanchnic circulation and metabolism in porcine endotoxin shock. METHODS: Twelve pigs were randomized to receive either vasopressin (VASO, n = 6) or vasopressin in combination with dobutamine (DOBU, n = 6) during endotoxin shock (E. coli endotoxin infusion). Endotoxin infusion rate was increased to induce hypotension after which vasoactive drugs were started. We aimed to keep systemic mean arterial pressure (MAP) >70 mmHg by vasopressin; the goal of dobutamine infusion was to prevent decrease in cardiac output often associated with vasopressin infusion. Regional blood flows, oxygen delivery and consumption, arterial and regional lactate concentrations were measured. RESULTS: Mean arterial pressure >70 mmHg was achieved in both the VASO and DOBU groups. After the primary decrease of cardiac output by vasopressin, systemic blood flow remained stable in vasopressin-treated animals. However, vasopressin as a monotherapy decreased portal venous blood flow. This was prevented by dobutamine. Vasopressin also induced splanchnic lactate release and arterial hyperlactatemia, which were not observed when dobutamine was combined with vasopressin. CONCLUSION: Dobutamine prevents adverse hemodynamic and metabolic effects of vasopressin in septic shock.

Dopexamine reverses colonic but not gastric mucosal perfusion defects in lethal endotoxin shock.

BACKGROUND: Whilst dopexamine appears to increase overall splanchnic blood flow in postoperative and septic patients, the effects on gastric mucosal perfusion are controversial and based on concomitantly increasing mucosal to arterial PCO(2) gradients (PdCO(2)). We hypothesized that dopexamine alters splanchnic blood flow distribution and metabolism during experimental endotoxin shock and modifies the inflammatory response induced by endotoxin. METHODS: In an experiment with anaesthetized normovolaemic, normoventilated pigs, 21 animals were randomized into: (i). subacute lethal endotoxin shock for 14 h (n=7 at baseline); (ii). endotoxin shock with dopexamine infusion (aiming to exceed baseline cardiac output, n=7); or (iii). controls (n=7). Regional blood flow and metabolism were monitored. RESULTS: Endotoxin produced a hypodynamic phase followed by a normo/hyperdynamic, hypotensive phase. Despite increasing systemic blood flow in response to dopexamine, proportional splanchnic blood flow decreased during the hypodynamic phase. Dopexamine gradually decreased fractional coeliac trunk flow, while fractional superior mesenteric arterial flow increased. Dopexamine induced early arterial hyperlactataemia and augmented the gastric PdCO(2) gradient while colonic luminal lactate release and colonic PdCO(2) gradient were reversed. Dopexamine did not modify the inflammatory response as evaluated by arterial IL-1beta and IL-6 concentrations. CONCLUSIONS: Dopexamine protects colonic, but not gastric mucosal epithelium in experimental endotoxin shock. This may be related to redistribution of blood flow within the splanchnic circulation.

Reperfusion but not acute ischemia in pig small intestine induces transcriptionally mediated heat shock response in situ.

BACKGROUND: Although there is data on the cytoprotective role of heat shock proteins in intestinal ischemia-reperfusion, the effects of ischemia and reperfusion per se on the small intestinal heat shock response have been poorly characterized. METHODS: Four female pigs were subjected to 60-min ischemia by superior mesenteric artery occlusion followed by 360-min reperfusion. Systemic and local hemodynamics were monitored. Samples from the jejunal mucosa and muscularis were obtained for histology and for time series molecular biologic analyses of heat shock transcription factor 1 (HSF1), hsp70 mRNA and Hsp70 protein. RESULTS: A 30-min reperfusion of jejunum after a preceding 1-hour ischemia results in a significantly increased DNA-binding activity of HSF1, in a 10-fold increase of hsp70 mRNA in the mucosal and in a 7-fold increase in the muscular layers. Translational activation and accumulation of Hsp70 protein occurs after 60 min of reperfusion in the intestine. Nevertheless, a 60-min ischemia inducing mucosal detachment does not induce the heat shock response at any level analyzed. CONCLUSIONS: Ischemia alone is insufficient to induce the heat shock response, whereas subsequent reperfusion induces the response via transcriptionally mediated induction of Hsp70 synthesis both in the mucosal and muscular layers.

Effects of systemic arterial hypoperfusion on splanchnic hemodynamics and hepatic arterial buffer response in pigs.

The hepatic arterial buffer response (HABR) tends to maintain liver blood flow under conditions of low mesenteric perfusion. We hypothesized that systemic hypoperfusion impairs the HABR. In 12 pigs, aortic blood flow was reduced by cardiac tamponade to 50 ml. kg(-1). min(-1) for 1 h (short-term tamponade) and further to 30 ml. kg(-1). min(-1) for another hour (prolonged tamponade). Twelve pigs without tamponade served as controls. Portal venous blood flow decreased from 17 +/- 3 (baseline) to 6 +/- 4 ml. kg(-1). min(-1) (prolonged tamponade; P = 0.012) and did not change in controls, whereas hepatic arterial blood flow decreased from 2 +/- 1 (baseline) to 1 +/- 1 ml. kg(-1). min(-1) (prolonged tamponade; P = 0.050) and increased from 2 +/- 1 to 4 +/- 2 ml. kg(-1). min(-1) in controls (P = 0.002). The change in hepatic arterial conductance (DeltaC(ha)) during acute portal vein occlusion decreased from 0.1 +/- 0.05 (baseline) to 0 +/- 0.01 ml. kg(-1). min(-1). mmHg(-1) (prolonged tamponade; P = 0.043). In controls, DeltaC(ha) did not change. Hepatic lactate extraction decreased, but hepatic release of glutathione S-transferase A did not change during cardiac tamponade. In conclusion, during low systemic perfusion, the HABR is exhausted and hepatic function is impaired without signs of cellular damage.

Gut luminal lactate release during gradual intestinal ischemia.

OBJECTIVES: Gut ischemia induced by occlusion of the superior mesenteric artery (SMA) results in release of lactate into the gut lumen. We studied the threshold of SMA flow reduction that leads to increased gut luminal lactate during stepwise reduction in SMA blood flow. DESIGN AND SETTING: A randomized, controlled animal experiment in a university experimental research laboratory. INTERVENTIONS: Anesthetized, normoventilated, normovolemic domestic pigs were randomized to ischemia ( n=7) and sham groups ( n=7). SMA blood flow was reduced stepwise at 15-min intervals by 22%, 44%, 66%, and 88% and kept constant thereafter for 60 min. MEASUREMENTS AND RESULTS: Jejunal luminal microdialysate lactate and mucosal pCO(2) were measured every 15 min. The luminal lactate increased over the upper normal limit of 0.2 mmol/l at a median SMA blood flow of 9.6 ml kg(-1) min(-1) (range 7.5-23.7). In five of seven animals the increase in luminal lactate was preceded by or accompanied by an increase in the mucosal-arterial pCO(2) gradient. CONCLUSIONS: There is a threshold of SMA blood flow below which gut luminal lactate increases, indicating mucosal anaerobic metabolism. Measurement of gut luminal lactate by microdialysis can be used to assess the adequacy of gut perfusion and the onset of anaerobic metabolism.

Gastric mucosal systemic partial pressure of carbon dioxide (PCO(2)) gradient in experimental endotoxin shock in swine--comparison of two methods.

OBJECTIVES: Clinically applicable methods for continuous monitoring of visceral perfusion/metabolism do not exist. Gastric mucosal end-tidal partial pressure of carbon dioxide (PCO(2)) gradient has been used, but it has limitations, especially in patients with lung injury and increased dead space ventilation. We studied the agreement between gastric mucosal end-tidal (DPCO(2gas)) and gastric mucosal arterial PCO(2) (D((t-a))PCO(2)) gradients, and especially the effect of dead space ventilation (V(d)/V(t) ratio) on the agreement. We hypothesized that DPCO(2gas) can be used as a semi-continuous indicator of mucosal arterial PCO(2) gradient in sepsis. DESIGN: A randomized, controlled animal experiment. SETTING: National laboratory animal center. INTERVENTIONS: Twelvehour infusion of endotoxin in landrace pigs. MEASUREMENTS AND RESULTS: We measured end-tidal PCO(2) continuously, gastric mucosal PCO(2) every 10 min (gas tonometry) and arterial PCO(2) every 120 min. Carbon dioxide production and the V(d)/V(t) ratio were determined by indirect calorimetry. In the endotoxin group ( n=7) cardiac index increased and systemic vascular resistance decreased. Endotoxemia increased dead space ventilation by 27% ( p=0.001). Both DPCO(2gas) and D((t-a))PCO(2)increased significantly in the endotoxin group ( p<0.0001 and p=0.049, respectively). Control animals remained stable throughout the experiment. When we compared DPCO(2gas) and D((t-a))PCO(2)(Bland-Altman analysis), the bias and precision were 0.9 and 0.9 kPa in the control group and 2.0 and 2.2 kPa in the endotoxin group, respectively. The disagreement between DPCO(2gas) and D((t-a))PCO(2) increased as the V(d)/V(t) ratio increased. CONCLUSIONS: DPCO(2gas) is a clinically applicable method for continuous monitoring of visceral perfusion/metabolism. Septic lung injury and increased dead space ventilation decrease the accuracy of the method, but this may not be clinically important.

Prevention of systemic hyperlactatemia during splanchnic ischemia.

Arterial blood lactate increases as a result of poor tissue perfusion. In splanchnic hypoperfusion, increased hepatic lactate uptake may delay increases in arterial blood lactate. We hypothesized that during isolated reduction of mesenteric blood flow, maintaining systemic blood volume and flow by fluid resuscitation may prevent systemic hyperlactatemia and therefore mask splanchnic ischemia. In a randomized study, 7 pigs were subjected to 4 h of splanchnic hypoperfusion by reducing the superior mesenteric artery blood flow to 4 +/- 0.8 mL/kg min [mean +/- standard deviation (SD)]. Seven pigs served as controls. Fluid was administered in order to keep the pulmonary artery occlusion pressure at 5 to 8 mm Hg. Cardiac output, portal vein, superior mesenteric, and hepatic arterial blood flow were measured every 30 min. Arterial, mixed venous, hepatic, portal, and mesenteric venous blood lactate, and jejunal mucosal pCO2 were measured at baseline and thereafter at 30-min intervals. The initial decrease in portal venous blood flow in the ischemic animals was subsequently counterbalanced by increasing hepatic arterial blood flow from 2 +/- 1 mL x kg(-1) x min(-1) at baseline to 11 +/- 4 mL x kg(-1) x min(-1) [after 4 h of ischemia; mean +/- standard deviation (SD), P = 0.02]. Jejunal mucosal- and mesenteric vein-arterial pCO2 gradients increased in the ischemic group from 11 +/- 8 mm Hg to 73 +/- 5 mm Hg (P = 0.02), and from 10 +/- 4 mm Hg to 44 +/- 8 mm Hg, respectively (P = 0.02). Mesenteric and portal venous lactate increased in the ischemic animals from 1.1 +/- 0.3 mmol/L to 4.2 +/- 1.0 mmol/L (P = 0.02), and from 1.0 +/- 0.2 mmol/L to 1.6 +/- 0.3 mmol/L, respectively (P = 0,03). While mesenteric lactate production and hepatic lactate uptake increased in parallel in the ischemic animals from 5 +/- 6 micromol x kg(-1) x min(-1) to 14 +/- 5 micromol x kg(-1) x min(-1) (P = 0.04), and from 14 +/- 7 micromol x kg(-1) x min(-1) to 24 +/- 6 micromol x kg(-1) x min(-1), respectively (P = 0.02), hepatic venous and arterial lactate, and apparent splanchnic lactate uptake and extraction did not change. We conclude that the hepatic lactate uptake increases in response to hepatic lactate influx. Systemic hyperlactatemia and increased hepatic venous lactate concentrations are late consequences of mesenteric hypoperfusion if hypovolemia is prevented. The net exchange of lactate across the splanchnic region does not reflect hepato-portal lactate kinetics in this animal model of intestinal hypoperfusion.

Intestinal luminal microdialysis: a new approach to assess gut mucosal ischemia.

BACKGROUND: The authors developed a microdialysis method for sampling lactate from the gut lumen to evaluate the metabolic state of the intestinal mucosa. The aim of the study was to evaluate the method in vivo during nonischemic systemic hyperlactatemia and gut ischemia. METHODS: Microdialysis capillaries were inserted in the lumen of jejunum, in the jejunal wall, and in the mesenteric artery and vein in anesthetized, normoventilated pigs. In the first experiment, infusion of lactate was used to clamp the arterial blood lactate at 5 mM and 10 mM (n = 6). In the second experiment, 90 min of intestinal ischemia was induced by total (n = 6) or partial (n = 6) occlusion of the superior mesenteric artery followed by 60 min of reperfusion. Sham-operated animals were used as controls (n = 6). RESULTS: Gut luminal lactate increased only slightly during the nonischemic hyperlactatemia: from a median baseline value of 0.10 (range, 0.06-0.28) to 0.50 (range, 0.15-1.18) and 0.86 (range, 0.35-2.05) mM. Total occlusion of superior mesenteric artery increased luminal lactate from a median of 0.09 (range, 0.06-0.17) to 2.37 (range, 1.29-2.98) and further up to 3.80 (range, 2.55-6.75) mM during reperfusion. Partial occlusion of superior mesenteric artery induced an increase from a median of 0.09 (range, 0.06-0.51) to 1.66 (range, 0.07-3.97) mM. Gut wall microdialysate lactate in deep and superficial layers followed the arterial and mesenteric vein microdialysate lactate. CONCLUSIONS: Luminal lactate concentration, as measured by microdialysis, increases substantially during gut ischemia but does not respond to systemic hyperlactatemia per se. In contrast, gut wall microdialysis cannot distinguish between gut ischemia and systemic hyperlactatemia. Gut luminal microdialysis provides a method for the assessment of intestinal ischemia with a potential for clinical application.

Splanchnic tissue perfusion in acute experimental pancreatitis.

BACKGROUND: Gut hypoperfusion may have a role in the pathogenesis of multiple organ failure, which is a the main cause of death in severe acute pancreatitis. We hypothesized that gut hypoperfusion is present early in acute pancreatitis and that supporting the systemic hemodynamics by fluid resuscitation would prevent this. METHODS: In a pig model of randomized, controlled experimental hemorrhagic pancreatitis induced by Na-taurocholate the animals were divided into four groups (n = 6 for each): 1) pancreatitis, 2) control, 3) pancreatitis and fluid resuscitation to keep the pulmonary capillary wedge pressure at 5 to 6 mmHg, and 4) control and fluid resuscitation as in group 3. Splanchnic perfusion was assessed by means of local PCO2 gap with intestinal tonometer, oxygen delivery and consumption, lactate production, and blood flow. The follow-up time was 6 h. RESULTS: The Pco2 gap increased in pancreatitis (1.72+/-0.17, 1.94+/-0.29, 1.75+/-0.22, 2.32+/-0.33; 9.40+/-2.16, 3.72+/-1.78, 0.84+/-0.39, 1.11+/-0.21 kPa, respectively; P < 0.05). Oxygen delivery in portal-drained organs decreased in pancreatitis (2.5+/-0.3, 2.6+/-0.2, 2.8+/-0.4, 2.3+/-0.2; 1.7+/-0.3, 2.3+/-0.3, 2.4+/-0.5, 2.3+/-0.3 ml/min x kg, respectively; P < 0.05). Regional oxygen consumption did not change. Arterial plasma lactate increased (1.20+/-0.19, 1.33+/-0.16, 1.14+/-0.15, 1.43+/-0.33; 3.81+/-1.31, 1.48+/-0.48, 1.12+/-0.18, 1.18+/-0.35 mmol/l, respectively; P < 0.05). The portal venous blood flow decreased 50% in pancreatitis, but with fluid resuscitation it increased 50%. CONCLUSIONS: Splanchnic hypoperfusion is present early in acute hemorrhagic pancreatitis. The signs of hypoperfusion can be prevented with fluid resuscitation.