Single-center nonrandomized clinical trial to assess the safety and efficacy of irreversible electroporation (IRE) ablation of liver tumors in humans: Short to mid-term results.

INTRODUCTION: A single-center nonrandomized clinical trial was performed to assess the safety and efficacy of IRE ablation of liver tumors in humans. METHODS: 38 malignant liver tumors on 30 patients were treated with IRE between September 2011 and September 2014. Treatment was with curative intent, and the diagnoses were colorectal cancer with liver metastases (CRLM) (n = 23), hepatocellular carcinoma (HCC) (n = 8) and other metastasis (n = 7). Patients were selected when surgery, radiofrequency ablation (RFA) or microwave ablation (MWA) was not an option, and when they met inclusion criteria (tumor size < 3 cm, 1-2 tumors). Patients were followed-up at 1 and 6 months with a contrast-enhanced computed tomography (CE-CT), and contrast-enhanced ultrasound (CE-US) at 3 months. RESULTS: Ablation success was defined as no evidence of residual tumor in the ablated area as confirmed by CE-CT and CE-US. At 3 months ablation success was 78.9%, and 65.8% at 6 months. There was no statistically significant difference between tumor volume (<5 cm3 vs >5 cm3, p = 0.518), and between diagnosis (CRLM vs HCC, p = 0.084) in terms of local recurrence. Complications were classified according to the standardized grading system of Society of Interventional Radiology (SIR). A minor complication occurred in six patients (20%), one patient (3.3%) suffered from a major complication (bile duct dilatation and stricture of the portal vein and bile duct). No mortalities occurred at 30 days. CONCLUSIONS: IRE appears to be a safe treatment modality for a selected group of patients with liver tumors and offers high local tumor control at 3 and 6 months.

Sister chromatid exchanges and chromosome aberrations in children after treatment for malignant lymphoma.

Sister chromatid exchanges and chromosomal aberrations were investigated in lymphocytes from 11 children with malignant lymphoma after cessation of treatment. Chemotherapy combined with radiation was administered, terminating between 4 months and 13 years before chromosome analyses were performed. The frequency of sister chromatid exchanges per chromosome was the same, 0.20, in the patients and a matched control group, although there was a significant heterogeneity between individuals. The number of cells with chromosome abnormalities increased from 2.9% in control children to 4.8% in treated patients, a nonsignificant increase. Only translocations showed a significant increase.

Increased frequency of chromosome abnormalities in fibroblasts from hairy cell leukemia patients.

A hereditary component is implicated in many different cancers, including hairy cell leukemia (HCL), and may involve an instability of the genome. We have previously documented recurrent clonal and non-clonal chromosomal abnormalities in hairy cells. To ascertain whether this instability of the genome is restricted to the malignant cells or if it might also include normal cells we performed cytogenetic investigations on skin fibroblasts and hairy cells from eight HCL patients and skin fibroblasts from eight referents. The frequency of chromosome abnormalities, regardless of clonality, was significantly increased in the fibroblasts from patients compared to referents. Also, five patients compared to one referent showed clonal abnormalities in their fibroblasts. Immunohistochemical investigations excluded the possibility that the fibroblast cultures were contaminated with hairy cells. Two patients had constitutional abnormalities, inv(5)(p13.1q13.3) and t(13;14), and one additional patient, possibly mosaic, showed the same abnormality, inv(9)(p21-22q22), in both fibroblasts (17/30) and blood (5/21) cells. Aberrations in patient fibroblasts also included sporadic inv(5), del(6)q, inv(19), and del(20)q, abnormalities previously shown to occur in hairy cells. A clonal expansion with trisomy 7 occurred in vitro as documented by fluorescence in situ hybridization (FISH). The only clonal abnormality occurring in a referent was -Y/-Y,+15 in an elderly male. In conclusion, a constitutional chromosomal instability may precede chromosome abnormalities and be of importance in the development of hairy cell leukemia.

Duodenal mucosal pH as a reperfusion indicator in pancreatic-duodenal transplantation in the pig.

We have studied differences in reperfusion between the pancreas and the duodenum after 6 hr of cold storage in a porcine whole-organ pancreaticoduodenal allograft transplantation model. Two different flush-out and storage solutions, Perfadex and EuroCollins, were compared. Graft duodenal mucosal pH (pHi) was measured as an indicator of duodenal mucosal reperfusion. Pancreatic reperfusion was estimated indirectly using a ratio between the release of immunoreactive cationic trypsin (irCT) to serum 10 and 60 min following reperfusion. Twelve pigs (Perfadex n = 6, EuroCollins n = 6) were transplanted and all showed preserved endocrine and exocrine function postoperatively. Our data support the concept that reperfusion of a pancreaticoduodenal graft can be estimated using duodenal pHi and that the ratio of irCT at 10 and 60 min gives an indirect estimate of pancreatic reperfusion. The results also show that grafts stored in EuroCollins reperfuse more slowly than grafts stored in Perfadex.

The effect of serotonin inhibition on initial microvessel hemostasis and platelet aggregation in vivo.

The role of serotonin (5-HT) in initial microvascular hemostasis is not fully understood. This study was made to evaluate the effect on hemostatic plug formation and laser-induced arteriolar microembolism of different substances which counteract the effect of 5-HT. Hemostatic plug formation time and stability was measured in the rabbit mesenteric microcirculation and laser-induced embolism in the rabbit ear chamber. Ketanserine, a selective 5-HT2-receptor blocker shortened arteriolar hemostatic plug formation time. Dihydroergotamine, an unselective blocker (with 5-HT-and alpha-adrenergic receptor affinity) increased venular hemostatic plug formation time and also decreased the hemostatic plug stability. Laser-induced platelet embolism was unaltered after both ketanserine and dihydroergotamine administration. The magnitude of these changes seems to exclude an important effect of 5-HT in initial microvessel hemostasis or on platelet activity.

The role of 5-hydroxytryptamine in the feline response to intravenous infusion of live E. coli.

A standardized septic shock was induced in cats by intravenous infusion of a live E. coli bacteria strain. The bacterial infusion induced a rapid haemodynamic response characterized mainly by a pulmonary arterial hypertension and a late phase characterized by systemic hypotension and hypodynamic circulation. Systemic arterial, pulmonary arterial, portal venous, left atrial pressures, max inspiratory-expiratory pressure difference in the trachea, aortic and intestinal blood flows were monitored. Arterial blood samples were taken for recording the number of circulating platelets and white blood cells and for determining the acid-base balance. The effect of pretreatment with ketanserin, a specific 5-hydroxytryptamine2 (5-HT2)-receptor blocker on these haemodynamic reactions was studied. In short term experiments on non-bacteriaemic control cats, ketanserin prevented the pulmonary hypertension induced by intravenous 5-HT infusions but not the increase in intestinal blood flow. Ketanserin induced a reduction of total peripheral (including intestinal) vascular resistance to blood flow but had no effect on aortic blood flow. After infusion of bacteria, ketanserin pretreated cats were more hypotensive due to a relative peripheral dilatation of the resistance vessels. Ketanserin pretreatment had no effect on the pulmonary vascular reactions, the tracheal pressure difference or the number of circulating platelets or white blood cells. Thus, except for a more pronounced hypotension early after bacterial infusion, ketanserin pretreatment did not influence the haemodynamic response. It is concluded that 5-HT is not of significant importance in the pathogenesis of the haemodynamic reactions following experimental bacteraemia.

Intestinal blood flow and intramucosal pH in experimental peritonitis.

BACKGROUND AND AIMS: Experimental peritonitis causes gut intramucosal acidosis indicating intramucosal ischemia. However, tissue acidosis may reflect other conditions than ischemia. An increased mucosal-arterial Pco2 difference ( Pco2-gap) is suggested to be a more adequate measure of tissue ischemia than intramucosal pH (pHi). This study was performed to elucidate whether keeping cardiac index (CI) and splanchnic blood flow normal or supranormal by administration of colloids and an inotropic drug could prevent the acidosis as well as reduce the Pco2-gap. A secondary aim was to study to what degree the low pHi in peritonitis really reflects ischemia. SUBJECTS: 24 anesthetized pigs (18-27 kg) divided into four groups. MODELS: A Swan-Ganz catheter, transonic flow meters and catheters for blood sampling were applied. pHi was calculated using tonometry. Standardized fecal peritonitis was induced, except in controls. One peritonitis group was given dextran (Group P(DEX)) and another in addition dobutamine (Group PDOB) to keep CI normal or supranormal, respectively. RESULTS: After 4 h, a significant drop in pHi was found in all peritonitis groups, most pronounced in untreated peritonitis (to 7.09+/-.02). Corresponding values in Group P(DEX) and Group P(DOB) were 7.22+/-.03 and 7.22+/-.01, respectively, and in controls 7.30+/-.02. The Pco2-gap and the mucosal-arterial [H+] difference ([H+]-gap) increased significantly in untreated peritonitis but did not increase in groups given dextran and dextran + dobutamine. CONCLUSION: Maintaining CI in peritonitis attenuated the reduction in pHi and prevented the increased Pco2- and [H+]-gap. It seems justified from these data to conclude that the somewhat reduced pHi in treated peritonitis groups did not reflect tissue ischemia.

Detection of liver ischemia using microdialysis during experimental peritonitis in pigs.

The liver oxygen delivery (DO2) and consumption (VO2) were measured in a porcine model of septic shock induced by fecal peritonitis. Lactate and hypoxanthine were simultaneously monitored in hepatic extracellular fluid and in central venous blood using a microdialysis technique. Animals were divided into a control group (n = 6) and a peritonitis group (n = 6). Peritonitis was induced by installation of a standardized amount of autologous feces into the abdominal cavity. The animals were followed for 5 h. The changes in the liver during peritonitis were, a decreased DO2, a increased, maintained, or decreased VO2, an increased oxygen extraction, and a loss of net hepatic lactate uptake. Parallel to these changes, systemic lactic acidosis developed. Intrahepatic lactate and hypoxanthine increased during peritonitis reflecting liver ischemia. The increase of these metabolites was seen concomitantly in the liver and in central venous blood. There was a wide variability of the individual response to the septic challenge among the animals. The limited hepatic oxygen delivery, and the increased needs for oxygen led to flow-dependent oxygen consumption, and signs of liver ischemia in severe sepsis. Intrahepatic and intravenous microdialysis may be useful for monitoring of the individual time course of hepatic and systemic ischemia in sepsis.

Small intestinal mucosal pH and lactate production during experimental ischemia-reperfusion and fecal peritonitis in pigs.

The aim of this study was to investigate mucosal pH and lactate production in a porcine model of ischemia/reperfusion and sepsis using both tonometry and a technique for segmental intestinal perfusion. Eighteen pigs (17-23 kg) were anesthetized and mechanically ventilated. They were divided into three groups and followed for 4 h. Group C (n = 6) served as controls. In the ischemia/reperfusion group (I/R; n = 6), the superior mesenteric artery was totally occluded for 60 min. In group P (n = 6), sepsis was induced by fecal peritonitis. Cardiac index (CI) was determined by thermodilution and blood flow in the superior mesenteric artery (QSMA), using a Transonic flow probe. Intramucosal pH (pHi) was calculated using tonometry. A special balloon tube for segmental perfusion was introduced in the midileum for lactate measurement. Lactate and oxygen saturation were measured in arterial blood and in the superior mesenteric vein. CI, QSMA, pHi, and lactate in blood and perfusate remained unchanged in controls. Occlusion of intestinal blood flow induced a fall in pHi from 7.28 +/- .02 to 6.76 +/- .04, a marked rise in lactate in the perfusate, and an increased arteriovenous lactate difference. During reperfusion, pHi tended to return to baseline values. Lactate in the perfusate and the arteriovenous lactate difference decreased. In sepsis there was a continuous reduction in CI and QSMA to 45 +/- 13% and 40 +/- 20% of baseline, respectively. pHi decreased moderately from 7.22 +/- .09 to 6.98 +/- .25. Lactate remained unchanged in blood and perfusate. Microscopic mucosal injury was observed in all animals subjected to ischemia/reperfusion and in three of six pigs in group P. A good association between pHi and lactate production was seen in ischemia/reperfusion. However, in sepsis, lactate in superior mesenteric venous blood or in intestinal perfusate did not increase, despite the fall in pHi. The mechanism causing ischemic mucosal injury has different characteristics in sepsis and in ischemia caused by arterial occlusion.

Alterations in mucosal immune cell distribution in septic rats.

A reduced cell-mediated immunity in the intestinal mucosa might promote gut barrier failure and bacterial translocation in shock. This study was performed to investigate changes from the normal distribution of cellular components of the immune system within the intestine during sepsis. Intra-abdominal sepsis was induced by cecal ligation and puncture. After 24 h, the animals were killed and specimens were taken from the small bowel. Immunohistochemical stainings were performed on frozen sections using monoclonal antibodies reactive with MHC class II positive cells (OX6), the alpha/beta antigen receptor on T lymphocytes (R73), CD4+ T lymphocytes (W3/25), CD8+ T lymphocytes (OX8), and macrophages (ED1). There was a significant reduction in the number of pan T lymphocytes as well as both CD4+ and CD8+ subsets in the mucosa of the septic rats as compared with sham operated rats (p < .01). In contrast, the populations of MHC class II positive cells and macrophages increased in sepsis (p < .01). We conclude that 24 h after the induction of peritonitis, there is an altered pattern of immunocompetent cells within the intestinal mucosa.

The mesenteric hemodynamic response to circulatory shock: an overview.

The mesenteric hemodynamic response to circulatory shock is characteristic and profound; this vasoconstrictive response disproportionately affects both the mesenteric organs and the organism as a whole. Vasoconstriction of post-capillary mesenteric venules and veins, mediated largely by the alpha-adrenergic receptors of the sympathetic nervous system, can effect an "autotransfusion" of up to 30% of the total circulating blood volume, supporting cardiac filling pressures ("preload"), and thereby sustaining cardiac output at virtually no cost in nutrient flow to the mesenteric organs. Under conditions of decreased cardiac output caused by cardiogenic or hypovolemic shock, selective vasoconstriction of the afferent mesenteric arterioles serves to sustain total systemic vascular resistance ("afterload"), thereby maintaining systemic arterial pressure and sustaining the perfusion of non-mesenteric organs at the expense of mesenteric organ perfusion (Cannon's "flight or fight" response). This markedly disproportionate response of the mesenteric resistance vessels is largely independent of the sympathetic nervous system and variably related to vasopressin, but mediated primarily by the renin-angiotensin axis. The extreme of this response can lead to gastric stress erosions, nonocclusive mesenteric ischemia, ischemic colitis, ischemic hepatitis, ischemic cholecystitis, and/or ischemic pancreatitis. Septic shock can produce decreased or increased mesenteric perfusion, but is characterized by an increased oxygen consumption that exceeds the capacity of mesenteric oxygen delivery, resulting in net ischemia and consequent tissue injury. Mesenteric organ injury from ischemia/reperfusion due to any form of shock can lead to a triggering of systemic inflammatory response syndrome, and ultimately to multiple organ dysfunction syndrome. The mesenteric vasculature is therefore a major target and a primary determinant of the systemic response to circulatory shock.

Influence of prostanoids on gastrointestinal mucosal injury in experimental septic shock.

Capillary stasis and mucosal injury in the stomach and small intestine were studied in septic shocked pigs. Septicemia was induced by live E. coli i.v. in 28 animals. Additionally, five animals were infused with Ringer's solution and served as sham controls. The 28 E. coli-infused animals were pretreated with either a cyclooxygenase inhibitor--indomethacin, n = 6, a thromboxane (TxA2)-synthetase inhibitor--UK 38,485 alone, n = 6, or combined with a serotonin-antagonist--ketanserin, n = 9. Seven E. coli-infused animals were left untreated and served as septic controls. The sham controls were hemodynamically stable and had normal histological findings. All bacteria-infused animals exhibited signs of septic shock with pronounced hemodynamic reactions. Attenuation of the bacteria-induced increase in pulmonary arterial blood pressure was found in all pretreated animals but most pronounced in the indomethacin-pretreated group which also showed protection against gastric mucosal injury and capillary stasis. TxA2-inhibited animals had aggravated capillary stasis and mucosal injuries. It is concluded that gastric mucosal damage could be modified by drugs influencing the prostanoid system. The "cytoprotective" effect of prostaglandins seem to be of minor importance for the prevention of the gastro-intestinal mucosal injury seen in some series.

The influence of a histamine2-receptor antagonist on the healing of an experimentally induced gastric mucosal lesion.

The effect of an H2-receptor antagonist (ranitidine) on the healing of gastric mucosal lesions was studied. Mucosal lesions were induced by a standardized thermo-mechanical technique. The healing process was assessed by macro- and light microscopical examination. It was further evaluated by measurements of the tissue contents of hydroxyproline, a chemical compound reflecting collagen, and of DNA and RNA, reflecting cell frequency and protein synthesis respectively, in the gastric wall from both injured and wound-free areas. The healing process was more rapid in ranitidine-treated animals than in controls. After four weeks, however, the lesion in nine out of ten animals had healed in the ranitidine-treated group and seven of nine rats in the control group. At that time the amounts of hydroxyproline, DNA and RNA did not differ between the two groups. These findings may be taken as an indication that the tissue components of the healed lesions were similar in ranitidine-treated rats and in the saline controls, i.e. the different speeds of the healing process did not seem to influence the components of the scar tissue.

Neutropenia prevents decrease in strength of rat intestinal anastomosis: partial effect of oxygen free radical scavengers and allopurinol.

A marked decrease in strength, probably due to local collagenolysis, occurs early after surgery in tissues adjacent to an incisional wound. To examine the role of the neutrophils, antineutrophil serum (ANS) was given to rats before and after a standardized end-to-end ileoileal anastomosis. Preimmune serum (PIS) was given to control rats. The decrease in anastomotic breaking strength, amounting to 55% in the PIS group, did not occur in ANS-treated rats, in which there was a decrease by more than 95% in the number of circulating polymorphonuclear cells. The decrease in tissue strength seems to be partly from oxygen free radicals, since the free radical scavengers superoxygen dismutase (SOD) and catalase prevented approximately 50% of the decrease. The xanthine oxidase inhibitor, allopurinol, prevented approximately 30% of the decrease. This is consistent with oxygen free radicals being partly generated by the neutrophils and partly generated after conversion of tissue xanthine dehydrogenase to xanthine oxidase. In contrast to ANS, SOD and catalase were unable to fully prevent the decrease in breaking strength. Therefore some other factor in addition to oxygen free radicals should be involved. One such factor may be the release of collagenolytic proteinases, e.g., elastase and cathepsin G, from the neutrophils.

The effect of dobutamine on distal colon ischaemia in the pig.

OBJECTIVE: To test the hypotheses that dobutamine increases intestinal blood flow, it reduces mucosal acidosis and it prevents mucosal injury in an experimental porcine model of distal colonic ischaemia. And the hypothesis that mannitol prevents reperfusion injury. DESIGN: Randomised animal experiment. SETTING: University Hospital, Department of Experimental Research. MATERIALS: Twenty-four pigs. INTERVENTIONS: Twenty-one pigs were subjected to 7 h of controlled non-occlusive intestinal ischaemia of the distal colon, consisting of an occlusion of the inferior mesenteric artery (IMA) and a constriction of the superior mesenteric artery (SMA). At 3.5 h six pigs were treated with dobutamine, six with mannitol (0.18 g/kgBW), six with dobutamine and mannitol and three served as controls. Three non-ischaemic pigs were treated with dobutamine. MEASUREMENTS AND RESULTS: All animals were haemodynamically stable throughout the experiment. There was no difference in any variable between the animals treated with mannitol and those not treated. The ischaemic dobutamine-treated animals increased their cardiac output (CO) by 14% compared to baseline and by 59% compared to controls. The median final dosage of dobutamine was 13.2 micrograms/kg per min (range 8.6-25.8). The blood flow in the restricted SMA, the intramucosal pH of the colonic mucosa (pHi) and the degree of histological mucosal injury were identical in animals treated with dobutamine and controls. The pH gap (pHa-pHi) correlated well (r = 0.97) with the PCO2 gap (aPCO2-intestinal PCO2). The non-ischaemic animals treated with dobutamine increased CO by 37% and blood flow of the SMA by 16%. CONCLUSIONS: Dobutamine increased CO but did not ameliorate or deteriorate colonic ischaemia in this experimental model. The PCO2 gap correlated well with the pH gap.

Tension leads to increased neutrophil accumulation and decreased laparotomy wound strength.

Wound margin strength was measured immediately after and at 72 hours after median laparotomy in rats. The laparotomy wound was sutured with or without tension, and wound margin strength was measured as breaking strength with the sutures in situ. In wounds sutured without tension, no decrease in breaking strength was observed at 72 hours; in rats sutured with tension, breaking strength decreased by 77%, and in almost half of the animals the sutures cut through. There was markedly increased accumulation of neutrophil leukocytes around the sutures in the tension group, as indicated by increased tissue myeloperoxidase activity. The decrease in breaking strength was abolished by treatment with an inhibitor of the collagen-degrading proteinases of the neutrophils (the soybean trypsin inhibitor). Although the decrease in breaking strength should be due to collagenolysis, there were no changes in collagen content or solubility around the sutures, indicating that the changes in collagen were too delicate to be revealed by the methods used. We conclude that the decrease in breaking strength was caused by the neutrophils.

Splanchnic oxygen consumption in septic and hemorrhagic shock.

Oxygen consumption (VO2) is dependent on oxygen delivery (DO2) in septic shock. Local hypoxia with later secondary organ failure may develop, however, despite an often hyperdynamic circulation. The splanchnic organs seem to be of vital importance in this context. In experiments performed in pigs we compared total body VO2 and DO2 with oxygen consumption and delivery in the gastrointestinal organs and the liver in two different shock states: (1) septic shock induced by peritonitis (n = 6) and (2) hemorrhagic shock (n = 6). Another group of six animals not in shock served as controls. Total, gastrointestinal, and liver DO2 decreased in a similar pattern in both septic and hemorrhagic shock. Gastrointestinal and liver VO2 increased in sepsis, whereas it was unchanged in hemorrhage. In the later phase of sepsis, liver VO2, but not gastrointestinal VO2, again decreased, because liver oxygen extraction was almost total and liver DO2 decreased further. The development of flow-dependent liver hypoxia was reflected in a decrease in liver lactate turnover (increased liver lactate release) during late sepsis. Early hypoxia in the splanchnic region is suggested as a plausible mechanism behind the development of secondary organ failure, especially in sepsis.

The sequence of development of intestinal tissue injury after strangulation ischemia and reperfusion.

Tissue injury at reperfusion has been reported after partial ischemia. However, previous attempts to demonstrate a component of injury caused by reperfusion after total ischemia have failed. This study was performed to evaluate the hypothesis that in such situations the extent of the tissue injury caused by ischemia itself prevented detection of a reperfusion component. Rats were subjected to near-total intestinal ischemia by means of a hydrostatic pressure clamp that produced preferential venous occlusion (strangulation) for periods from 1 to 90 minutes. Tissue injury was evaluated microscopically by a blinded examiner. Ischemic periods of 20 minutes or less did not induce detectable tissue injury. Longer durations of ischemia caused villous injury: the longer the period of ischemia, the more extensive the tissue injury. However, there was no exacerbation of injury seen after reperfusion, regardless of the duration of ischemia. In a separate series of rats, total arterial occlusion was employed without concomitant venous congestion. Such isolation arterial occlusion of 40 to 60 minutes' duration was followed by a statistically significant exacerbation of tissue injury at reperfusion. Thus total intestinal ischemia may be followed by reperfusion injury if there is no concomitant congestion and if ischemic injury is not too extensive.

Effects of positive end-expiratory pressure on splanchnic circulation and function in experimental peritonitis.

Splanchnic and central hemodynamic effects of positive end-expiratory pressure (PEEP) were studied in anesthetized pigs using mechanical ventilatory assistance, with or without sepsis (fecal peritonitis). One hour after sepsis, PEEP (10 cm H2O) was applied (n = 6). Another group (n = 6) had sepsis without PEEP. In one group (n = 6) without sepsis, PEEP was applied after 1 hour, while a fourth group (n = 5), without sepsis or PEEP, served as a control. The group with PEEP and sepsis had reduced cardiac index, portal venous blood flow, and liver surface blood flow. The group with PEEP alone had reduced splanchnic circulation by increasing gastrointestinal vascular resistance, while the group with sepsis alone had increased portal vascular resistance. In a separate series with sepsis, intermittent PEEP, and vigorous fluid resuscitation, it was demonstrated that avoiding hypovolemia did not seem to protect from the PEEP effects on the splanchnic circulation. The combination of sepsis and PEEP was not additive on portal blood flow reduction but reduced bile production.

Cardiac and pulmonary function in regional intestinal shock.

After a two-hour period of regional intestinal shock (arterial inflow pressure 30 to 35 mm Hg; electrical stimulation of regional vasoconstrictor fibers at 6 Hz) a pronounced cardiovascular derangement is observed as reflected in a rapid fall in arterial blood pressure. In this study, central hemodynamics and lung function were investigated to elucidate if functional changes in the thoracic organs might explain the cardiovascular collapse. No alteration of pulmonary function was observed. A negative inotropic influence on the heart was, however, noted as judged by a decreased left ventricular stroke volume and left ventricular maximal pressure change in the face of an increased left ventricular end diastolic pressure. Based on earlier observations with the same shock model, it is proposed that the cardiac effects were caused by cardiotoxic material released from the hypoxic gut.