Exogenous adrenomedullin prevents and reverses hypodynamic circulation and pulmonary hypertension in ovine endotoxaemia.

BACKGROUND: Hypodynamic septic shock is associated with a poor prognosis. The present randomized-controlled laboratory experiment was designed to test the hypothesis that the vasodilatory peptide hormone adrenomedullin (ADM) is a useful agent to prevent and reverse the development of hypodynamic circulation in ovine endotoxaemia. METHODS: Twenty-four healthy ewes were chronically instrumented for haemodynamic monitoring and randomly allocated to either the control, treatment, or prophylaxis group (n = 8 each). After a baseline (BL) measurement in the healthy state, all sheep were subjected to a continuous endotoxin infusion started at 10 ng kg(-1) min(-1) and doubled every hour six times. After 4 h of endotoxin challenge, the treatment group received ADM (50 ng kg(-1) min(-1)) for the remaining 3 h of the experiment. The prophylaxis group received a simultaneous infusion of endotoxin and ADM (50 ng kg(-1) min(-1)) from the beginning to the end of the 7 h intervention period. RESULTS: In the control and treatment groups, the ewes exhibited a hypodynamic circulation at 4 h (>20% reduction in cardiac index, both P < 0.01 vs BL). Endotoxin also increased mean pulmonary arterial pressure (MPAP) and arterial lactate concentrations. Prophylactic infusion of ADM prevented the occurrence of pulmonary hypertension and hypodynamic circulation and thereby blunted the increase in arterial lactate concentrations. In the treatment group, ADM administration increased CI (P < 0.001) and reduced both MPAP (P = 0.023) and arterial lactate concentrations (P < 0.001 each at 7 h) when compared with the control group. CONCLUSIONS: This study demonstrates that exogenous ADM prevents and reverses hypodynamic circulation, attenuates pulmonary hypertension, and limits lactic acidosis in ovine endotoxaemia.

Effects of sympathetic nerve blockade on vasoconstrictive properties of nitric oxide synthase inhibition in sheep.

OBJECTIVE: Inhibition of nitric oxide synthase causes intense vasoconstriction. This effect is thought to be dependent on sympathetic nerve activity. Thus, we investigated the vasoconstrictive effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in sheep, in which a reversible sympathetic block was established by thoracic epidural anesthesia. METHODS: Sheep (n = 11) were surgically prepared for chronic study. After at least 5 days of recovery, L-NAME was continuously administered and hemodynamics were monitored. This was done in sheep with and without sympathetic blockade in randomized order. RESULTS: The vasoconstrictive effects of L-NAME were similar in sheep with and without sympathetic blockade. CONCLUSION: The obtained results suggest that the vasoconstrictive properties of nitric oxide synthase inhibitors are independent of sympathetic tone.

S-ethylisothiourea, a nonamino acid inhibitor of nitric oxide synthase, reverses septic vasodilation in sheep.

S-ethylisothiourea (3936W92) is a nonamino acid antagonist of nitric oxide synthase. Its selectivity for the inducible form of nitric oxide synthase is twice as high as for the constitutive form of the enzyme. We tested 3936W92 in 20 sheep, which were surgically prepared for chronic study. In all sheep, a hyperdynamic sepsis was induced by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, nine sheep received a continuous infusion of 3936W92 over the next 24 h, whereas the control group (n = 9) received saline instead. Two sheep died within the first 24 h of sepsis. 3936W92 caused a complete reversal of the hyperdynamic circulation, while sheep in the control group remained hyperdynamic. Although the cardiac index decreased significantly during treatment with 3936W92 (7.9 +/- .8 vs. 6.0 +/- .7 l/min/m2), a simultaneous increase in oxygen extraction prevented oxygen consumption from falling.

Nitric oxide synthase inhibition versus norepinephrine in ovine sepsis: effects on regional blood flow.

Hypotension is a serious problem in septic patients. We investigated regional perfusion in several organs during treatment of hyperdynamic sepsis in sheep. Sepsis was induced and maintained for the entire experiment with a continuous infusion of live Pseudomonas aeruginosa. Treatment with either norepinephrine or the nitric oxide synthase inhibitor L omega-mono-methyl-arginine (L-NMMA) was begun after 24 h of sepsis and continued for 24 h. The norepinephrine dosage was adjusted to achieve the same increase in mean arterial pressure as that obtained by a fixed dose of L-NMMA (7 mg/kg/h). Blood flows were analyzed by the microsphere technique. Both compounds restored blood pressure effectively, but only L-NMMA caused a significant increase in systemic vascular resistance, concomitant with a significant fall in cardiac output. Sepsis caused an increase in myocardial blood flow and a redistribution of blood flow away from the pancreas and the stomach. Renal blood flow was not significantly elevated. During treatment with either compound, renal blood flow remained unchanged, despite a fall in cardiac output in the L-NMMA group. Unchanged renal blood flow combined with the restoration of arterial blood pressure caused a significant increase in urine output. Both L-NMMA and norepinephrine caused a redistribution of blood flow to the colon. Pancreatic blood flow was further reduced by L-NMMA but the oxygen extraction improved simultaneously, so that oxygen availability in the pancreas might have been unchanged. Because ischemic pancreatitis in sepsis is likely to trigger multiorgan failure, further investigations in that area are desirable.

Effects of alpha-trinositol on systemic inflammation and renal function in ovine bacterial sepsis.

Neuronally secreted peptides are important mediators of hemodynamic changes in the systemic inflammatory response. The inositol derivative D-myo-inositol[1,2,6]triphosphate (alpha-trinositol) has been demonstrated to be a specific nonpeptide antagonist of vasoconstriction induced by neuropeptide Y. We induced sepsis by a 48 h continuous infusion of Pseudomonas aeruginosa (10(6) colony-forming unit/min intravenously [i.v.]) in 12 chronically instrumented, conscious sheep. After 24 h, the animals were randomized to receive either alpha-trinositol (i.v. bolus of 2 mg/kg, followed by a continuous infusion of 3.5 mg/kg/h) or the saline carrier. alpha-Trinositol increased the heart rate (108 +/- 4 to 152 +/- 9 beats per minute) and reduced the stroke volume index (65 +/- 5 to 49 +/- 2 mL/beat/m2) but did not change cardiac index. Left ventricular stroke work decreased significantly (80 +/- 9 to 58 +/- 7 g.m/m2). All blood flows except the infrarenal aortic flow were increased after 24 h, but treatment decreased only the flow to the hind limb region. Urine output and fractional sodium excretion significantly increased without osmotic diuretic effects after alpha-trinositol. In treated animals, we found significantly lower leukocyte counts in all organ tissues. We conclude that alpha-trinositol modulates the cardiac performance and the local inflammatory response in tissues, and improves the fluid balance in septic sheep.

Inhalation injury increases the anastomotic bronchial blood flow in the pouch model of the left ovine lung.

Pulmonary parenchymal damage often occurs after airway injury. Bronchial venous drainage empties into the pulmonary microvasculature. We developed an in vivo model to study the bronchopulmonary portal system after smoke inhalation injury. Eight ewes were instrumented with hydraulic occluders on the left pulmonary artery (LPA), the left pulmonary vein, and the bronchoesophageal artery (BEA); a catheter in the LPA; and Swan-Ganz and femoral artery catheters. The vasculature between the occluders was defined as pouch. At stable mean arterial and right pulmonary arterial pressures, LPA occlusion reduced the left pulmonary artery pressure (LPAP) from 17 +/- 1 mmHg to 8 +/- 1 mmHg (p < .05). After left pulmonary vein occlusion, LPAP rose to 28 +/- 4 mmHg (p < .05 vs. baseline), indicating that systemic blood had entered the pouch. Opening the pouch to atmospheric pressure revealed an anastomotic bronchial blood flow (anastomotic Qbr) of .76 +/- .11% of cardiac output (CO). BEA occlusion reduced the anastomotic Qbr to .32 +/- .06% of CO (p < .05). Smoke inhalation injury resulted in a further increase in the maximal LPAP to 38 +/- 5 mmHg (p < .05 vs. right pulmonary artery pressure). The anastomotic Qbr rose to 1.29 +/- .13% of CO (p < .05) and was reduced to .40 +/- .09% of CO (p < .05) by BEA occlusion. Inhalation injury increased the anastomotic Qbr mainly due to BEA vasodilatation. Because the BEA supplies the injured airway, it may deliver deleterious material to the lung parenchyma.

Comparison of the haemodynamic effects of nitric oxide synthase inhibition and nitric oxide scavenging in endotoxaemic sheep.

OBJECTIVE: The present study compared the effects of nitric oxide (NO) synthase inhibition and NO scavenging with haemoglobin in endotoxaemic sheep. DESIGN: 12 sheep were instrumented for chronic study. Six sheep received LG-nitro-arginine-methylester (L-NAME, 2.5 mg/kg bolus followed by a continuous infusion of 0.5 mg/kg per h), the other 6 sheep received pyridoxalated haemoglobin polyoxyethylene conjugate (PHP, 100 mg/kg bolus followed by a continuous infusion of 20 mg/kg per h). MEASUREMENTS AND RESULTS: Haemodynamic and oxygenation parameters were measured in healthy sheep, after infusion of Salmonella typhosa endotoxin (10 ng/kg per min) for 24 h and after infusion of L-NAME or PHP. The infusion of endotoxin resulted in a hypotensive, hyperdynamic circulation. Infusion of L-NAME increased mean arterial pressure (MAP) from 76.1 +/- 4.2 mmHg to normal values of 95.8 +/- 5.7 mmHg (p < 0.05). PHP increased MAP from 73.0 +/- 3.0 to 88.6 +/- 4.7 mmHg (p < 0.05). This increase in MAP was associated in the L-NAME group with a more prominent drop in cardiac index (from 10.2 +/- 0.4 to 7.0 +/- 0.51.min-1.m-2; p < 0.05) than in the PHP group (from 10.7 +/- 0.2 to 9.3 +/- 0.61.min-1.m-2). During the first 90 min of infusion, cardiac index remained lower in the L-NAME group than in the PHP group. The increase in pulmonary vascular resistance was also higher in the L-NAME group. CONCLUSION: These results suggest, that at the doses used in the experiment, NO scavenging with PHP has smaller effects on cardiac index and pulmonary vascular resistance than NO synthase inhibition with L-NAME. Therefore, the concept of NO scavenging in hyperdynamic sepsis should be further evaluated.

Nitric oxide and endothelial permeability.

Nitric oxide synthase inhibition reverses systemic vasodilation during sepsis but may increase endothelial permeability. To assess adverse effects on the pulmonary vasculature, 12 sheep were chronically instrumented with lung lymph fistulas and hydraulic pulmonary venous occluders. Escherichia coli endotoxin (lipopolysaccharide; 10 ng . kg-1 . min-1) was continuously infused for 32 h. After 24 h, six animals received 25 mg/kg of Nomega-nitro-L-arginine methyl ester (L-NAME), and six received saline. All sheep developed a hyperdynamic circulatory response and elevated lymph flows by 24 h of lipopolysaccharide infusion. L-NAME reversed systemic vasodilation, increased pre- and postcapillary pulmonary vascular resistance index, pulmonary arterial pressure, and, transiently, effective pulmonary capillary pressure. Lung lymph flows were not different between groups at 24 h or thereafter. Calculated as changes from baseline, however, lung lymph flow was higher in the L-NAME group than in the control animals, with a trend toward lower lymph-to-plasma protein concentration ratio at 25 h. Permeability analysis at 32 h by the venous occlusion technique showed normal reflection coefficients and elevated filtration coefficients without differences between groups. Reversal by L-NAME of the systemic vasodilation during endotoxemia was associated with high pulmonary vascular resistance without evidence of impaired pulmonary endothelial barrier function.

Haemodynamic effects of dopexamine and nitric oxide synthase inhibition in healthy and endotoxaemic sheep.

Chronically instrumented awake healthy sheep (n = 6) received the synthetic catecholamine, dopexamine, during or without a background infusion of the nitric oxide synthase inhibitor. L-nitro-arginine-methylester (L-NAME). Three days later, hypotensive-hyperdynamic circulation was induced and maintained by continuous infusion of Salmonella typhosa endotoxin (10 ng/kg per min). After 24 h of continuous endotoxin infusion, the dopexamine L-NAME protocol was repeated. In healthy and endotoxaemic animals with and without nitric oxide synthase inhibition dopexamine caused the same haemodynamic changes: heart rate and cardiac output increased, mean arterial pressure and systemic vascular resistance decreased. L-NAME infusion induced normalisation of the hypotonic-hyperdynamic circulation in endotoxaemic animals. Dopexamine reduced some adverse effects of L-NAME treatment, like increased pulmonary vascular resistance and decreased oxygen delivery. In conclusion the haemodynamic effects of dopexamine are independent of the amount of nitric oxide production. Dopexamine may attenuate some of the adverse effects of nitric oxide synthase inhibition.

Enhancement of axillary brachial plexus block anesthesia by coadministration of neostigmine.

BACKGROUND AND OBJECTIVES: The acetylcholinesterase inhibitor neostigmine has shown peripherally mediated analgesic action in recent preclinical and clinical studies. The present study investigates the effectiveness of adding neostigmine to a local anesthetic, mepivacaine, in patients receiving axillary brachial plexus block for upper extremity surgery. METHODS: In a double-blind, randomized study 34 patients were assigned to the treatment group: Neostigmine (NM) (500 microg) + mepivacaine (M) (500 mg) (NM, n = 17) as drugs for the plexus block, or to control group: mepivacaine (500 mg) + saline (0.9%, 1 mL) (M, n = 17). RESULTS: The onset and duration of sensory and motor block was similar in both groups. Patients receiving NM had significantly lower pain ratings [visual analogue scores (VAS): 14.7 +/- 9.9 vs 32.4 +/-23.5; P < .05] 24 hours after surgery, and a lower number of patients in the NM group needed supplemental analgesics during the first 24 hours postoperatively. No adverse events were recorded for either group. CONCLUSIONS: Peripherally administered neostigmine improves postoperative analgesia in axillary brachial plexus block.

Inhaled nitric oxide selectively reduces pulmonary hypertension after ovine smoke inhalation but does not improve oxygenation.

Inhaled nitric oxide (NO) is known to selectively reduce pulmonary hypertension and improve the ventilation-perfusion relationship in subjects with lung injury of various origin. However, some forms of lung injury do not react to inhaled NO at all, or show only a reduction in pulmonary arterial pressure. Very little is known about the effects of inhaled NO after smoke inhalation injury. We investigated the effects of inhaled NO in an established model of ovine smoke inhalation injury. Chronically instrumented sheep (n = 8) had tracheostomies and were insufflated with smoke generated from burning cotton cloth (4 times at 12 breaths each). They were then connected to a ventilator with oxygen-enriched air to achieve arterial oxygen tensions within the normal range. After 48 hours, NO was added to the inspired gas in ascending concentrations of up to 100 ppm. Systemic and pulmonary hemodynamics as well as oxygen transport were analyzed. Inhaled NO dose dependently lowered the pulmonary hypertension. Concentrations higher than 20 ppm did not further reduce the pulmonary artery pressure. Right ventricular stroke work index was significantly improved owing to the reduction in pulmonary vascular resistance. Arterial oxygenation, however, was not optimized by inhaled NO, probably because of interstitial edema formation.

Processing of stored packed red blood cells using autotransfusion devices decreases potassium and microaggregates: a prospective, randomized, single-blinded in vitro study.

The aim of the study was to compare the potential of autotransfusion devices to reduce non-infectious complications related to transfusion of long-stored packed red blood cells (PRBC; n= 57), such as changes in electrolytes, blood cells and the load of free microaggregates. Following a baseline measurement, a blood pool of three PRBC was divided into three equal volumes and washed with either the Haemonetics Cell Saver (HCS) or the continuous autotransfusion system (C.A.T.S), using the quality (CATS(quality)) and emergency (CATS(emergency)) mode. After the washing procedure, measurements for electrolytes, blood cells and free microaggregates were repeated (n= 19 each). Compared with baseline, the investigated autotransfusion devices reduced the median load of potassium (baseline: 52 mEq L(-1); HCS: 4 mEq L(-1); CATS(quality): 4 mEq L(-1); CATS(emergency): 17 mEq L(-1); each P < 0.001), restored a physiologic electrolyte balance and significantly decreased the load of leucocytes, glucose and protein. Whereas the quantity of microaggregates was not reduced by HCS, CATS(emergency) decreased the load of cell fragments below 7.8 microm (P < 0.05 vs. baseline). Using CATS(quality) decreased the load of cell fragments not only to a diameter below 7.8 microm (P < 0.001 vs. baseline) but also of microaggregates between 7.8 and 17.6 microm (P < 0.05 vs. baseline). In situations where long-stored PRBC have to be transfused, the procedure described here may be feasible to reduce clinically relevant side effects, i.e. hyperkalaemia and microvascular obstruction secondary to free cell fragments. This approach could be especially useful in patients undergoing massive transfusion and/or suffering from renal failure.

[Role of adrenomedullin in the pathogenesis and treatment of cardiovascular dysfunctions and sepsis]. / Bedeutung von Adrenomedullin Pathogenese und Behandlung kardiovaskulärer Dysfunktionen der Sepsis.

Adrenomedullin (AM) is an endogenous vasodilatory peptide hormone, which plays a key role in the regulation and preservation of cardiovascular and pulmonary functions. Clinical and experimental studies have demonstrated that AM represents an alternative therapeutic option in the treatment of pulmonary hypertension. In addition, AM proved to be useful in the treatment of cardiovascular dysfunctions, such as arterial hypertension and congestive heart failure following myocardial infarction. Recent research has also shown that AM plays a pivotal role in the development of sepsis-associated hemodynamic and microcirculatory disorders. Experimental studies also suggest that infusion of exogenous AM might be a rational approach to prevent and treat hypodynamic septic shock. The objectives of this review article are to characterize the regulative properties of AM and to discuss clinical and experimental studies which allow to judge the role of AM in the setting of cardiovascular dysfunction and sepsis.

Autotransfusion and blood-sparing techniques in infants and children.

While several techniques to reduce perioperative blood loss have been established for surgery in adults, not all of them are applicable in paediatric surgery. Further, far less is known about the efficacy of these techniques in this specific population. Consequently, techniques for the prevention of blood loss are often neglected. However, it is these young patients, with their remaining life expectancy, who will benefit the most from any prevented infection (HIV, hepatitis, etc.) or from any immunological complications. Hemodilution is limited because of the high percentage of fetal hemoglobin in small infants, as well as the additional anaesthetic needed to obtain blood. Until recently, intraoperative autotransfusion was ineffective in small children due to technical limitations; however, advanced technology now renders intraoperative autotransfusion possible, even in infants weighing less than 20 kg.

Inhaled vasodilator therapy for treatment of acute lung injury.

In randomized controlled trials, inhaled nitric oxide failed to provide significant clinical benefit in patients with acute lung injury. Despite temporary improvement in oxygenation, inhaled nitric oxide neither improved survival, nor decreased length of mechanical ventilation. Thus, with the exception of severe hypoxaemia refractory to conventional therapy, inhaled nitric oxide is not indicated in patients with acute lung injury. Inhalation of prostacyclin and prostaglandin E1, respectively, has been associated with an improvement in oxygenation and a decrease in pulmonary artery pressure. Prospective randomized trials are warranted to assess the impact of inhaled prostaglandins on the outcome of patients with acute lung injury.

[Massive transfusion with the Rapid Infusion System. Its effect on core body temperature]. / Massivtransfusion mit dem Rapid Infusion System. Einfluss auf die Körperkerntemperatur.

Extensive blood loss requires adequate volume replacement. However the infused volume cannot be adequately warmed especially when high infusion rates are necessary. Subsequently, hypothermia develops and results in hemodynamic instability and coagulopathy. The Rapid Infusion System (RIS) allows high infusion rates (up to 1.5 l/min) while at the same time guaranteeing sufficient warming. The efficacy of the RIS was investigated in 43 consecutive patients who required a massive transfusion. The average volume transfused in these patients was 31.7 +/- 4.5 l (minimum: 7.8 l; maximum: 165.3 l) which is equal to an average exchange of 6.4 times the circulating blood volume (maximum: 39.4 blood volumes). The replacement of such high blood volumes has not yet been published in a series of patients. Despite these high transfusion rates, the body core temperature was maintained at 35.85 +/- 0.1 degrees C. Only five patients had a body core temperature below 34 degrees C, all were trauma patients and four of these five patients already had a preoperative temperature below 34 degrees C. The mortality in this study was 28%, which is markedly reduced in comparison to previous publications although they all considered at patients with significantly less blood loss. Maintaining normothermia and normovolemia by the use of the RIS may explain the improved outcome.