Effects of epinephrine compared with the combination of dobutamine and norepinephrine on gastric perfusion in septic shock

OBJECTIVE: In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock. METHODS: In a prospective randomized study on 2 parallel groups, systemic and pulmonary hemodynamics (arterial and Swan-Ganz catheters), gastric mucosal blood flow (laser Doppler flowmetry technique), hepatic function (indocyanine green clearance), and blood gases were evaluated just before catecholamine infusion and when mean arterial pressure reached 70 to 80 mm Hg. Epinephrine or norepinephrine were titrated (from 0.1 microg/kg per minute, with 0.2 microg/kg per minute increases every 5 minutes). Dobutamine was continuously infused at 5 microg/kg per minute. RESULTS: Twenty-two patients were included (11 in each group). At randomization there was no significant difference between groups. At the time of evaluation, mean arterial pressure was 78 +/- 3 and 77 +/- 5 mm Hg in the epinephrine and dobutamine-norepinephrine groups, respectively. There was no significant difference between groups regardless of the systemic and pulmonary hemodynamic or blood gas variable considered. Nevertheless, compared with dobutamine-norepinephrine, epinephrine tended to induce greater values for cardiac index (5.0 +/- 1.6 versus 4.2 +/- 1.5 L/min per square meter; P =.078) and oxygen transport (617 +/- 166 versus 481 +/- 229 mL/min per square meter; P =.068). Epinephrine also induced significantly greater values of gastric mucosal blood flow (662 +/- 210 versus 546 +/- 200 units; P =.011) but did not modify indocyanine green clearance. CONCLUSIONS: In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 microg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index.     

The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats

Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that opioids can induce NO release in endothelium as well as in neural cells. Cholestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels of endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), NG-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than in sham-operated animals (115 +/- 12 mm2 vs. 72 +/- 11 mm2, P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the severity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent administration of naltrexone with L-arginine was protective against ethanol-induced gastric damage in both normal and cholestatic groups. Administration of naltrexone with L-NAME had the same effect in cholestatic and control rats and increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 microM vs. 39 +/- 3 microM, P < 0.05). Pretreatment of animals with naltrexone significantly reduced plasma levels of NO2- + NO3- in cholestatic animals, but not in control rats (33 +/- 6 microM vs. 32 +/- 4 microM). The protective effect of L-NAME against gastric damage in cholestatic rats can be explained by inhibition of NO overproduction and it seems that interaction between opioids and NO may have an important role in generation of NO overproduction and gastric complications in cholestatic rats.     

Nitric oxide (NO)-releasing naproxen (HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic Acid 4-(nitrooxy)butyl ester]) interactions with aspirin in gastric mucosa of arthritic rats reveal a role for aspirin-triggered lipoxin, prostaglandins, and NO in gastric protection

Administration of selective and nonselective cyclooxygenase (COX)-2 inhibitors to rheumatoid arthritis patients taking low doses of acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal bleeding. The present study was undertaken to investigate whether administration of HCT-3012 [(S)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid 4-(nitrooxy)butyl ester], a nitric oxide (NO)-releasing derivative of naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on arthritis score and interleukin-6 plasma levels, coadministration of naproxen (10 mg/kg/day) and celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates arthritis development (P <0.01 versus arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P <0.01 versus ASA alone). In contrast, coadministration of HCT-3012 (15 mg/kg/day) significantly attenuated arthritis development, because HCT-3012 was equally or more effective than naproxen and celecoxib in attenuating local and systemic inflammation (P >0.001 versus arthritis) without exacerbating gastric mucosal injury caused by ASA. Arthritis development associates with gastric COX-2 induction, mRNA and protein, and enhanced gastric prostaglandin E2 (PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including celecoxib, were effective in reducing gastric PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of aspirin-triggered lipoxin (ATL), a COX-2-derived lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with naproxen and celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that HCT-3012 derived from NO has the potential to compensate for inhibition of PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and coxibs in rheumatic patients that take low doses of ASA.     

The angiotensin type 1 receptor antagonist, eprosartan, attenuates the progression of renal disease in spontaneously hypertensive stroke-prone rats with accelerated hypertension

The effects of the angiotensin type 1 (AT(1)) receptor antagonist, eprosartan, were studied in a model of severe, chronic hypertension. Treatment of male spontaneously hypertensive stroke prone rats (SHR-SP) fed a high-fat, high-salt diet with eprosartan (60 mg/kg/day i.p.) for 12 weeks resulted in a lowering of blood pressure (250 +/- 9 versus 284 +/- 8 mm Hg), renal expression of transforming growth factor-beta mRNA (1.5 +/- 0.2 versus 5.4 +/- 1.4) and the matrix components: plasminogen activator inhibitor-1 (5.2 +/- 1.4 versus 31.4 +/- 10.7), fibronectin (2.2 +/- 0.6 versus 8.2 +/- 2.2), collagen I-alpha 1 (5.6 +/- 2.0 versus 23.8 +/- 7.3), and collagen III (2.7 +/- 0.9 versus 7.6 +/- 2.1). Data were corrected for rpL32 mRNA expression and expressed relative to Wistar Kyoto (WKY) rats [=1.0]. Expression of fibronectin protein was also lowered by eprosartan (0.8 +/- 0.1 versus 1.9 +/- 0.5), relative to WKY rats. Eprosartan provided significant renoprotection to SHR-SP rats as measured by decreased proteinuria (22 +/- 2 versus 127 +/- 13 mg/day) and histological evidence of active renal damage (5 +/- 2 versus 195 +/- 6) and renal fibrosis (5.9 +/- 0.7 versus 16.4 +/- 1.9) in vehicle- versus eprosartan-treated rats, respectively. Our results demonstrated that AT(1) receptor blockade with eprosartan can reduce blood pressure and preserve renal structure and function in this model of severe, chronic hypertension. These effects were accompanied by a decreased renal expression of transforming growth factor-beta1, plasminogen activator inhibitor-1, and several other extracellular matrix proteins compared with vehicle-treated SHR-SP.     

Protection of the gastric mucosa by linoleic acid--a nutrient essential fatty acid

We studied whether linoleic acid, a precursor for arachidonic acid and prostaglandins, could protect the gastric mucosa against ethanol-induced injury. Fasted male rats received intragastric pretreatment with 1 ml of one of: a) solubilizer; b) solubilized linoleic acid (74 mg); or c) solubilized oleic acid (74 mg) (a nonessential fatty acid). One hour later, 2 ml 100% ethanol was given intragastrically. Three hours after ethanol administration, the gastric mucosa was assessed for gross necrosis and for histologic changes. Three hours after ethanol administration in solubilizer, pretreated-group gross mucosal necrosis involved 35 +/- 3% of total mucosal area, while deep histologic necrosis involved 52 +/- 4% of the mucosal strip length. Pretreatment with linoleic acid (but not oleic acid) significantly reduced gross histologic necrosis, to 2.3 +/- 0.5%, and deep histologic necrosis to 4 +/- 2% (both p less than 0.001 versus solubilizer group). The protective action of linoleic acid was significantly reduced (greater than 10-fold) by pretreatment with indomethacin (prostaglandins synthetase inhibitor), suggesting prostaglandins as mediators of protection. The present study showed that effective protection of the gastric mucosa against ethanol injury can be achieved by intragastric administration of linoleic acid, a dietary essential fatty acid.     

Comparison of a 10-breaths-per-minute versus a 2-breaths-per-minute strategy during cardiopulmonary resuscitation in a porcine model of cardiac arrest

BACKGROUND: Hyperventilation during cardiopulmonary resuscitation (CPR) is harmful. METHODS: We tested the hypotheses that, during CPR, 2 breaths/min would result in higher cerebral perfusion pressure and brain-tissue oxygen tension than 10 breaths/min, and an impedance threshold device (known to increase circulation) would further enhance cerebral perfusion and brain-tissue oxygen tension, especially with 2 breaths/min. RESULTS: Female pigs (30.4 +/- 1.3 kg) anesthetized with propofol were subjected to 6 min of untreated ventricular fibrillation, followed by 5 min of CPR (100 compressions/min, compression depth of 25% of the anterior-posterior chest diameter), and ventilated with either 10 breaths/min or 2 breaths/min, while receiving 100% oxygen and a tidal volume of 12 mL/kg. Brain-tissue oxygen tension was measured with a probe in the parietal lobe. The impedance threshold device was then used during an 5 additional min of CPR. During CPR the mean +/- SD calculated coronary and cerebral perfusion pressures with 10 breaths/min versus 2 breaths/min, respectively, were 17.6 +/- 9.3 mm Hg versus 14.3 +/- 6.5 mm Hg (p = 0.20) and 16.0 +/- 9.5 mm Hg versus 9.3 +/- 12.5 mm Hg (p = 0.25). Carotid artery blood flow, which was prospectively designated as the primary end point, was 65.0 +/- 49.6 mL/min in the 10-breaths/min group, versus 34.0 +/- 17.1 mL/min in the 2-breaths/min group (p = 0.037). Brain-tissue oxygen tension was 3.0 +/- 3.3 mm Hg in the 10-breaths/min group, versus 0.5 +/- 0.5 mm Hg in the 2-breaths/min group (p = 0.036). After 5 min of CPR there were no significant differences in arterial pH, PO2, or PCO2 between the groups. During CPR with the impedance threshold device, the mean carotid blood flow and brain-tissue oxygen tension in the 10-breaths/min group and the 2-breaths/min group, respectively, were 102.5 +/- 67.9 mm Hg versus 38.8 +/- 23.7 mm Hg (p = 0.006) and 4.5 +/- 6.0 mm Hg versus 0.7 +/- 0.7 mm Hg (p = 0.032). CONCLUSIONS: Contrary to our initial hypothesis, during the first 5 min of CPR, 2 breaths/min resulted in significantly lower carotid blood flow and brain-tissue oxygen tension than did 10 breaths/min. Subsequent addition of an impedance threshold device significantly enhanced carotid flow and brain-tissue oxygen tension, especially in the 10-breaths/min group.     

Role of central and peripheral mechanisms in the action of alpha-methyldopa on blood pressure and renin secretion.

The mechanism by which alpha-methyldopa lowers arterial pressure and suppresses renin secretion was investigated in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were prevented by adjusting a suprarenal aortic clamp. After intravenous alpha-methyldopa (100 mg/kg) mean arterial pressure (MAP) decreased form 127+/-3 to a mean minimum of 107+/-4 mm Hg (P less than .01) and plasma renin activity (PRA) decreased from 20.6+/-4.8 to 10.9+/-1.7 ng/ml/3 hr (P less than .05). Blockade of peripheral dopa decarboxylase with intravenous carbidopa (20 mg/kg) significantly attenuated the hypotensive action of intravenous alpha-methyldopa but MAP still decreased from 145+/-6 to 130+/-5 mm Hg(P less than .001). Intravenous carbidopa completely abolished the fall in PRA produced by intravenous alpha-methyldopa (16.8+/-2.8 to 16.9+/-2.1 ng/ml/3 hr.) Intraventricular carbidopa (3 microng/kg/min) did not block the hypotensive (135+/-8 to 113+/-7 mm Hg, P less than .01) or renin-lowering effect (24.3+/-5 to 13.4+/-3.2 ng/ml/3 hr, P less than .01) of intravenous alpha-methyldopa (0.5 mg/kg decreased MAP from 118 +/- 5 to 104 +/- 5 mm Hg (P less than 0.001) but had no effect on PRA (23.4+/-6 TO 19.4+/-7 NG/ML/3 hr.) Intraventricular alpha-methylnorepinephrine (2 microng/kg) also decreased MAP from 127+/-5 to 112+/-3mm Hg (P less than .006) but again failed to significantly alter PRA (36.1+/-11.8 to 37.2+/-15 ng/ml/3 hr). These results indicate that there is both a central and peripheral component to the antihypertensive effect of alpha-methyldopa in the dog and that the suppression of renin secretion results from a peripheral action of the drug.     

Buspirone raises blood pressure through activation of sympathetic nervous system and by direct activation of alpha1-adrenergic receptors after severe hemorrhage

5-Hydroxytryptamine 1A (5-HT1A) receptor agonists reverse the hypotensive and sympathoinhibitory responses to severe hemorrhage in rats. To determine whether 5-HT1A receptor-mediated pressor responses in hypovolemic animals are due to sympathoexcitation and/or direct vasoconstriction, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to the partial 5-HT1A receptor agonist buspirone or the more selective, full 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were compared in intact and ganglionic blocked, hemorrhaged Sprague-Dawley rats. Buspirone produced dose-dependent increases in BP (110 +/- 4(**), 86 +/- 4(**), 65 +/- 7 mm Hg), HR [369 +/- 10(**), 337 +/- 14, 277 +/- 16 beats per minute (bpm)], and RSNA (114 +/- 36(**), 34 +/- 21, -23 +/- 25% baseline for 0.2, 0.1, and 0 mg/kg; (**)p < 0.01 versus 0 mg/kg, 3 min after injection). Ganglionic blockade with hexamethonium chloride blocked the pressor effect of 9.9 microg/kg 8-OH-DPAT and attenuated, but did not block, the pressor response to 0.2 mg/kg buspirone (85 +/- 7 versus 46 +/- 6 mm Hg for buspirone + ganglionic blockade versus saline + ganglionic blockade; p < 0.01). In subsequent tests, rats treated with the selective alpha1-adrenergic receptor antagonist prazosin (25 microg/kg) continued to show extensive tachycardic (+73 +/- 26 bpm) and sympathoexcitatory (128 +/- 55% baseline) responses to 0.2 mg/kg buspirone. Ganglionic blockade combined with prazosin completely blocked all responses to buspirone. Buspirone (0.2 mg/kg) produced significant bradycardic (-89 +/- 12 bpm; p < 0.01) and sympathoinhibitory (-72 +/- 7% baseline; p < 0.01) responses in euvolemic rats 3 min after injection. It is concluded that the pressor effect of buspirone is unique to hypovolemic animals and is mediated by sympathetic activation as well as direct activation of vascular alpha1-adrenergic receptors.     

Does splanchnic ischemia occur in isolated neurotrauma? A prospective observational study.

OBJECTIVE: To characterize the incidence and severity of splanchnic ischemia, as defined by gastric tonometry, in patients with isolated severe head injury and to examine the relationship between cerebral hemodynamics and splanchnic ischemia. DESIGN: Prospective observational study. SETTING: Neurosurgical intensive care unit in a tertiary referral center. PATIENTS: Ten patients with severe neurotrauma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean arterial pressure, intracranial pressure, and gastric mucosal P(CO2) measurements were recorded at 15-min intervals. Intramucosal pH was calculated every 3 hrs. All patients received stress ulcer prophylaxis. Nine patients received noradrenaline infusions to maintain a target cerebral perfusion pressure of 70 mm Hg. The mean baseline gastric mucosal P(CO2) and intramucosal pH were 38+/-10 torr and 7.38+/-0.1 pH units, respectively. Nine patients manifested low intramucosal pH during the study period. Gastric mucosal P(CO2) values ranged from 36 to 132 torr. Intramucosal pH measurements ranged from 6.9 to 7.47. The mucosal gap ranged from -12 to +93 torr (mean +/- SD, 17+/-17 torr). The pH gap ranged from -0.1 to +0.54 pH units (mean +/- SD, 0.14+/-0.11 pH units). There was no statistically significant relationship between cerebral hemodynamics, the use of inotropes, and gastric mucosal P(CO2), or intramucosal pH. CONCLUSIONS: Splanchnic ischemia (intramucosal pH, <7.3) occurs commonly in isolated neurotrauma, with a statistically nonsignificant trend toward development of mucosal ischemia with decreased cerebral perfusion.     

Reducing ventilation frequency during cardiopulmonary resuscitation in a porcine model of cardiac arrest

INTRODUCTION: American Heart Association/American College of Cardiology guidelines recommend a compression-to-ventilation ratio (C/V ratio) of 15:2 during cardiopulmonary resuscitation (CPR) for out-of-the-hospital cardiac arrest. Recent data have shown that frequent ventilations are unnecessary and may be harmful during CPR, since each positive-pressure ventilation increases intrathoracic pressure and may increase intracranial pressure and decrease venous blood return to the right heart and thereby decrease both the cerebral and coronary perfusion pressures. HYPOTHESIS: We hypothesized that reducing the ventilation rate by increasing the C/V ratio from 15:2 to 15:1 will increase vital-organ perfusion pressures without compromising oxygenation and acid-base balance. METHODS: Direct-current ventricular fibrillation was induced in 8 pigs. After 4 min of untreated ventricular fibrillation without ventilation, all animals received 4 min of standard CPR with a C/V ratio of 15:2. Animals were then randomized to either (A) a C/V ratio of 15:1 and then 15:2, or (B) a C/V ratio of 15:2 and then 15:1, for 3 min each. During CPR, ventilations were delivered with an automatic transport ventilator, with 100% oxygen. Right atrial pressure, intratracheal pressure (a surrogate for intrathoracic pressure), aortic pressure, and intracranial pressure were measured. Coronary perfusion pressure was calculated as diastolic aortic pressure minus right atrial pressure. Cerebral perfusion pressure was calculated as mean aortic pressure minus mean intracranial pressure. Arterial blood gas values were obtained at the end of each intervention. A paired t test was used for statistical analysis, and a p value < 0.05 was considered significant. RESULTS: The mean +/- SEM values over 1 min with either 15:2 or 15:1 C/V ratios were as follows: intratracheal pressure 0.93 +/- 0.3 mm Hg versus 0.3 +/- 0.28 mm Hg, p = 0.006; coronary perfusion pressure 10.1 +/- 4.5 mm Hg versus 19.3 +/- 3.2 mm Hg, p = 0.007; intracranial pressure 25.4 +/- 2.7 mm Hg versus 25.7 +/- 2.7 mm Hg, p = NS; mean arterial pressure 33.1 +/- 3.7 mm Hg versus 40.2 +/- 3.6 mm Hg, p = 0.007; cerebral perfusion pressure 7.7 +/- 6.2 mm Hg versus 14.5 +/- 5.5 mm Hg, p = 0.008. Minute area intratracheal pressure was 55 +/- 17 mm Hg . s versus 22.3 +/- 10 mm Hg . s, p < 0.001. End-tidal CO(2) with 15:2 versus 15:1 was 24 +/- 3.6 mm Hg versus 29 +/- 2.5 mm Hg, respectively, p = 0.001. Arterial blood gas values were not significantly changed with 15:2 versus 15:1 C/V ratios: pH 7.28 +/- 0.03 versus 7.3 +/- 0.03; P(aCO(2)) 37.7 +/- 2.9 mm Hg versus 37.6 +/- 3.5 mm Hg; and P(aO(2)) 274 +/- 36 mm Hg versus 303 +/- 51 mm Hg. CONCLUSIONS: In a porcine model of ventricular fibrillation cardiac arrest, reducing the ventilation frequency during CPR by increasing the C/V ratio from 15:2 to 15:1 resulted in improved vital-organ perfusion pressures, higher end-tidal CO(2) levels, and no change in arterial oxygen content or acid-base balance.     

Sympathoadrenal stimulation, not endothelin, plays a role in acute pressor response to cyclosporine in anesthetized rats.

The possible role of sympathoadrenal stimulation and endothelin release in cyclosporine (CS)-induced hypertension was ascertained in intact and pithed rats. CS (20 and 40 mg/kg), administered by i.v. infusion over 10 min, produced a dose-dependent increase in blood pressure: 19 +/- 5 and 31 +/- 2 mm Hg in intact rats and 13 +/- 4 and 18 +/- 2 mm Hg in pithed rats. In intact rats, pretreatment with reserpine (5 mg/kg, i.p.) or hexamethonium (10 mg/kg, i.v.) greatly blunted the pressor responses to CS (40 mg/kg) (7 +/- 3 and 11 +/- 2 mm Hg, respectively). In pithed rats, the blood pressure responses to CS (40 mg/kg) were significantly impaired, but were not further modified by phenoxybenzamine (3 mg/kg, i.v.), whereas adrenalectomy completely abolished the CS-induced pressor responses (0 +/- 1 mm Hg). CS (40 mg/kg) did not potentiate pressor responses to sympathetic nerve stimulation (0.1 and 0.3 Hz) or vasoconstrictors, including angiotensin II (0.03 microgram/kg, i.v.), phenylephrine (1 microgram/kg, i.v.) and arginine vasopressin (0.075 microgram/kg) in pithed rats. In addition, CS (40 mg/kg, i.v.) did not cause elevation of plasma immunoreactive endothelin-1 and -3. Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension. It is concluded that the acute blood pressure response to CS manifests great dependence on sympathetic nervous system but appears independent of endothelin release.     

An extended interval dosing method for gentamicin in neonates.

Traditional gentamicin dosing every 8-24 h depending on age and weight in neonates does not provide the ideal concentration-time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8-24 h, aiming for peak concentrations (Cmax) of 6-10 mg/L and trough concentrations (Cmin) <2 mg/L. After the first dose, the mean (+/- s.d.) Cmax was 5.5 +/- 0.7 mg/L with sub-therapeutic concentrations (<6 mg/L) in 62% of patients, while the mean Cmin was >2 mg/L in 15% of the neonates. After the third dose the Cmax was 7.5 +/- 1.5 mg/L, with 17% <6 mg/L, whereas the mean Cmin was 2.2 +/- 1.1 mg/L with 49% of values >2 mg/L. An extended interval dosing method (24, 36 and 48 h) for infant weights of 0.75-5 kg was developed by simulation, and audited prospectively in 51 neonates. Prospective analysis of the extended interval dosing method showed a mean Cmax after the first dose of 13.1 +/- 3.6 mg/L, while the mean Cmin was 0.7 +/- 0.6 mg/L. Seventy-eight per cent had Cmax of >10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0-24 was 93 mg*h/L (target = 100 mg*h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.     

Role of ATP-sensitive potassium channels in prostaglandin-mediated gastroprotection in the rat

This study compares the involvement of ATP-sensitive potassium (K(ATP)) channels and prostaglandins in various forms of gastroprotection in the rat. Instillation of 1 ml of 70% ethanol induced severe gastric mucosal damage (lesion index 39 +/- 0.8), which was substantially but not maximally reduced by oral pretreatment with 16,16-dimethyl-prostaglandin (PG) E(2) (75 ng/kg), 20% ethanol (1 ml), sodium salicylate (15 mg/kg), the metal salt lithium chloride (7 mg/kg), the sulfhydryl-blocking agent diethylmaleate (5 mg/kg), and the thiol dimercaprol (10 mg/kg). Administration of indomethacin (20 mg/kg) increased gastric mucosal damage induced by 70% ethanol (lesion index 45 +/- 0.8) and significantly reduced the protective effect of 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The blocker of K(ATP) channels glibenclamide (5-10 mg/kg) significantly antagonized the protective effect of 16,16-dimethyl-PGE(2), 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The inhibition of protection induced by glibenclamide was reversed by pretreatment with the K(ATP) channel activator cromakalim (0.3-0.5 mg/kg). In conclusion, our results indicate a role of K(ATP) channels in the gastroprotective effect of 16,16-dimethyl-PGE(2) and of the other agents tested. Since the protection afforded by these agents is additionally indomethacin-sensitive, it is suggested that under these conditions endogenous prostaglandins act as activators of K(ATP) channels, and this mechanism, at least in part, mediates gastroprotection.     

Increased gut permeability and bacterial translocation in Pseudomonas pneumonia-induced sepsis

OBJECTIVE: Gut injury and barrier dysfunction may contribute to the pathogenesis of sepsis and multiple organ dysfunction syndrome. The objective of this study was to determine whether gut injury could be demonstrated in hyperdynamic, normotensive sepsis induced by Pseudomonas pneumonia. DESIGN: Randomized animal study. SETTING: University laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Sepsis was induced by intratracheal instillation of Pseudomonas aeruginosa. MEASUREMENTS AND MAIN RESULTS: We measured gut mucosal and microvascular injury. In the first experiment, gut mucosal permeability was measured by 51Cr-EDTA uptake in control (n = 6), pneumonia 20-hr (n = 4), and pneumonia 40-hr (n = 4) groups. In the second experiment, microvascular permeability was measured by albumin extravasation, and morphologic abnormalities were scored in control (n = 6), pneumonia 20-hr (n = 9), and pneumonia 40-hr (n = 11) groups. Bacterial translocation to mesenteric lymph nodes was determined in both experiments. Cardiac index increased significantly in the pneumonia compared with control rats (64+/-2.1, 68+/-1.3, vs. 46+/-2 mL/min/100 g, p < .05; all results are listed in the order of pneumonia 20-hr, pneumonia 40-hr, and control groups as mean +/- SEM). Mean blood pressure was normal and was not different between groups (112+/-3, 111+/-2, vs. 118+/-2 mm Hg). 51Cr-EDTA recovery in urine 6 hrs after gavage increased significantly in both pneumonia groups vs. controls (17.5+/-2.2%, 17.9+/-7%, vs. 4+/-0.7%; p < .05). Albumin leak (tissue/plasma ratio) increased significantly in the middle and distal small intestine in the pneumonia 40-hr group vs. controls (0.68+/-0.05, 0.76+/-0.07, vs. 0.45+/-0.04, p < .05 in the middle small gut; 0.75+/-0.09, 0.85+/-0.07, vs. 0.51+/-0.05, p < .05 in the distal small gut). Bacterial translocation to mesenteric lymph nodes increased significantly in pneumonia 40-hr rats vs. controls (positive culture 67% vs. 8%; p < .05). CONCLUSIONS: This study demonstrates gut mucosal and microvascular injury and gut barrier dysfunction in normotensive sepsis secondary to bacterial pneumonia. The mechanism and significance of the injury need to be determined.     

Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. METHODS AND RESULTS: Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. RESULTS: The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). CONCLUSIONS: Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.     

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension.

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagoinst of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metroprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 +/- 3.8 (SEM)/10 +/- 2.1 mm Hg in the lying position and 23 +/- 4.4/9 +/- 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady-state plasma concentrations of metoprolol varied 17-fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p less than 0.05) and decrease in exercise tachycardia (r = 0.65, p less than 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mg/kg. Metoprolol decreased PRA by 67 +/- 1.9 and 71 +/- 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p less than 0.05) but not to the plasma steady-state levels of metoprolol, the degree of beta receptor blockade, and the decrease in PRA.     

Influence of low-level resistance to vancomycin on efficacy of teicoplanin and vancomycin for treatment of experimental endocarditis due to Enterococcus faecium.

Emergence of vancomycin-resistant strains among enterococci raises a new clinical challenge. Rabbits with aortic endocarditis were infected with Enterococcus faecium BM4172, a clinical strain resistant to low levels of vancomycin (MIC, 16 micrograms/ml) and susceptible to teicoplanin (MIC, 1 micrograms/ml), and against its susceptible variant E. faecium BM4172S obtained in vitro by insertional mutagenesis (MICs, 2 and 0.5 micrograms/ml, respectively). Control animals retained 8 to 10.5 log10 CFU/g of vegetation. We evaluated in this model the efficacy of vancomycin (30 mg/kg of body weight; mean peak and trough serum levels, 27 and 5 micrograms/ml, respectively), teicoplanin (standard dose, 10 mg/kg; mean peak and trough levels, 23 and 9 micrograms/ml, respectively; and high dose, 20 mg/kg; mean peak and trough levels, 63 and 25 micrograms/ml, respectively), gentamicin (6 mg/kg; mean peak and trough levels, 8.6 and less than 0.1 micrograms/ml, respectively), alone or in combination, given every 12 h intramuscularly for 5 days. Teicoplanin standard dose was as active as vancomycin against both strains. Vancomycin was not effective against E. faecium BM4172 but was highly effective against E. faecium BM4172S (7.5 +/- 1.1 log10 CFU/g of vegetation versus 4.9 +/- 1.0 log10 CFU/g of vegetation for vancomycin against E. faecium BM4172 and E. faecium BM4172S, respectively; P = 0.0012). A high dose of teicoplanin was more effective than vancomycin against E. faecium BM4172 (4.4 +/- 1.8 log10 CFU/g of vegetation versus 7.5 +/- 1.1 log10 CFU/g of vegetation for teicoplanin high dose and vancomycin, respectively; P less than 0.05). Against E. faecium BM4172 glycopeptide-gentamicin combinations were the most effective regimens in vitro and in vivo (2.8 +/- 0.7 and 3.5 +/- 1.3 log10 CFU/g of vegetation for vancomycin plus gentamicin and teicoplanin standard dose plus gentamicin, respectively; P < 0.05 versus single-drug regimens). We concluded that high-dose teicoplanin or the combination of a glycopeptide antibiotic plus gentamicin was effective against experimental infection due to E. faecium with low-level resistance to vancomycin.     

Ranitidine kinetics and dynamics. II. Intravenous dose studies and comparison with cimetidine

Intravenous ranitidine has been shown to reduce pentagastrin-stimulated gastric secretion. Eight normal men received, in randomized order, 60 mg ranitidine or 300 mg cimetidine intravenously over 2 min. Both ranitidine and cimetidine induced decreases in volume hydrogen ion content and pepsin activity of stimulated gastric juice. Ranitidine half-life (t1/2) was 2.1 +/- 0.1 hr and cimetidine (t1/2) was 1.5 +/- 0.1 hr. Ranitidine volume of distribution was 1.6 +/- 0.1 l/kg and that of cimetidine was 1.12 +/- 0.12 l/kg. The clearance of ranitidine was 0.54 +/- 0.04 l/kg hr-1 and that of cimetidine was 0.5 +/- 0.05 l/kg hr-1. It is suggested that the intravenous loading dose of ranitidine necessary to attain a serum concentration of 200 micrograms/l (which would achieve a 50% inhibition of gastric acid) is 0.3 mg/kg, followed by an infusion rate of 0.11 mg/kg hr-1.     

The effect of sodium on hemodynamic changes during coronary angiography with nonionic contrast media

To investigate the effect of sodium on cardiac hemodynamics, sodium chloride was added to nonionic contrast media to a 0.9% concentration and was compared with the standard media iohexol, iopamidol, and ioversol. Left coronary angiography was performed in 10 closed-chest, atrial-paced dogs with 10 ml injections of each preparation in a randomized and blinded fashion. The maximum changes in left ventricular systolic pressure, mean aortic pressure, left ventricular and diastolic pressure, and maximal rise of left ventricular pressure were measured. The left ventricular systolic pressure and mean aortic pressure decreased by 17 +/- 7 mm Hg and by 12 +/- 5 mm Hg with iohexol plus 0.9% NaCl, but only by 5 +/- 4 mm Hg and by 4 +/- 3 mm Hg with iohexol alone (p less than 0.001). The left ventricular and end diastolic pressure increased by 2.2 +/- 0.6 mm Hg with iohexol plus 0.9% NaCl, but did not change with iohexol alone (p less than 0.001). Left ventricular dp/dt decreased by 204 +/- 161 mm Hg/sec with iohexol plus 0.9% NaCl but increased by 392 +/- 122 mm Hg/sec with iohexol alone (p less than 0.001). Similar results were obtained from experiments with iopamidol versus iopamidol plus 0.9% NaCl and ioversol versus ioversol plus 0.9% NaCl. Ioversol plus 5% dextrose or ioversol plus 2.1% choline chloride (isomolar to ioversol plus 0.9% NaCl) produced a significant increase in left ventricular systolic pressure and left ventricular dp/dt (versus ioversol plus 0.9% NaCl, p less than 0.001). Thus, sodium, but not the osmolality or chloride, contributed to the negative inotropic effect of the contrast media.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of cyclooxygenase isoenzymes, nitric oxide, and afferent neurons in gastric mucosal defense in rats

The cyclooxygenase (COX)-2 inhibitors 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5II)-furanone (DFU) (0.02-2 mg/kg) and N-[2-(cyclohexyloxy)-4-nitrofenyl]-methanesulfonamide (NS-398) (0.01-1 mg/kg), the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (0.05-5 mg/kg), and dexamethasone (1 mg/kg) were studied in rats challenged with intragastric acid (300 mM HCl). All compounds induced severe gastric damage when rats were treated concurrently with the inhibitor of constitutive and inducible nitric-oxide (NO) synthase N(G)-monomethyl-L-arginine methyl ester (L-NAME) (3 or 40 mg/kg). DFU and NS-398 caused significantly less damage in rats receiving the selective inhibitor of inducible NO synthase N-(3-(aminomethyl)benzyl)acetamidine (1400W) (0.3 mg/kg). The COX-1 inhibitor SC-560 induced moderate damage in the acid-challenged stomach even without suppression of NO, but damage was aggravated by L-NAME. The COX-3 inhibitor phenacetin (400 mg/kg) did not injure the gastric mucosa despite suppression of NO. Furthermore, DFU, NS-398, SC-560, and dexamethasone caused severe injury in the acid-challenged stomach of rats pretreated with capsaicin to ablate afferent neurons. The mucosal damage induced by the COX-1 inhibitor, the COX-2 inhibitors, and dexamethasone in L-NAME- or capsaicin-treated rats was reversed by coadministration of 16,16-dimethyl-prostaglandin E2 (2 x 8 ng/kg). Gross mucosal damage was paralleled by histology. Our results support the concept that endogenous NO, prostaglandins, and afferent neurons act in concert in the regulation of gastric mucosal integrity. The prostaglandins necessary for mucosal defense in the face of NO suppression, and afferent nerve ablation can be derived either from COX-1 or COX-2. The data do not propose a protective role for a phenacetin-sensitive COX-3. Our findings suggest that not only COX-1 but also COX-2 has important functions in the maintenance of gastric integrity.