Treating pulmonary hypertension post cardiopulmonary bypass in pigs: milrinone vs. sildenafil analog.

Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 microg/kg; sildenafil-analog (n=5) 500 microg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes . cm . sec(-5) at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.

Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension.

OBJECTIVES: To evaluate the effects of phosphodiesterase type III and V (PDEIII and PDEV) inhibition on pulmonary and systemic haemodynamics in a porcine model of acute pulmonary hypertension. METHODS: Twenty-four adult swine were anaesthetized with 1 MAC isoflurane and mechanically ventilated with an FI(O(2)) of 100%. Micromanometer-tipped catheters were placed in the ascending aorta, pulmonary artery and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue, U46619. The animals were then randomized to four groups: Group 1 (n=6) received 50 mg of sildenafil (PDEV inhibitor) diluted in water via an orogastric tube; Group 2 (n=6) received 50 microg kg(-1) of i.v. milrinone (PDEIII inhibitor); Group 3 (n=6) received sildenafil followed by milrinone; and Group 4 (n=6) received placebo via an orogastric tube. RESULTS: Pulmonary hypertension was achieved in all animals. Calculated pulmonary vascular resistance decreased by an average of 36% after sildenafil (P<0.05), 41% after milrinone (P<0.05), and 61% with both drugs combined (P<0.05). Systemic vascular resistance decreased by 37% (P<0.05) with milrinone alone, and 36% (P<0.05) with milrinone and sildenafil combined but it was preserved in the sildenafil group. Cardiac output and right ventricular dP/dT were significantly improved after milrinone or both drugs combined, but not with sildenafil. CONCLUSION: Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined achieved a better haemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic haemodynamic profile (systemic vasodilation, cardiac output, right ventricular dP/dT) is improved with milrinone but not with sildenafil.

Single-stage transmediastinal replacement of the ascending, arch, and descending thoracic aorta.

BACKGROUND: Aneurysms of the ascending, arch, and descending thoracic aorta are typically managed with two operations. The first stage involves replacement of the ascending and arch aorta leaving a segment of graft in the proximal descending aorta with a mortality and stroke risk of 8%. The second stage involves replacement of the descending aorta with a mortality of 5% and a paraplegia risk of 5% to 10%. Some patients refuse surgical completion and others are at increased risk to undergo the second stage thoracotomy, leaving them with untreated descending thoracic aortic aneurysms vulnerable to rupture. A single-stage transmediastinal operation used in 14 patients is described. METHODS: Under circulatory arrest, the descending thoracic aorta is opened. A wire is passed up to the arch and a graft is brought down and secured excluding the descending thoracic aneurysm. The arch vessels are attached as a single patch and the graft is brought forward, replacing the ascending aorta. RESULTS: Fourteen patients have undergone single-stage replacement of the ascending, arch, and descending aorta with a 14% mortality rate and 14% incidence of paraplegia. CONCLUSIONS: Patients with aneurysms of the ascending, arch, and descending thoracic aorta can be managed with a single operation with comparable mortality and morbidity of the two-stage approach.

Right ventricular outflow tract obstruction in an older woman: facilitated diagnosis with transesophageal echocardiography-guided biopsy.

Fibrosarcoma is a rare primary cardiac malignancy. We report the case of a 70-year-old woman who had signs of right ventricular outflow tract obstruction caused by a fibrosarcoma. The pivotal role of multiplanar transesophageal echocardiography in characterizing masses in this location and in guiding transvenous biopsy is discussed.

Intraoperative diagnosis of aortic pseudoaneurysm with transesophageal echocardiography.

A pseudoaneurysm of the ascending aorta is a rare complication of aortic valve endocarditis that requires prompt diagnosis. Several imaging strategies can be used; however, transesophageal echocardiography (TEE) has been utilized more frequently due to its superior resolution in detection of aortic valve complications. This case presents a patient with prosthetic valve dysfunction in which intraoperative TEE was used to diagnose a previously undetected aortic pseudoaneurysm, thus leading to a change in surgical management.

Colon perforation after lung transplantation.

BACKGROUND: Colon perforation has been previously described after solid organ transplantation. Since the inception of the lung transplant program at the University of Colorado 60 isolated lung transplantations have been performed. Four of these patients have suffered spontaneous colonic perforation. METHODS: The case history of each lung transplant patient with a colon perforation and the literature were reviewed. RESULTS: An increased incidence of colon perforation in lung transplant patients was identified. Diverticulitis was found to be the predominant cause, and an association with steroids was noted. The two deaths in this series were in patients receiving high-dose steroids in whom invasive Aspergillus infections developed. CONCLUSIONS: Careful screening of the gastrointestinal tract before transplantation is advocated. A steroid-sparing immunosuppressive regimen is recommended. All lung transplant patients with abdominal complaints require an aggressive work-up, and surgeons should have a low threshold for laparotomy. Conservative surgical principles, including resection of the perforated segment of colon and proximal end-colostomy rather than primary anastomosis, are necessary for the optimal outcome.

Quantitative and qualitative aspects of the hibernation-related reduction of morphine physical dependence in the ground squirrel (Citellus lateralis).

The development of morphine physical dependence in the contrasting brain states of the nonhibernating (NH) vs. the hibernating (H) condition was measured in the ground squirrel hibernator Citellus lateralis. Morphine was infused continuously into the lateral ventricle (3.44, 6.88 and 13.75 micrograms/hr for periods of 1, 3 and 6 days) in NH and H animals, followed by measurement of the naloxone (1 mg/kg s.c.) evoked abstinence syndrome during the NH state (i.e., H animals were tested after arousal to the NH state). The results showed that morphine treatment during the NH state resulted in significant naloxone-evoked abstinence and an overall dose- and duration-related increase in the strength of the abstinence syndrome. By contrast, morphine treatment during hibernation resulted in significantly reduced abstinence compared with that observed after treatment during the NH state, with no significant morphine dose-response or duration-response trends evident. However, H-state morphine treatment did produce a dose-related reduction of hibernation bout duration. The reduction in the strength of dependence during the H state was associated with a qualitative change in the abstinence syndrome, as revealed by exploratory factor analysis. This change was reflected by an approximate reversal of the rank order of abstinence signs. These results demonstrate that hibernation-related changes in central nervous system function significantly reduce the liability for and change the character of the development of morphine dependence.

Morphine physical dependence in the hibernator: central nervous system mechanisms underlying the development of dependence remain functional during depression induced by pentobarbital anesthesia.

Earlier work suggested that adaptive mechanisms of the hibernating brain may also block the development of morphine physical dependence. To test an alternate view that CNS depression itself might be the major factor in the failure of dependence to develop, we compared the strength of dependence produced by morphine (two 75-mg pellets, s.c.) given for 12 hr in the presence, versus in the absence, of continuous pentobarbital anesthesia in nonhibernating ground squirrels (Citellus lateralis) and, in addition, in rats. Dependence was measured by the naloxone (5 mg/kg, s.c.) evoked abstinence syndrome in the awake state. The results demonstrated that pentobarbital-induced general anesthesia does not significantly reduce the development of morphine dependence in either species. We conclude that CNS depression alone does not account for the hibernation-related reduction in morphine physical dependence.

Comparison of subjective ratings of function with observed functional ability of frail older persons.

BACKGROUND: Important clinical decisions often hinge on patients' functional status. Previous studies have shown disagreement among sources of ratings of patients' functional status. This study compared patient self-ratings, family member ratings, and physician ratings of patient function to performance-based functional testing criteria. METHODS: Five activities of daily living of 73 older patients were studied at admission to a rehabilitation unit following discharge from an acute care community hospital. Data were collected from patients, family members, and physicians and were compared with performance-based function testing. RESULTS: Patient ratings were significantly more accurate than physician ratings for walking, transferring, and telephoning. Patients were significantly more accurate than family members for rating walking and telephoning, but patients were not significantly more accurate than family members or physicians for rating eating or dressing. CONCLUSIONS: We conclude that decisions about patients' functional level should be based on performance testing. If performance testing is unavailable, patients' own ratings are most accurate, followed by family ratings. Physicians' ratings are least accurate.

The antinociceptive activity of paracetamol in zymosan-induced peritonitis in mice: the role of prostacyclin and reactive oxygen species.

1. Oral administration of high doses of paracetamol (600 mg kg-1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6-keto-PGF1 alpha) induced by intraperitoneal administration of zymosan in mice. The high oral doses of paracetamol required were accompanied by behavioural toxicity which may have contributed to the inhibition of writhing. 2. The number of writhes per mouse and the proportion of mice writhing at least once correlated significantly with the levels of 6-keto-PGF1 alpha. However, inhibition of writhing by paracetamol occurred at higher levels of 6-keto-PGF1 alpha than was previously observed with acidic non-steroidal anti-inflammatory agents. 3. When injected i.p., PGI2, carbacyclin and iloprost (agonists at the PGI2 receptor) induced writhing. Intraperitoneal injection of PGI2 reversed the inhibition of writhing induced by indomethacin (1 mg kg-1, p.o.) but not that induced by oral administration of paracetamol. 4. Paracetamol at 800 mg kg-1, p.o., inhibited carbacyclin-induced writhing but indomethacin at 1 mg kg-1 p.o. did not. Paracetamol administered i.p. at 100 mg kg-1 reduced the peritoneal levels of 6-keto-PGF1 alpha and inhibited zymosan-induced but not carbacyclin-induced writhing and did not produce behavioural toxicity. 5. The in vitro potency of paracetamol as a prostaglandin synthesis inhibitor is known to be reduced by the presence of lipid peroxides. However, no lipid peroxides, measured as thiobarbituric acid reactive material, were detected in the peritoneal lavage fluid of zymosan-injected mice. 6. Intraperitoneal administration of a mixture of superoxide dismutase and catalase reduced detectable superoxide anion by 98% without inhibiting the writhing response to zymosan or the antinociceptive potency of paracetamol. 7. The data are consistent with the suggestion that inhibition of PGI2 synthesis in the peritoneal cavity by paracetamol is responsible for only a part of its antinociceptive activity in this test. However, extremely high oral doses of paracetamol were required which produced behavioural toxicity which clearly contributed to the inhibition of writhing. The low potency of paracetamol in this model cannot be attributed to the generation of lipid peroxides via the oxidative burst.

Comparison of the anaphylactoid response induced in rats by castanospermine and dextran.

The plant alkaloid castanospermine (10 mg/kg or higher, i.p.; 400 mg/kg, p.o.) induced in some rat strains an anaphylactoid reaction similar to that induced by dextran, i.e. erythema and edema of the snout, ears and paws, for several hours after administration. 86% of the rats from a responsive strain responded to castanospermine while 79% responded to dextran. Rats which responded to castanospermine showed marked, but transient, tachyphylaxis to a second dose of castanospermine or dextran. Rats maintained on a complex-carbohydrate-free diet also responded to castanospermine, excluding the possibility that the effect was due to absorption of dextran-like, dietary, complex carbohydrates. These data raise the possibility that some apparent food allergies in man could be due to the presence in the diet of plant alkaloids with properties similar to those of castanospermine.

Multiple topical applications of arachidonic acid to mouse ears induce inflammatory and proliferative changes.

The response to daily topical applications of arachidonic acid (0.25-4 mg/ear/day) to the ears of outbred CD-1 mice was monitored. The first application produced erythema, extravasation of plasma proteins resulting in an increase in ear weight, and some neutrophil accumulation (detected histologically and quantified by myeloperoxidase content). The second application produced minimal edema but did cause erythema and a greater accumulation of neutrophils. Subsequent daily application caused erythema, neutrophil accumulation, and an increase in ear weight predominantly due to cell proliferation (epidermis and connective tissue). Daily applications of other unsaturated fatty acids did not match the response induced by arachidonic acid. Mast cell deficient mice (W/Wv) exhibited a smaller edema response to the first dose of arachidonic acid compared to either their wild-type controls or CD-1 mice. In addition, W/Wv mice exhibited a smaller ear weight increase and myeloperoxidase accumulation following eight daily doses of arachidonic acid. However, epidermal proliferation was similar in all the strains of mice tested. These data suggest that the edema caused by the first topical application of arachidonic acid is partly mast cell mediated. Mast cells also appear to be involved in the neutrophil infiltration induced by multiple topical applications, but not in the epidermal proliferation.

The role of prostaglandins in the nociceptive response induced by intraperitoneal injection of zymosan in mice.

Intraperitoneal injection of zymosan (1 mg in 0.5 ml saline) in mice induces a transient writhing response accompanied by the synthesis of small amounts of prostaglandin E2(PGE2, less than 2 ng) and larger amounts of PGI2 (200 ng per mouse), measured as its non-enzymatic breakdown product, 6-keto-PGF1 alpha. Although both centrally-acting analgesics (morphine, clonidine) and prostaglandin biosynthesis inhibitors (aspirin, indomethacin, ibuprofen) blocked the writhing response to intraperitoneal injection of zymosan, only the latter reduced prostaglandin levels in the peritoneal cavity. The writhing response correlated equally well with PGE2 levels and 6-keto-PGF1 alpha levels when data from mice treated with centrally-acting analgesics were excluded. However, intraperitoneal injection of PGI2, but not PGE2, reversed the analgesia induced by indomethacin in zymosan-injected mice. Centrally-acting agents, but not ibuprofen, blocked the ability of PGI2 to reverse the analgesic activity of indomethacin. PGI2 (2 micrograms per mouse), injected intraperitoneally in otherwise untreated mice, induced writhing. These data indicate that PGI2 is the prostaglandin involved in mediation of the writhing response to zymosan and that prostaglandin biosynthesis inhibitors, but not centrally-acting analgesics, exert their analgesic activity by reducing the peritoneal level of PGI2. It is possible that PGI2 may have the ability to stimulate pain receptors directly in the mouse peritoneal cavity, in addition to its previously recognized ability to sensitize pain receptors to other pain-producing stimuli.

Intraperitoneal injection of zymosan in mice induces pain, inflammation and the synthesis of peptidoleukotrienes and prostaglandin E2.

Intraperitoneal injection of zymosan in mice induced rapid extravasation and accumulation of plasma protein in the peritoneal cavity. Neutrophils began to appear in the peritoneal cavity after a lag period of approximately 3 hours. The injected mice exhibited a pain response (writhing) during the first 30 minutes after injection, but writhing ceased before protein or cell accumulation had reached maximum levels. The injection of zymosan induced synthesis of PGE2 (measured by RIA) which reached maximum levels at 30 minutes, then declined slowly. Peptido-leukotriene levels (detected by bioassay, RIA and HPLC) increased rapidly after injection, reached a peak within an hour of injection and declined to undetectable levels within 4 hours. The early peptido-LT was predominantly LTC4, while later, LTE4 was the major component. LTD4 levels remained low throughout and no LTB4 was detected at any time. Indomethacin treatment elevated levels of peptido-LTs, reduced PGE2 levels and inhibited writhing. Phenidone reduced peptido-LT levels. In vitro studies demonstrated that zymosan stimulates LTC4 synthesis by peritoneal cells whereas LTE4, LTD4, LTB4 or monoHETES were not detectable (using HPLC methods). The source of enzymes responsible for the in vivo metabolism of LTC4 to LTD4 and LTE4 could not be identified.

The immunopharmacologic and anti-inflammatory properties of RMI 9563 with special reference to its effect on the complement system.

The immunopharmacology of RMI 9563 - bis[3-(diethylamino)propyl]fluoranthene-3,9-dicarboxylate dihydrochloride--has been described. The compound, when given parenterally, inhibited several cell-mediated immune responses (EAE, tuberculin skin reaction, adjuvant arthritis) in rats, enhanced IgM and IgG antibody-producing cells in mice, and displayed anti-inflammatory activity in several models (carrageenan paw edema, adjuvant arthritis, direct passive Arthus reaction--a model of inflammation that is immunologically induced and complement-dependent). RMI 9563 suppressed the activation of complement in vitro by the selective inhibition of C1 esterase.