Effect of rifampin on the pharmacokinetics, safety and tolerability of navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-XL , in patients with cancer.

WHAT IS KNOWN AND OBJECTIVE: Navitoclax, a first-in-class small molecule Bcl-2 family inhibitor, is metabolized in vitro by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4. Drugs that affect CYP3A4 may therefore have an impact on the pharmacological profile of navitoclax. This study evaluated the effects of co-administration of a potent CYP3A4 inducer rifampin on the pharmacokinetic and safety profiles of navitoclax. METHODS: This open-label, fixed-sequence, 2-period study was performed in twelve subjects with non-haematologic or haematologic malignancy that was relapsed or refractory to standard therapy. A 7-day washout period separated the two treatment periods. On Study Day 1 and Day 8, subjects received a single 250 mg oral dose of navitoclax. Rifampin 600 mg was administrated once daily (QD) on Study Day 4 through Day 10. Blood samples for navitoclax assay were collected prior to dosing (0 h) and at a series of time points through 72 h after dosing on Study Day 1 and Day 8. RESULTS AND DISCUSSION: Co-administration of a single 250 mg dose of navitoclax with 600 mg QD doses of rifampin had a negligible effect on the maximum plasma concentration (Cmax ) of navitoclax [ratio of geometric least square means: 0·84 (90% CI: 0·61-1·16)] but moderately decreased the area under the plasma concentration-time curve (AUC) of navitoclax [ratio of geometric least square means: 0·59 (90% CI: 0·44-0·80)]. Rifampin did not affect the half-life of navitoclax. Co-administration of rifampin did not appear to significantly change the safety profile of navitoclax in the limited number of patients evaluated in this study. WHAT IS NEW AND CONCLUSION: Co-administration navitoclax with rifampin moderately decreased navitoclax AUC, which could be partly due to the induction effect of rifampin on CYP3A4. Further assessment on the mechanism of drug interaction is warranted.

Chronic homocysteine exposure upregulates endothelial adhesion molecules and mediates leukocyte: endothelial cell interactions under flow conditions.

AIMS: Homocysteine upregulates expression of adhesion molecules on endothelial cells which recruits leukocytes and initiates atherosclerosis. Endothelial cells in hyperhomocysteinemic patients are continuously exposed to high levels of homocysteine. This study exposed adult endothelial cells and endothelial cells from immune naïve foetal tissue to homocysteine chronically and studied effects on cellular adhesion molecule expression under static and flow conditions. METHODS: Human umbilical vein endothelial cells (HUVEC) and human saphenous vein endothelial cells (HSVEC) were cultured in medium containing 1 mM dl-homocysteine or l-cysteine for 5-9 days. Proliferation was assessed. Cells were subjected to flowing neutrophils and numbers of tethered, rolled fixed and transmigrated neutrophils on endothelial cells were counted and compared to controls. Immunofluorescence staining with antibodies against Intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin were used to quantify expression. RESULTS: Chronic treatment with 1 mM homocysteine inhibited proliferation of HUVEC and HSVEC. Homocysteine treated cells showed significantly increased expression of ICAM-1, E-selectin and to a lesser extent P-selectin. In both cell types, homocysteine significantly increased interactions between neutrophils and endothelial cells under flow conditions (p < 0.05) while cysteine had no effect. CONCLUSION: Endothelial cells from adult and immune naïve foetal tissue showed similar responses to chronic treatment with homocysteine.

Role of ischaemic preconditioning in liver regeneration following major liver resection and transplantation.

Liver ischaemic preconditioning (IPC) is known to protect the liver from the detrimental effects of ischaemic-reperfusion injury (IRI), which contributes significantly to the morbidity and mortality following major liver surgery. Recent studies have focused on the role of IPC in liver regeneration, the precise mechanism of which are not completely understood. This review discusses the current understanding of the mechanism of liver regeneration and the role of IPC in this setting. Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords "liver", "ischaemic reperfusion", "ischaemic preconditioning", "regeneration", "hepatectomy" and "transplantation". The underlying mechanism of liver regeneration is a complex process involving the interaction of cytokines, growth factors and the metabolic demand of the liver. IPC, through various mediators, promotes liver regeneration by up-regulating growth-promoting factors and suppresses growth-inhibiting factors as well as damaging stresses. The increased understanding of the cellular mechanisms involved in IPC will enable the development of alternative treatment modalities aimed at promoting liver regeneration following major liver resection and transplantation.

alpha-melanocyte-stimulating hormone modulates nitric oxide production in melanocytes.

We have previously observed that melanocytes produce nitric oxide in response to ultraviolet radiation and lipopolysaccharide and in this study have examined how these responses are affected by alpha-melanocyte-stimulating hormone. Nitric oxide production by cultured cells was measured electrochemically in real time using an ISO-nitric oxide sensor probe. B16 mouse melanoma cells released nitric oxide in response to lipopolysaccharide and the effects were enhanced in cells that had been grown in the presence of 10-11-10-9 M alpha-melanocyte-stimulating hormone prior to stimulation. At concentrations in excess of 10-9 M alpha-melanocyte-stimulating hormone decreased nitric oxide production. Preincubation with lipopolysaccharide, a well-known inducer of inducible nitric oxide synthase, also increased nitric oxide production but this response was reduced by alpha-melanocyte-stimulating hormone. alpha-Melanocyte-stimulating hormone also increased the levels of nitric oxide produced in response to ultraviolet radiation (20-100 mJ per cm2) in B16 cells. The same effect was seen in human melanocytes and as this was inhibited by aminoguanidine would appear to involve an induction of inducible nitric oxide synthase. Reverse transcription-polymerase chain reaction showed that melanocytic cells express inducible nitric oxide synthase mRNA. Western blotting analysis and immunocytochemistry confirmed the presence of inducible nitric oxide synthase protein in B16 cells and FM55 human melanoma cells and that the levels were increased in response to alpha-melanocyte-stimulating hormone. alpha-Melanocyte-stimulating hormone, however, decreased inducible nitric oxide synthase protein expression, which occurred in response to lipopolysaccharide. These results suggest that alpha-melanocyte-stimulating hormone regulates nitric oxide production in melanocytic cells by modulating the induction of inducible nitric oxide synthase. Additional experiments showed that nitric oxide increased melanin production by B16 cells and human melanocytes. This is in keeping with a melanogenic role for nitric oxide but whether its production by melanocytes in response to alpha-melanocyte-stimulating hormone is associated with such a role or whether it has some other significance relating to melanocyte differentiation or in mediating immunomodulatory actions of alpha-melanocyte-stimulating hormone remains to be seen.

Predictors of health after operation for aortoiliac occlusive and aneurysmal disease.

BACKGROUND: We assessed the impact of comorbid conditions and revascularization for aortoiliac occlusive and aneurysmal disease and determined the functional health status of patients with the Medical Outcomes Study SF36 Health Survey. METHODS: One hundred twenty-five patients were surveyed prospectively, before operation, and at intervals ranging from 2 weeks to 2 years after operation. To identify the factors that influenced functional health, multiple regression analysis was performed to test the hypothesis that age, pulmonary disease, atherosclerotic heart disease, diabetes, aortoiliac occlusive disease (AOD) versus aneurysmal disease, and the preoperative physical summary score affected outcome. RESULTS: Regression analysis identified that before operation, the physical summary score (PCS) was affected by pulmonary disease, atherosclerotic heart disease, and AOD, and patients with AOD had significantly worse PCS than patients with aneurysmal disease (43.2 +/- 12.6 vs 30.1 +/- 8.3, P <.05). This difference was also present after 3 to 12 months, and the preoperative PCS was the strongest predictor of the postoperative score. For patients followed up between 1 and 2 years, there was no significant difference among the groups, and atherosclerotic heart disease and pulmonary disease were identified to most affect the PCS. CONCLUSIONS: Patients with AOD have significantly impaired physical function (as compared with patients with aneurysmal disease) that is successfully reversed with a surgical procedure. The functional health of patients after operation for aneurysmal disease returns to baseline after 3 and 12 months. Ultimately, cardiac and pulmonary comorbidities have a continued effect on the functional health of patients.

Flow modulates endothelial regulation of smooth muscle cell proliferation: a new model.

BACKGROUND: With a co-culture model, we have previously demonstrated that endothelial cells (ECs) exert regulatory control over smooth muscle cell (SMC) behavior. ECs appeared to stimulate SMC proliferation in static culture. This study was performed to test the hypothesis that the EC stimulation of SMC proliferation was effected by shear stress. METHODS: Bovine SMCs were cultured on a thin semipermeable membrane either alone or opposite ECs in co-culture (SMC/EC). A novel parallel-plate flow device was developed and used for exposing the EC side of the co-culture to shear stress. EC and SMC proliferation rates were determined after 24 hours' exposure to 0, 1, or 10 dynes/cm2 of shear stress. RESULTS: SMC proliferation decreased significantly from 362 +/- 65 cpm/microgram DNA (control, mean +/- SEM) to 68 +/- 43 cpm/microgram (1 dyne/cm2) and 99 +/- 18 cpm/microgram (10 dynes/cm2)(P < .05). EC proliferation after flow decreased as compared with no-flow controls 71 +/- 15 cpm/micrograms DNA (control, mean +/- SEM) to 29 +/- 5 cpm/microgram (1 dyne/cm2) and 21 +/- 4 cpm/microgram (10 dynes/cm2)(P < .05). CONCLUSIONS: In a model designed to study SMC/EC interactions in a flow environment, it was seen that EC exposure to shear stress alters the growth characteristics of SMCs. This suggests that hemodynamic mechanical forces may be sufficient to alter the EC regulation of SMC behavior.

Predictors of health after revascularization for extremity ischemia.

BACKGROUND: To assess the impact of surgical revascularization for lower extremity ischemia, we determined (with the use of the SF-36 health survey) the functional health status of patients who underwent either inflow or outflow procedures. METHODS: The SF-36 survey was given prospectively to 104 patients before operation and at intervals ranging from 10 days to 1 year after operation from January 1998 to July 1999. To determine whether revascularization was associated with improved patient health status, mean scores were compared before and after operation by univariate and multivariate analysis. To identify the factors that influenced patient health status, we performed multiple regression analysis to test the hypothesis that outcome is affected by age, gender, time since procedure, diabetes, indication, and inflow versus outflow procedure. RESULTS: There was a significant decrease in the general health score of patients before outflow bypass as compared with inflow procedure (45.3 +/- 5.3 versus 32.1 +/- 3.3 [mean +/- SEM]; P <.05). After the procedure, only those patients who had undergone inflow procedures had improved outcome scores. Diabetes, outflow procedures, limb salvage as indication, and time since operation were determined by multiple regression affecting outcome scores to be significant factors. CONCLUSIONS: The SF-36 health survey demonstrated that diabetes, procedure type, indication, and time after procedure significantly affected the functional outcome for patients who were treated surgically for lower extremity ischemia. Despite successful revascularization, significant deficits in functional health remain in patients with lower extremity ischemia.

Predicting cerebral ischemia during carotid endarterectomy.

We reviewed 86 consecutive patients undergoing elective carotid endarterectomy to determine whether preoperative clinical and angiographic data could be used to predict the risk of intraoperative cerebral ischemia during carotid occlusion. Electroencephalographic (EEG) monitoring with on-line Berg-Fourier transformation was carried out in all patients. A total of 32 patients (37.2%) underwent intraoperative shunting. Of these, 13 had no EEG changes but underwent shunting because of the surgeon's preference, while 19 patients underwent shunting because of EEG changes consistent with cerebral ischemia. There was one permanent (1.2%) and one transient (1.2%) neurologic deficit. Angiographic findings, clinical histories, and intraoperative EEGs were retrospectively reviewed to determine which risk factors best predicted the occurrence of intraoperative cerebral ischemia. Stroke within six weeks increased the risk of intraoperative cerebral ischemia 20-fold. Intracranial disease and contralateral carotid stenosis increased the risk of ischemia 17-fold and 16-fold, respectively. Statistical summation of all risk factors yielded a probability equation for EEG change that accurately quantitated pre-operative risk. Prospective application of this probability equation may simplify operative decision making if EEG monitoring is not available.

Evidence for nitric oxide as an inhibitory neurotransmitter in rabbit isolated anococcygeus.

The role of nitric oxide (NO) and ATP as putative inhibitory non-adrenergic, non-cholinergic (NANC) neurotransmitters was investigated in rabbit isolated anococcygeus after block of adrenergic and cholinergic responses, and raising tone with histamine. NANC nerve stimulation produced rapid relaxations which were completely abolished by tetrodotoxin. The magnitude of the NANC inhibitory responses was significantly reduced by the nitric oxide synthase inhibitors NG-nitro-L-arginine (NO-Arg) and NG-nitro-L-arginine methyl ester (L-NAME). This effect could be partially reversed by L-arginine but not by D-arginine. Oxyhaemoglobin inhibited NANC nerve responses and sodium nitroprusside mimicked the effects of NANC nerve stimulation. NO-Arg also reduced the magnitude of the inhibitory junction potentials recorded from the smooth muscle cells during NANC nerve stimulation. Exogenously applied ATP and adenosine each produced concentration dependent relaxations which were unaffected by the NO-synthase inhibitor NO-Arg. Relaxations to adenosine were virtually abolished by the P1 purinoceptor antagonist 8-(p-sulphophenyl)theophylline. Relaxations to ATP were also significantly reduced, indicating that part of the response to exogenous ATP is due to its breakdown to adenosine and subsequent action on P1 purinoceptors. Relaxations of the tissue to ATP and adenosine were unaffected by the P2 purinoceptor antagonist suramin. NANC nerve mediated responses were not significantly changed by either 8-(p-sulphophenyl)theophylline or suramin. These results suggest that NO is involved in inhibitory NANC neurotransmission in the rabbit isolated anococcygeus, but do not support a role for ATP as a NANC neurotransmitter in this tissue.

Haem biosynthesis in the unconjugated hyperbilirubinaemias: observations in the Gunn rat model.

Disturbances of the enzymes of haem biosynthesis have been reported in patients with unconjugated hyperbilirubinaemia. We have examined the excretion of haem precursors in the Gunn rat which suffers from severe unconjugated hyperbilirubinaemia. In urine, levels of aminolaevulinic acid and total porphyrin were significantly reduced when compared to controls. In feces both coproporphyrin and protoporphyrin levels were reduced in Gunn rats, the former being more affected. Blood porphyrin levels in control and Gunn rats were similar.

Antiphospholipid antibodies lead to increased risk in cardiovascular surgery.

BACKGROUND: Antiphospholipid (APL) antibodies are a heterogenous group of antibodies that have been associated with an increase in bleeding complications and a marked increase in thrombotic events, both of which result in significant patient morbidity and mortality. PATIENTS AND METHODS: A retrospective analysis of patients identified to be positive for APL via a university thrombosis registry who had cardiovascular surgery between 1989 and 1994. RESULTS: Seventy-one patients positive for APL antibodies were identified. Of those patients, 19 had cardiovascular surgical procedures (11 women and 8 men, mean age 58.4 years, range 38 to 78). A total of 48 cardiovascular surgical procedures (mean 2.5 procedures/patient) were performed in the 19 patients. These procedures included 13 lower-extremity reconstructions, 11 upper-extremity reconstructions/fistulas, 8 cardiac valve replacements, 5 coronary artery bypass procedures, 5 major amputations, 4 infrarenal aortic reconstructions, and 2 carotid endarterectomies. Sixteen of the 19 patients (84.2%) suffered major postoperative complications. These included 16 thrombosed grafts, 5 strokes, 5 major bleeding events, 2 pulmonary emboli, and 2 myocardial infarctions. Ultimately, 12 of the 19 patients (63.2%) died of complications related to surgery. CONCLUSIONS: This series of patients confirms that patients with circulating APL antibodies are prone to excessive postoperative morbidity and mortality after cardiovascular surgical procedures. The presence of APL antibodies may be a maker of increased risk of complications after cardiovascular surgery.

The utility of dobutamine echocardiography in preoperative evaluation for elective aortic surgery.

BACKGROUND: Preoperative cardiac evaluations have been advocated prior to major vascular procedures to reduce the incidence of postoperative cardiac complications. This study was undertaken to evaluate the efficacy and predictive value of routine dobutamine echocardiography (DE) in the screening of patients undergoing elective aortic surgery. METHODS: Dobutamine echocardiography was performed preoperatively on all patients having elective aortic procedures by our university surgical group from June 1995 to August 1996. The cardiac morbidity and mortality from this group were compared with that of a similar group undergoing elective aortic procedures from June 1993 to May 1995 with no dobutamine echocardiography (NDE). RESULTS: Although there was no statistically significant difference in either overall mortality (4.4% in NDE vs. 2.3% in DE) or cardiac mortality (2.9% in NDE vs. 0% in DE) between the two groups, cardiac events occurred only in those patients with previous coronary artery disease. In addition, dobutamine echocardiography had a negative predictive value of 97% CONCLUSIONS: Although routine screening is not necessary, selective screening of patients using dobutamine stress echocardiography is justified because of its high negative predictive value.

Bile duct cells in primary biliary cirrhosis are 'primed' for apoptosis.

OBJECTIVE: Primary biliary cirrhosis (PBC) is characterized by progressive, immune-mediated destruction of bile ducts (<75 microm diameter) and secondary changes related to cholestasis which may involve apoptosis. In this study we sought to examine the protein expression of genes involved in apoptosis in biliary epithelium of PBC cases. DESIGN: In order to investigate the susceptibility of biliary epithelial cells to apoptosis and their ability to proliferate, we examined the expression of a number of apoptosis related proteins in early and late stage PBC and histologically normal liver control tissue using immunohistochemistry. METHODS: Liver biopsies from 15 early (stages I and II) and 14 late (stages III and IV) cases of PBC and 15 normal cases were examined immunohistochemically for expression of p53, CD95/Fas, bax, bcl-x, bcl-2 and the proliferation marker Ki-67. RESULTS: CD95/Fas, bax and bcl-x were identified in biliary epithelium in 8/15, 11/15 and 8/15 normal biopsies. Weak expression of bcl-2 was found, but p53 was not identified. In cases of PBC surviving bile ducts showed strong bax and bcl-x expression. Inflammatory infiltrates were strongly bcl-2 positive. In cases showing a marked ductular reaction there was increased reactivity for bax and bcl-x in ductules. No change in CD95/Fas or p53 expression was seen. An increase in Ki-67 positive biliary epithelial cells was seen in PBC cases, indicating cell cycle activity. CONCLUSIONS: Bile duct epithelium constitutively expresses several genes involved in the execution of apoptosis but these cells also retain the ability to proliferate.

Fibromuscular dysplasia of the brachial artery: an endovascular approach.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic segmental disease of unknown etiology primarily affecting muscular arteries of intermediate size. The pathology affects the renal arteries in the majority of cases, followed by the carotid, vertebral, and ilio-femoral arteries. There have been only six reported cases of FMD involving the brachial artery. This case report describes the seventh case and illustrates an endovascular approach to this clinical entity. A 63-year-old female with a history of hypertension presented to vascular surgery clinic with a 4-day history of numbness, pain, and coolness of her left hand. On physical exam, the patient had a normal axillary and brachial pulse, but had only a Doppler signal of the left ulnar artery. There was no Doppler signal of the radial artery. Segmental pressures and PVR waveforms were normal in the upper arm, but there was a significant blunting of the waveform and decrease in pressure at the level of the wrist. An arteriogram revealed significant narrowing and irregularity of the brachial artery with a characteristic "string-of-beads" appearance. There was complete thrombosis of the radial artery and evidence of fresh thrombus in the distal brachial artery. The patient was treated with intra-arterial infusion of urokinase with restoration of the radial pulse and resolution of her symptoms. Subsequently, the patient had a percutaneous transluminal balloon angioplasty of the involved segment of brachial artery, with normal PVR's and segmental pressures upon completion. FMD of the brachial artery and its sequelae are extremely rare, and therefore, there is no consensus on proper management.(ABSTRACT TRUNCATED AT 250 WORDS)

Persistent sciatic artery in association with varicosities and limb length discrepancy: an unrecognized entity?

The persistence of the sciatic artery is an unusual occurrence, with an angiographically demonstrated incidence of 0.06%. There have been 71 cases previously reported. We report an additional case in a 14-year-old boy who presented with a chief complaint of unsightly varices. The involved right limb was notably shorter than the uninvolved left lower extremity. Work-up included physical examination, duplex studies, venography, and angiography. Our patient was found to have a patent deep venous anatomy with valvular incompetency associated with complete persistence of the sciatic artery and a foreshortened right leg. He has done well with conservative treatment. The persistence of a sciatic artery has occasionally been associated with other anomalies including Mullerian and left renal agenesis, A-V fistula formation, hypertrophy or hypotrophy, multiple hemangiomata, neurofibromatosis, or anomalies of leg arteries. The literature describes three previous case reports in which patients presented with gross varicosities and were incidentally found to have persistent sciatic arteries as well as limb length discrepancies. Our patient is a fourth example of this syndrome. This pattern of physical attributes has not been previously described as a distinct entity. The association of venous incompetency, limb discrepancies, and persistence of the sciatic artery may be an incidental finding or may represent a related embryologic event. This relationship merits consideration in a young patient presenting with severe venous varicosities.

Elective aortic surgery with minimal banked blood.

It has been a historical supposition that aortic surgery, even in an elective setting, has been associated with the transfusion of large amounts of blood products. We feel that this assumption is now dated, and in fact far fewer patients now receive allogenic blood products. To assess this assumption, we carried out a retrospective chart review of all patients who underwent elective aortic surgery over an 18-month period from April 1994 to October 1995. Factors analyzed included type of procedure, blood loss, amount of Cell Saver blood replaced, need for autologous blood transfusion, and need for allogenic blood transfusion. Sixty-seven patients underwent elective aortic surgery with either an aortic tube graft (23), an aortobiiliac graft (25), or an aortobifemoral graft (19). The male:female ratio was 48:19, with a mean age of 67 years (range, 42-85 years). Mortality and morbidity were 4.4 per cent and 8.9 per cent, respectively. The average blood loss per patient was 770 cc. Cell saver was used in 65 patients, with the average amount of blood returned being 542 cc. Overall, 73 per cent of patients did not require allogenic blood transfusion, and 58 per cent did not need any type of transfusion. Of those who stored autologous blood prior to operation, none required allogenic blood perioperatively. With the new advances in autologous blood transfusion both by predeposit and salvage transfusion, we have greatly reduced the need for transfusion of allogenic blood products in patients undergoing major aortic surgery. This is reassuring, and although increasing short-term cost, will reduce the morbidity-infectious, noninfectious, and immunologic-associated in prior decades with allogenic blood transfusions. We strongly recommend the use of Cell Saver techniques, and also, where possible, patients should be encouraged to donate their own blood prior to major aortic procedures for future transfusion.

Porcine model for vascular graft studies.

Models for the study of prosthetic vascular graft infection have been studied frequently in the dog and rabbit. We have developed a reproducible swine model to study this problem and its treatment. The cardiovascular system, healing characteristics, and the bloodstream clearance of bacteria in swine more closely resembles those of humans than do other animal models. The low cost and availability of the swine is an additional attractive aspect. One hundred fifty-six farm-bred pigs have undergone infrarenal aortic replacement with a 3-cm segment of 6-mm prosthetic graft over the past two years. Graft infection was produced by (1) direct inoculation of 10(6) Staphylococcus aureus at the time of the surgery or (2) intravenous infusion of bacteria (10(2)-10(6) organisms/mL) immediately after surgery. All animals were sacrificed 1 to 4 weeks later, depending on the study design. Cultures, histology, and electron microscopy were performed on each graft. Anesthetic complications were rare (2.5%). Postoperative complications leading to animal death decreased with increasing experience (11.5%), but included graft thrombosis, bleeding, sepsis, intussusception, and colonic ischemia. Wound infection was the most common cause of morbidity. The swine model is an attractive alternative to that of other animals for the study of prosthetic vascular graft infections. Further details of the operative technique and the comparison to the human and other animal models is discussed.

Species differences in the clearance of Staphylococcus aureus bacteremia.

Studies on vascular graft infections may be influenced by species differences in bacteria clearance. The present study compares the bloodstream elimination of Staphylococcus aureus (S. aureus) in dogs and pigs. Four mongrel dogs and four Yorkshire pigs received a 20-min infusion of 10(6) S. aureus labeled with indium-131. Through a catheter placed in the infrarenal aorta, blood samples were removed at intervals for 5 h after infusion. The liver, spleen, and lungs were biopsied at 5 h. Blood and tissue samples were then counted in a gamma counter. The calculated phagocytotic index, k, for dogs was 8.6 X 10(-4), while for pigs it was 1.5 X 10(-3), indicating significantly faster bacterial clearance in pigs (p = .009). After 2 1/2 h, significantly fewer counts were present in pigs at most time points (p less than .05). Organ counts indicated higher counts in the dog liver and spleen and in the lungs of pigs (p less than .0001). This study indicates that S. aureus bacteremia is cleared faster by pigs, primarily by the lungs, compared to dogs, in which liver-spleen clearance predominated. These differences should be considered when the results of graft infection studies are compared.

Replication of the compartment syndrome in a canine model: experimental evaluation of treatment.

The sequence of acute ischemia, reperfusion, and elevated tissue pressure, with subsequent neuromuscular damage, results in the clinical entity known as the compartment syndrome. We have developed a canine hindlimb model that successfully replicates these clinical features. Surgical devascularization of both hindlimbs at the popliteal level isolates perfusion to a single vascular pedicle. Total ischemia is produced in the left limb for 8 h, while the right limb serves as a surgical control. Ischemia is confirmed by measurement of transfascial oxygen tension (TF-PO2) as well as lactate and blood gases in the venous effluent. Pressure in the anterior compartment of the hindlimb is monitored by the slit catheter technique. After reperfusion, muscle damage is assessed by histology, creatine phosphokinase (CPK), and uptake of technetium-99m pyrophosphate (Tc-PyP), expressed as a ratio of the experimental (L) limb to the control (R) limb (L/R ratio). Muscle necrosis was greatest in untreated controls; the L/R ratio was 8.9 +/- 5.0. Significant diminution of muscle necrosis was achieved by fasciotomy prior to reperfusion (2.6 +/- 0.8), mannitol (1.8 +/- 0.6), albumin-conjugated superoxide dismutase (SOD) 2.8 +/- 0.8), native SOD (2.3 +/- 1.0), fasciotomy combined with SOD (1.9 +/- 0.7), and continuous heparin (1.6 +/- 0.4) (p less than .01 vs controls). When fasciotomy was delayed until 2 h after reperfusion, there was no significant decrease in the L/R ratio (5.4 +/- 1.5; p = .15). Early fasciotomy following prolonged severe limb ischemia remains the treatment of choice, although these results suggest an emerging role for nonsurgical therapies as well. A summary of work done with this model as well as a review of other techniques is presented, along with a discussion of the pathophysiology of the compartment syndrome.

A persistent hindlimb ischemia model in the rabbit.

The study of new approaches for the treatment of limb-threatening ischemia has been hampered by the lack of a suitable animal model of persistent limb ischemia. We describe the development and evaluation of an animal model of persistent hindlimb ischemia, in which ischemia was induced in the left hindlimb of 28 rabbits by ligation of the distal external iliac artery and excision of the common and superficial femoral arteries. The severity of the ischemia and its relief in each animal were evaluated every 10 days postoperatively until day 40 (all animals) or day 90 (five animals). Nine animals developed superficial tissue necrosis in the foot, but no deaths were attributable to the ischemia-inducing procedure. Angiography demonstrated minimal collateralization and sluggish filling of distal vessels up to postoperative day 90. This was accompanied by a decrease at rest in the calf blood flow ratio (p < 0.005 vs day 0), an increase in lactic acid in the femoral venous blood (left vs right side, p < 0.002) up to postoperative day 40, and a decrease in the calf blood pressure ratio (p < 0.0001 vs day 0) up to day 90. Histologic study of the gastrocnemius muscle demonstrated evidence of atrophy and fibrosis in the left hindlimb. This model can be used to evaluate direct and indirect approaches to the treatment of chronic limb ischemia.