Esophageal pressure: research or clinical tool?

Esophageal manometry has traditionally been utilized for respiratory physiology research, but clinicians have recently found numerous applications within the intensive care unit. Esophageal pressure (PEs) is a surrogate for pleural pressures (PPl), and the difference between airway pressure (PAO) and PEs provides a good estimate for the pressure across the lung also known as the transpulmonary pressure (PL). Differentiating the effects of mechanical ventilation and spontaneous breathing on the respiratory system, chest wall, and across the lung allows for improved personalization in clinical decision making. Measuring PL in acute respiratory distress syndrome (ARDS) may help set positive end expiratory pressure (PEEP) to prevent derecruitment and atelectrauma, while assuring peak pressures do not cause over distension during tidal breathing and recruitment maneuvers. Monitoring PEs allows improved insight into patient-ventilator interactions and may help in decisions to adjust sedation and paralytics to correct dyssynchrony. Intrinsic PEEP (auto-PEEP) may be monitored using esophageal manometry, which may also improve patient comfort and synchrony with the ventilator. Finally, during weaning, PEs may be used to better predict weaning success and allow for rapid intervention during failure. Improved consistency in definition and terminology and further outcomes research is needed to encourage more widespread adoption; however, with clear clinical benefit and increased ease of use, it appears time to reintroduce basic physiology into personalized ventilator management in the intensive care unit.

Nanoparticle delivery of mycophenolic acid upregulates PD-L1 on dendritic cells to prolong murine allograft survival.

Conventional immunosuppressive drug delivery requires high systemic drug levels to provide therapeutic benefit, but frequently results in toxic side effects. Novel drug delivery methods, such as FDA-approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), are promising drug delivery platforms to reduce drug doses and minimize toxicity. Using murine models of skin transplantation, we investigated whether PLGA NPs would effectively deliver mycophenolic acid (MPA), a common clinical immunosuppressant, and avoid the toxicity of conventional drug delivery. We found that intermittent treatment with NPs encapsulated with MPA (NP-MPA) resulted in a significant extension of allograft survival than intermittent conventional MPA treatment even though the concentration of MPA within NP-MPA was a 1000-fold lower than conventional drug. Importantly, recipients who were administered NP-MPA intermittently avoided drug toxicity, whereas those treated with daily conventional drug manifested cytopenias. Dendritic cells (DCs) endocytosed NP-MPA to upregulate programmed death ligand-1 (PD-L1) and displayed a decreased ability to prime alloreactive T cells. Importantly, the ability of NP-MPA to promote allograft survival was partly PD-L1 dependent. Collectively, this study indicates that NPs are potent drug delivery tools that extend allograft survival without drug toxicity.

On-pump versus off-pump coronary artery bypass: independent risk factors and off-pump graft patency.

OBJECTIVE: Current knowledge on off-pump coronary artery bypass (OPCAB) generally stems from single surgeons' experience or from series where OPCABs constituted a minor fraction of coronary operations. The present center decided to venture as far into OPCAB as possible during 1999. The present series thus represents the average surgeon's experience. METHODS: During 1999, 533 patients underwent coronary artery bypass grafting using cardiopulmonary bypass (CPB) in 368 and OPCAB in 165 including the circumflex artery (CX) area in 91. Coronary arteriography was performed before discharge in the first 103 OPCAB patients. RESULTS: The CPB and OPCAB groups differed as regards left ventricular ejection fraction (53+/-13 versus 57+/-11, P < 0.0001) and frequency of triple-vessel or left main stem disease (84 versus 32%, P < 0.0001) but were comparable as regards diabetes (12%), prior myocardial infarct (57%), unstable angina (21%), and previous heart surgery (3%). Using multivariate analyses, 30-day mortality (1.3%), P-creatine kinase myocardial band (CKMB) > 80 microg/l (11.1%), re-sternotomy for bleeding (4.5%) or dehiscense (1.7%), transitory cerebral ischemia and stroke (1.7%), supraventricular tachycardia (27.4%), and hospital stay (mean 8 days) were unrelated to off- versus on-pump surgery as well as to OPCAB in triple-vessel disease. CX branches < or = 1mm, > or = 5 distal anastomoses, prior heart surgery, right coronary artery (RCA) branches < or = 1.5mm, 8-21 days old myocardial infarct, female gender, and preoperative acute arrhythmia (among others) were identified as independent risk factors for mortality or increased CKMB in all 533 patients. The latter five risk factors were reproduced in the OPCAB group isolated. The patency in the 103 OPCABs was 95.3, 91.8, and 85.3% in the left anterior descending artery (LAD), CX, and RCA, respectively. Patency was inversely related to diameter of the grafted vessel in the LAD and CX areas, unlike the RCA area. CONCLUSIONS: The results after beating heart surgery were good also in patients with triple-vessel disease, but specific gains relative to on-pump surgery could not be shown. The independent risk factors in the OPCAB group may indicate relative contraindications for OPCAB grafting.

Impaired fibrinolysis determines the outcome of percutaneus transluminal coronary angioplasty (PTCA).

BACKGROUND: Coronary artery stenosis lesions dilated by percutaneus transluminal coronary angioplasty (PTCA) show a disappointingly frequent recurrence of stenosis. We have investigated the possible role of fibrinolysis and various platelet-release factors - specifically in the locality of the affected vessel - by following 19 patients for 6 months after PTCA. METHODS: PTCA was performed on 19 patients with a significant primary coronary stenosis, proven by quantitative CAAS analysis. Blood for measurement of local fibrinolysis and platelet activity was drawn from the aortic root and the coronary sinus, at three times: just before PTCA, 10 min after it, and 6 months later. RESULTS: The incidence of restenosis at the 6 months follow-up was 37%. PTCA almost doubled the platelet-derived growth factor level (PDGF) in coronary sinus blood in all patients. The seven restenosis patients had a substantially higher tissue plasminogen activator inhibitor antigen (PAI-1ag) level in the aortic root before PTCA than the 12 who remained stenosis-free (mean 62.4 +/- 31.6 ng mL -1 compared with 33.1 + 25.3; P < 0.04) and a lower tissue plasminogen activator activity (t-PAac) level (mean 0.32 +/- 0.19 IU mL-1 compared with 0.68 +/- 0.34; P < 0.03). This was corroborated by the levels of tissue plasminogen activator inhibitor activity (PAI-1ac). At reassessment after 6 months, the restenosis patients had developed, in coronary sinus blood, a large rise of PAI-1ac (7.7 +/- 4.8 IU mL-1 rising to 15.7 +/- 13.9, P < 0.04) and a large rise of of PAI-1ag (48.8 +/- 31.3 ng mL-1 vs. 72.4 +/- 47.2; P < 0.03). But no such increase occurred in the patients who remained stenosis-free. Conclusion Our results indicate that the minor balloon injury, which is inseparable from PCTA, stimulates the local release of PDGF. We suggest that, in those patients whose fibrinolytic activity is inherently low, this rise of PDGF could be a major causative factor in restenosis. We also discuss the possibility that the preoperative level of PAI-1ac could provide a limited but useful prediction of the outcome of PTCA.

[Coronary artery bypass without use of the heart-lung-machine]. / Koronar bypass uden hjerte-lunge-maskine.

INTRODUCTION: Off pump coronary artery bypass via sternotomy (OPCAB) and via a small left anterior thoracotomy (MIDCAB) on the anterior coronary arteries of the heart was introduced at the present center in 1997. Starting this year we decided to increase OPCAB and MIDCAB to constitute at least 50% of CAB procedures including the posterior aspect of the heart. METHODS: From January 1st through April 16th 1999 we performed 152 CAB procedures: 108 CABG, 6 MIDCAB, 13 OPCAB (on the anterior cornary arteries) and 25 OPCAB-Cx (including the circumflex artery). OP procedures were done using OCTOPUS-II to expose and stabilize the arteriotomies, and control angiography was performed before discharge. RESULTS: Off pump CAB was performed in 2% of the first 50 CAB patients, 36% of the next 50 and 50% of the last 52. The CABG and OPCAB-Cx groups were comparable as regards degree of coronary artery disease and number of distal anastomoses, but differed as regards poor left ventricular function and unstable preoperative status. Early mortality was 1.9% in the CABG group and 0% in the OP groups. Control angiograms in the OP groups showed a patency from 92 to 100%. CONCLUSIONS: In this short preliminary series, it was possible to increase the fraction of OP procedures to nearly 50% with good results.

[Abciximab (ReoPro) in the treatment of acute coronary syndromes]. / Abciximab (ReoPro) ved behandling af akutte koronare syndromer.

Platelet activation plays a major role in the pathophysiology of acute coronary syndromes (ACS). Inhibition of platelet function is the basic pharmacological treatment of ACS. Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of ACS and in the prevention of complications after percutaneous coronary interventions (PCI). Several large clinical trials have demonstrated the effectiveness of this class of agents. The first of these agents to show beneficial effects after coronary interventions was the mouse/human chimeric Fab fragment antibody c7E3 abciximab (ReoPro). The purpose of this article is to describe the pharmacology of abciximab and to review the results of the clinical trials carried out with the drug in patients with ACS, treated either with or without acute/elective PCI.

[Contrast echocardiography. Basic principles and clinical applications]. / Kontrastekkokardiografi. Basale principper og kliniske applikationer.

Recent advances in ultrasound technology and intravenous contrast agents have made it possible for contrast echocardiography to move from bench to bedside. Ultrasound contrast agents enhance endocardial border delineation and the Doppler signal, which may improve the diagnostic accuracy of echocardiography in selected patients. The most exciting feature of contrast echocardiography is its capability to achieve a quantitative assessment of myocardial perfusion, and the method may thus provide a range of clinical applications in patients with ischaemic heart disease.

Hodgkin's disease presenting with a bronchoesophageal fistula.

Bronchoesophageal fistula is a rare complication of Hodgkin's disease. We report a case of Hodgkin's disease presenting with a bronchoesophageal fistula that was successfully treated with bipolar esophageal exclusion and substernal gastric bypass. Direct invasion from mediastinal lymph nodes was the probable cause. Although bronchoesophageal fistula can result as a complication during the course of treatment for Hodgkin's disease, it rarely occurs as the presenting feature. Early recognition and surgical treatment are key aspects of management.

The Barath Cutting Balloon versus conventional angioplasty. A randomized study comparing acute success rate and frequency of late restenosis.

In a randomized multicenter study initial success rate and 6 months' follow-up were compared between coronary angioplasty performed with the Barath Cutting Balloon (group A, n = 32) and conventional balloons (group B, n = 32) in patients with type A or B lesions in native coronary arteries. The culprit lesion was not reached in one patient in group A. Initial success rates were similar with and without additional stenting (8 in group A and 10 in group B). Angiographic follow-up data (in 95%) revealed a non-significant improvement in minimal lumen diameter, diameter stenosis in group A. Restenosis developed in 16.7% of group A vs 25.8% of group B, (p = 0.57). A separate analysis of stented patients showed no restenosis in group A and restenosis in 4 out of 10 patients in group B (p = 0.10). A possible beneficial effect of the Cutting Balloon with respect to in-stent restenosis requires further studies.

Community-acquired urinary tract infection in adults: a hospital viewpoint.

The clinical and epidemiologic spectrum of 175 cases of community-acquired urinary tract infection (UTI) were evaluated at a university hospital. Patients were grouped in five different categories of which complicated UTI was the most common (39%). Bacteraemia was detected in eight patients (18%) of this group and in five (12%) with acute uncomplicated pyelonephritis. A single organism was isolated in 166 cases (95%). The rate of Escherichia coli bacteriuria ranged from 60% (asymptomatic bacteriuria) to 94% (uncomplicated cystitis). Of the 184 isolates, 92% were susceptible to ciprofloxacin and significantly high rates of resistance were found for ampicillin, cefazolin, cefuroxime, and co-trimoxazole. Isolates causing uncomplicated UTI had significantly high rates of resistance to ampicillin, amoxycillin-clavulanate and co-trimoxazole and those causing complicated UTI, had significantly high rates of resistance to most oral antibiotics tested, except quinolones and nitrofurantoine. Community-acquired UTI requiring hospital evaluation occurs in a complex group of patients, and current patterns of antibiotic resistance make it difficult to suggest empiric oral treatments in this setting.

Future directions in esophageal cancer.

The incidence of esophageal cancer in the United States has been increasing in recent years. Since multimodality therapy for esophageal cancer has produced discouraging results, recent approaches have focused on molecular biological techniques, positron emission tomography, and minimally invasive surgery to improve pretreatment staging which will facilitate a more accurate assessment of new treatment. This article summarizes the results of studies investigating these approaches and outlines the strategy currently used at the University of Pittsburgh Medical Center.

Detection of micrometastases in histologically negative lymph nodes in esophageal cancer.

BACKGROUND: New molecular techniques may identify micrometastases in histologically negative lymph nodes and have an impact on the staging of esophageal cancer. We investigated the role of the reverse transcriptase-polymerase chain reaction (RT-PCR) assay to identify micrometastases in esophageal cancer. METHODS: The RT-PCR assay to detect carcinoembryonic antigen (CEA) messenger ribonucleic acid (mRNA) was performed on lymph nodes from patients with esophageal cancer and benign esophageal disorders. The presence of CEA mRNA in lymph nodes was considered evidence of metastases. RESULTS: Histopathologic study revealed metastases in 50 (41%) of 123 lymph nodes from 30 patients with esophageal cancer. All histologically positive lymph nodes contained CEA mRNA by RT-PCR. Of 73 histologically negative lymph nodes, 36 (49%) contained CEA mRNA, a significant increase compared with the histopathologic diagnosis (p < 0.001). Lymph nodes in patients with benign disease contained no CEA mRNA. In 10 patients, histologic stage was NO. Five of them were also negative by RT-PCR, and all are alive with only one recurrence. In the remaining 5 patients, RT-PCR was positive for occult lymph node metastases; 2 have died of disease, and 1 is alive with recurrent disease. CONCLUSIONS: In patients with esophageal cancer, RT-PCR detects more lymph node metastases than does histopathology. Initial follow-up suggests a positive RT-PCR with negative histologic findings may have poor prognostic implications. Further studies will be needed to confirm any clinical implications.

Detection of occult lymph node metastases in esophageal cancer by minimally invasive staging combined with molecular diagnostic techniques.

BACKGROUND AND OBJECTIVES: Lymph node metastases are the most important prognostic factor in patients with esophageal cancer. Histologic examination misses micrometastases in up to 20% of lymph nodes evaluated. In addition, non-invasive imaging modalities are not sensitive enough to detect small lymph nodes metastases. The objective of this study was to investigate the use of reverse transcriptase-polymerase chain reaction (RT-PCR) of messenger RNA (mRNA) for carcinoembryonic antigen (CEA) to increase the detection of micrometastases in lymph nodes from patients with esophageal cancer. METHODS: RT-PCR of CEA mRNA was performed in lymph nodes from patients with malignant and benign esophageal disease. Each specimen was examined histopathologically and by RT-PCR and the results were compared. RESULTS: Metastases were present in 29 of 60 (48%) lymph nodes sample by minimally invasive staging from 13 patients with esophageal cancer when examined histopathologically. RT-PCR identified nodal metastases in 46 of these 60 (77%) samples. RT-PCR detected CEA mRNA in all 29 histologically positive samples and in 17 histologically negative lymph nodes. All lymph nodes from patients with benign disease (n = 15) were negative both histopathologically and by RT-PCR. The stage of two patients was reclassified based on the RT-PCR results, which identified lymph node spread undetected histopathologically. Both of these patients developed recurrent disease after resection of the primary tumor. CONCLUSIONS: RT-PCR is more sensitive than histologic examination in the detection of lymph node metastases in esophageal cancer and can lead to diagnosis of a more advanced stage in some patients. The combination of minimally invasive surgical techniques in combination with new molecular diagnostic techniques may improve our ability to stage cancer patients.

Pharmacokinetic analysis of gentamicin thrice and single daily dosage in pediatric cancer patients.

Fifty-two children suffering from different types of malignancies were included and evaluated for the pharmacokinetics of gentamicin thrice or single daily dosage protocols. All the study population received a total dose of 5 mg/kg daily. Thirty children received gentamicin thrice daily, and 22 were treated using the single daily protocol; all had fever and neutropenia when included. The individual pharmacokinetic parameters were calculated using a one-compartment model for two blood gentamicin samples. The mean (SD) t 1/2 (h), clearance (mL/min/BSA), Vss (L/kg), Cmax (micrograms/mL), and Cmin (micrograms/mL) were 3.05 (1.0) and 3.9 (0.6) h, 136 (61.3) and 99.9 (65.3) mL/min/BSA, 0.4035 (0.167) and 0.457 (0.17) L/kg, 5.2 (2.0) and 11.5 (4.2) micrograms/mL, 0.8 (0.6) and 0.18 (0.1) microgram/mL for thrice and single daily dosage schedules, respectively. The single gentamicin daily dose protocol had a significantly longer t 1/2, shorter clearance normalized to BSA, higher Cmax, and lower Cmin in comparison with the thrice daily schedule. We recommend the use of gentamicin at 5 mg/kg daily delivered as a single daily dose for pediatric cancer patients with fever and neutropenia, in spite of the measured pharmacokinetic differences, which in our opinion have no clinical significance.

Danish multicenter randomized study of invasive versus conservative treatment in patients with inducible ischemia after thrombolysis in acute myocardial infarction (DANAMI). DANish trial in Acute Myocardial Infarction.

BACKGROUND: The aim of the DANish trial in Acute Myocardial Infarction (DANAMI) study was to compare an invasive strategy of percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) with a conservative strategy in patients with inducible myocardial ischemia who received thrombolytic treatment for a first acute myocardial infarction (AMI). METHODS AND RESULTS: Of the 503 patients randomized to an invasive strategy, PTCA was performed in 266 (52.9%) and CABG in 147 (29.2%) from 2 to 10 weeks after the AMI. Of the 505 patients in the conservative treatment group, only 8 (1.6%) had been revascularized 2 months after the AMI. The patients were followed up from 1 to 4.5 years. The primary end points were mortality, reinfarction, and admission with unstable angina. At 2.4 years' follow-up (median), mortality was 3.6% in the invasive treatment group and 4.4% in the conservative treatment group (not significant). Invasive treatment was associated with a lower incidence of AMI (5.6% versus 10.5%; P=.0038) and a lower incidence of admission for unstable angina (17.9% versus 29.5%; P<.00001). The percentages of patients with a primary end point were 15.4% and 29.5% at 1 year, 23.5% and 36.6% at 2 years, and 31.7% versus 44.0% at 4 years (P=<.00001) in the invasive and conservative treatment groups, respectively. At 12 months, stable angina pectoris was present in 21% of patients in the invasive treatment group and 43% in the conservative treatment group. CONCLUSIONS: Invasive treatment in post-AMI patients with inducible ischemia results in a reduction in the incidence of reinfarction, fewer admissions due to unstable angina, and lower prevalence of stable angina. We conclude that patients with inducible ischemia before discharge who have received treatment with thrombolytic drugs for their first AMI should be referred to coronary arteriography and revascularized accordingly.

Nerve growth factor (NGF)-mediated protection of neural crest cells from antimitotic agent-induced apoptosis: the role of the low-affinity NGF receptor.

Prevention by nerve growth factor (NGF) of apoptotic death in neural cells has been variously ascribed to binding of NGF to its low-affinity (p75) or high-affinity (trkA) receptor or to a cooperative interaction between the two. In a series of studies using, in turn, neuroblastoma cell lines that express only p75, mutant NGF species that bind selectively to either p75 or trkA, and a polyclonal antibody that binds to the NGF-binding domain of p75, we demonstrate that NGF binding to p75 is both necessary and sufficient for the abrogation of apoptosis in neuroblastoma cells treated with antimitotic agents.