Clinical determinants of intestinal failure and death in preterm infants with surgical necrotizing enterocolitis.

OBJECTIVE: We sought to investigate the clinical determinants of intestinal failure and death in preterm infants with surgical NEC. METHODS: Retrospective comparison of clinical information between Group A = intestinal failure (Parenteral nutrition (PN) >90 days) and death and Group B = survivors and with PN dependence < 90 days in preterm infants with surgical NEC. RESULTS: Group A (n = 99/143) had a lower mean gestational age (26.4 weeks [SD3.5] vs. 29.4 [SD 3.5]; p = 0.013), lower birth weight (873 gm [SD 427g] vs. 1425 gm [894g]; p = <0.001), later age of NEC onset (22 days [SD20] vs. 16 days [SD 17]; p = 0.128), received surgery later (276 hours [SD 544] vs. 117 hours [SD 267]; p = 0.032), had cholestasis, received dopamine (80.6% vs. 58.5%; p = 0.010) more frequently and had longer postoperative ileus time (19.8 days [SD 15.4] vs. 11.8 days [SD 6.5]; p = <0.001) and reached full feeds later (93 days [SD 45] vs. 44 [SD 22]; p = <0.001) than Group B.On multivariate logistic regression, higher birth weight was associated with lower risk (OR 0.35, 95% CI 0.15-0.82; p = 0.016) of TPN > 90 days or death. Longer length of bowel resected (OR 1.76, 95% CI 1.02-3.02; p = 0.039) and longer postoperative ileus (OR 2.87, 95% CI 1.26-6.53; p = 0.011) were also independently associated with TPN >90days or death adjusted for gestational age and antenatal steroid treatment. CONCLUSION: In preterm infants with surgical NEC, clinical factors such as lower birth weight, longer bowel loss, and postoperative ileus days were significantly and independently associated with TPN >90 days or death.

Clinical impact of analgesic-sedative agents and peri-operative clinical status on white matter brain injury in preterm infants following surgical NEC.

BACKGROUND: The potential influence of exposure to analgesic-sedative agents (ASA) before, during, and after surgical NEC and peri-operative clinical status on white matter injury (WMI) in preterm infants has not been fully defined, and a comprehensive evaluation may inform future research and clinical interventions. METHODS: A retrospective study comparing ASA exposure before/during /after surgical NEC and peri-operative clinical status in neonates with and without WMI. RESULTS: Infants with any WMI (grade 2-4, n = 36/67, 53.7%) had a higher number of surgical procedures receiving ASA (5 [IQR: 3, 8] vs. 3 [2, 4]; p = 0.002) and had a longer duration of hypotension during their first (48.0 hours [26.0, 48.0] vs. 15.5 [6, 48]; p = 0.009) and second surgery (20 hours [0, 48h] vs. 0 [0, 22]; p = 0.017), received more hydrocortisone (35% vs.13.3%,p = 0.04) than those without any WMI. There were no differences in fentanyl/morphine/midazolam exposure before/during/after the NEC onset in the two groups.Infants with severe WMI (19/67, 28.3%, grade 3/4) had a higher incidence of AKI (P = 0.004), surgical morbidity (p = 0.047), more surgical procedures (6.5 [3, 10] vs. 4 [2, 5]; p = 0.012), and received higher mean fentanyl doses(p = 0.03) from birth until NEC onset than those without severe WMI. The univariate associations between these factors and severe WMI remained insignificant after multivariable logistic regression. CONCLUSION: Infants with WMI had more surgical procedures receiving ASA and had a longer duration of hypotension during surgeries. A large multicenter prospective study is needed to understand the full impact of ASA.

Clinical determinants and impact of hemorrhagic lesions on intestinal pathology in preterm infants with surgical necrotizing enterocolitis.

OBJECTIVE: We sought to determine the clinical and histopathological factors associated with intestinal hemorrhage and its correlation with clinical outcomes in neonates with surgical necrotizing enterocolitis (NEC). METHODS: A retrospective study compared clinical and histopathology information in neonates following surgical NEC with severe hemorrhage and those with mild/moderate hemorrhagic lesions seen on resected intestine pathology. RESULTS: The infants with severe hemorrhage (Grade 3-4, 81/148, 54.7%) had significantly lower exposure to antenatal steroids (52.5 % vs 76.9 %; p = 0.004), had higher gestational age (28.5 weeks [7.14] vs. 26.58 [2.90]; p = 0.034), lost more bowel length (p = 0.045), had higher CRP levels at 2 weeks (p = 0.035), and had less intestinal failure ([30.3 % vs 52.5 %]; p = 0.014) than mild/moderate (Grade 0-2, 67/148, 45.2%) hemorrhage group. Those with severe hemorrhage had significantly higher mean inflammation score (2.67 [0.94] vs. 1.63 [0.92]; p = <0.001), higher necrosis scores (1.95 [1.28] vs. 1.49 [1.35]; p = 0.037), higher neovascularization (p = 0.01), higher fibroblasts (p = 0.023) and higher lymphocyte percentages up to 48 hours (p < 0.05) following NEC than mild/ moderate hemorrhage group.On multivariable regression, less exposure to antenatal steroids (OR 0.18 [95% CI 0.05-0.58]; p = 0.005), higher inflammation (OR 3.7 [95% CI 2.09-7.32]; p = 0.001), and lymphocyte count on the day of onset/24 hours following NEC (OR 1.06 [95% CI 1.02-1.11]; p = 0.005) were independently associated with a higher odd of severe intestinal hemorrhage. CONCLUSION: The surgical NEC infants with intestinal hemorrhage were less likely to have antenatal steroid exposure but had higher inflammation grade and lymphocyte counts following NEC onset on multivariable regression modeling.

Precision Medicine at the University of Alabama at Birmingham: Laying the Foundational Processes Through Implementation of Genotype-Guided Antiplatelet Therapy.

Precision medicine entails tailoring treatment based on patients' unique characteristics. As drug therapy constitutes the cornerstone of treatment for most chronic diseases, pharmacogenomics (PGx), the study of genetic variation influencing individual response to drugs, is an important component of precision medicine. Over the past decade investigations have identified genes and single-nucleotide polymorphisms (SNPs) and quantified their effect on drug response. Parallel development of point-of-care (POC) genotyping platforms has enabled the interrogation of the genes/SNPs within a timeline conducive to the provision of care. Despite these advances, the pace of integration of genotype-guided drug therapy (GGTx) into practice has faced significant challenges. These include difficulty in identifying SNPs with sufficiently robust evidence to guide clinical decision making, lack of clinician training on how to order and use genotype data, lack of clinical decision support (CDS) to guide treatment, and limited reimbursement. The University of Alabama at Birmingham's (UAB) efforts in precision medicine were initiated to address these challenges and improve the health of the racially diverse patients we treat.

Does the presence of thrombus seen on a coronary angiogram affect the outcome after percutaneous coronary angioplasty? An Angiographic Trials Pool data experience.

OBJECTIVES: This study aimed to determine whether pre-existing angiographic thrombus was associated with adverse in-hospital and six-month outcomes after percutaneous coronary interventions. BACKGROUND: There are conflicting data about whether pre-existing thrombus is an independent predictor of adverse in-hospital and short-term outcome after coronary interventions. METHODS: The Angiographic Trials Pool, a data set derived from eight prospective randomized trials, was analyzed. The study population consisted of 7,917 patients who underwent coronary interventions between 1986 and 1995. Two trials were excluded because they did not collect information regarding thrombus. Patients from the other six trials were divided on the basis of the presence or absence of thrombus. RESULTS: In patients with (n = 2,752) and without (5,165) thrombus, in-hospital mortality following angioplasty was low (0.8 vs. 0.6%, p = 0.207). Several adverse outcomes were higher in patients with thrombus: death/myocardial infarction (8.4 vs. 5.5%, p < or = 0.001), in-hospital abrupt closure (5.9 vs. 3.9%, p < or = 0.001) and an in-hospital composite of death, myocardial infarction and/or repeat revascularization (15.4 vs. 11.2%, p < or = 0.001). Six-month mortality was low and comparable between the two groups (2.1 vs. 1.8%, p = 0.34), but the incidence of six-month death/myocardial infarction was higher in patients with thrombus (11.7 vs. 8.7%, p < or = 0.0001). CONCLUSIONS: Percutaneous coronary angioplasty can be performed with low mortality in patients with pre-existing thrombus, although these patients are at higher risk of in-hospital and six-month death/myocardial infarction. Continued efforts are required to optimize the outcome in these high risk patients.

Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience.

OBJECTIVES: The objective of this study was to test the hypothesis that the intracoronary administration of a direct donor of nitric oxide is a safe and effective method to treat impaired blood flow (no-reflow phenomenon) that occurs during percutaneous transluminal coronary interventions (PTCI). BACKGROUND: The absence of blood flow or decreased blood flow in a coronary artery following PTCI despite the presence of a patent epicardial vessel or graft is designated "no-reflow" or "impaired flow." This alteration in blood flow is a serious complication of percutaneous revascularization strategies that results in an increased incidence of morbidity, myocardial infarction and mortality. METHODS: Nineteen consecutive patients undergoing standard percutaneous revascularization procedures complicated by either no-reflow or impaired flow that received intracoronary nitroprusside treatment were studied. One patient had two procedures performed on two separate grafts on two successive days. Interventions were performed on either saphenous vein grafts or native vessels and utilized angioplasty, stent deployment or rotational atherectomy strategies. Following interventions that were associated with impaired flow, varying total doses (of nitroprusside 50 to 1,000 microg) were administered into the coronary artery or saphenous vein graft. The angiographic archives before and after intracoronary administration of nitroprusside were analyzed for TIMI grade flow and a frame count method was used to quantitate blood flow velocity. RESULTS: Following a PTCI that resulted in either no-reflow or impaired flow, nitroprusside (median dose 200 microg) was found to lead to a highly significant and rapid improvement in both angiographic flow (p < 0.01 compared with pretreatment angiogram) and blood flow velocity (p < 0.01 compared with pretreatment angiogram). No significant hypotension or other adverse clinical events were associated with nitroprusside administration. CONCLUSIONS: The direct nitric oxide donor nitroprusside is an effective, safe treatment of impaired blood flow and no-reflow associated with PTCI. The use of nitroprusside to treat syndromes secondary to microvascular dysfunction may provide a novel therapeutic strategy for treating no-reflow or impaired blood flow following percutaneous interventions.

Glycoprotein IIb/IIIa receptor therapy in percutaneous coronary intervention and non-ST-segment elevation acute coronary syndromes. Estimating the economic implications.

In addition to efficacy and safety, cost is an important determinant of the use of glycoprotein IIb/IIIa (GPIIb/IIIa) therapy in patients with acute coronary syndromes (ACS) or undergoing percutaneous coronary intervention (PCI). In PCI, the average procurement cost of GPIIb/IIIa therapy ranges from $US400 to $US1500 (1999 values) per patient treated, depending on agent, dose and duration of infusion. Prospective economic substudies with abciximab and tirofiban have demonstrated subsequent cost savings that partially offset the procurement costs of the agents. The drug procurement costs per death or myocardial infarction (MI) prevented in PCI appear to vary from $US10,500 to $US37,000, depending on the agent. Abciximab has been proven to provide a survival benefit in the setting of PCI, including coronary stenting. Analyses of abciximab use yield cost-effectiveness ratios of $US2875 to $US14,765 per life-year or quality-adjusted life-year saved, which compares favourably with most widely accepted therapies. In non-ST-segment elevation ACS, drug procurement costs range from $US700 to $US1700 per patient treated, also depending on agent, dose and duration of infusion. Evidence of cost offsets from changes in subsequent resource utilisation are limited and seem contingent upon a conservative risk-stratification approach. Drug procurement costs have been calculated as $US32,000 to $US82,000 per death or MI prevented in the ACS trials. Cost-effectiveness ratios of $US16,000 per life-year saved for the US and Western European cohorts in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial are favourable. If these analyses prove correct, the cost effectiveness of GPIIb/IIIa receptor therapy for patients with non-ST-segment elevation ACS will also compare favourably with other widely accepted therapies in industrialised countries. More clinical and economic data are necessary to allow better selection of specific patients who will receive the most benefit from GPIIb/IIIa therapy in healthcare systems with limited resources.

Economic issues in glycoprotein IIb/IIIa receptor therapy.

Efficacy, safety, and cost will determine the use of glycoprotein IIb/IIIa therapy in patients with acute coronary syndromes or those patients undergoing percutaneous coronary intervention (PCI). Prospective randomized studies with abciximab, eptifibatide, and tirofiban have demonstrated the superior efficacy and relative safety of IIb/IIIa therapy in these 2 broad patient groups. In medical practice, we by necessity make decisions to administer or withhold therapies based on implicit concepts of cost-effectiveness and efficacy and safety. We herein review available economic data on IIb/IIIa therapy to assist in this decision-making process. The procurement costs of the IIb/IIIa receptor antagonists vary considerably for both acute coronary syndrome and patients undergoing PCI. In PCI, these procurement costs range from $436 to $1407 per patient treated with commonly used regimens. Economic substudies of PCI trials with abciximab and tirofiban demonstrate medical cost savings that partially offset drug procurement costs. The number of dollars spent on IIb/IIIa agents per death or myocardial infarction prevented in patients undergoing PCI ranges from $13,000 to $37,000. Abciximab has cost-effectiveness ratios of $4000 to $7000 per life-year saved in patients undergoing PCI. The incremental cost-effectiveness of IIb/IIIa blockade in the setting of planned stenting is unknown. In patients with acute coronary syndrome, procurement costs range from $1050 to $1548 per patient treated. Expenditures per death or myocardial infarction prevented in patients with acute coronary syndrome range from $32,000 to $82, 000. Inadequate direct cost data exist to calculate cost effectiveness ratios for this group, but only high-risk patients will likely have cost-effectiveness ratios that most Western health-care systems can afford.

Safe use of platelet GP IIb/IIIa inhibitors.

The platelet membrane glycoprotein IIb/IIIa receptor inhibitor abciximab is used for the treatment of patients undergoing high-risk percutaneous coronary interventions and is used in approximately one third of coronary interventions in the United States and a growing number of procedures in Europe. Recent clinical trials have shown that this potent antiplatelet agent significantly reduces the incidence of death and nonfatal myocardial infarction and the need for revascularization. With expanding experience since the commercial release of abciximab in February 1995, several strategies to enhance the safety of abciximab have emerged. In particular, new data confirm that the risk of bleeding--identified as a concern in the original EPIC trial--can be substantially reduced through the use of low-dose adjunctive heparin, early sheath removal, and fastidious postprocedure vascular access site care. Other recommendations for enhancing the safety of potent antiplatelet agents in a variety of clinical situations are provided. The following article reflects insights regarding the safety of glycoprotein IIb/IIIa inhibitors expressed by a group of international experts convened in Davos, Switzerland, February 16, 1997. This report attempts to review clinical progress to date, formulate recommendations, and map out potentially fruitful lines of inquiry for future investigation.

Abciximab therapy in percutaneous intervention: economic issues in the United States.

Whether abciximab therapy should be the standard of care during percutaneous intervention in the United States depends on its efficacy, safety, and economics. In view of the EPIC, CAPTURE, and EPILOG data, few question the superior efficacy and relative safety of abciximab compared with conventional high-dose heparin therapy during percutaneous intervention. Economic considerations have been the major issue limiting its use. Review of the economic data demonstrates that the incremental direct medical care cost of abciximab therapy is $290 to $600 per patient treated in the EPIC and EPILOG populations. In the patients with acute myocardial infarction and unstable angina, abciximab appears to reduce direct medical costs (produce cost savings) at 6 months. Given abciximab's significant incremental effectiveness, its relatively small incremental cost yielded a highly cost-effective therapy in the EPIC and EPILOG patient populations. Additional economic issues relate to minimizing bleeding complications, indirect costs, reduced frequency of emergency procedures, and rationalizing provider/payor policies and incentives to produce the optimal individual patient and societal outcomes. The currently available data concerning the efficacy, safety, and cost provide a compelling argument for embracing abciximab therapy in the treatment of patient subsets where it will be a cost-saving or cost-neutral adjunct to percutaneous coronary intervention. In other subsets, the direct medical cost will likely not be fully recouped, but the incremental cost-effectiveness will compare favorably to other widely accepted therapies.

Safe use of platelet GP IIb/IIIa inhibitors.

The platelet membrane glycoprotein IIb/IIIa receptor inhibitor abciximab is used for the treatment of patients undergoing high-risk percutaneous coronary interventions and is used in approximately one third of coronary interventions in the United States and a growing number of procedures in Europe. Recent clinical trials have shown that this potent antiplatelet agent significantly reduces the incidence of death and nonfatal myocardial infarction and the need for revascularization. With expanding experience since the commercial release of abciximab in February 1995, several strategies to enhance the safety of abciximab have emerged. In particular, new data confirm that the risk of bleeding-identified as a concern in the original EPIC trial-can be substantially reduced through the use of low-dose adjunctive heparin, early sheath removal, and fastidious postprocedure vascular access site care. Other recommendations for enhancing the safety of potent antiplatelet agents in a variety of clinical situations are provided. The following article reflects insights regarding the safety of glycoprotein IIb/IIIa inhibitors expressed by a group of international experts convened in Davos, Switzerland, February 16, 1997 This report attempts to review clinical progress to date, formulate recommendations, and map out potentially fruitful lines of inquiry for future investigation.

Abciximab therapy in percutaneous intervention: economic issues in the United States.

Whether abciximab therapy should be the standard of care during percutaneous intervention in the United States depends on its efficacy, safety, and economics. In view of the EPIC, CAPTURE, and EPILOG data, few question the superior efficacy and relative safety of abciximab compared with conventional high-dose heparin therapy during percutaneous intervention. Economic considerations have been the major issue limiting its use. Review of the economic data demonstrates that the incremental direct medical care cost of abciximab therapy is $290 to $600 per patient treated in the EPIC and EPILOG populations. In the patients with acute myocardial infarction and unstable angina, abciximab appears to reduce direct medical costs (produce cost savings) at 6 months. Given abciximab's significant incremental effectiveness, its relatively small incremental cost yielded a highly cost-effective therapy in the EPIC and EPILOG patient populations. Additional economic issues relate to minimizing bleeding complications, indirect costs, reduced frequency of emergency procedures, and rationalizing provider/payor policies and incentives to produce the optimal individual patient and societal outcomes. The currently available data concerning the efficacy, safety, and cost provide a compelling argument for embracing abciximab therapy in the treatment of patient subsets where it will be a cost-saving or cost-neutral adjunct to percutaneous coronary intervention. In other subsets, the direct medical cost will likely not be fully recouped, but the incremental cost-effectiveness will compare favorably to other widely accepted therapies.

Stent procedure complicated by thrombus formation distal to the lesion within a muscle bridge.

We report here a case of a patient who underwent percutaneous intervention to the left anterior descending artery, complicated by thrombus formation within the myocardial bridge distal to the lesion. There was complete angiographic resolution of thrombus and restoration of the normal antegrade blood flow after infusion of glycoprotein IIb/IIIa antagonist (abciximab). Our observation may suggest that the presence of myocardial bridging distal to coronary lesions should be considered seriously in preprocedural evaluation of the lesions as a potential risk factor for intracoronary thrombus formation. The main coronary arteries and the proximal segments of their major branches lie free on the epicardial surface of the heart. However, in some instances these vessels may penetrate into the muscle being surrounded by the myocardium, with the overlying muscle referred to as a "bridge". Myocardial bridging appears to be a congenital anomaly, due to failure of exteriorization of the primitive coronary intratrabecular arterial network. It occurs in 5-86% of patients in autopsy studies, and it is observed as systolic coronary artery narrowing in 0.5-12% of patients undergoing coronary arteriography. Although the gross anatomist had long recognized that the epicardial coronary artery might on occasion course directly through a segment of cardiac muscle, the physiological significance of this phenomenon was considered benign. This is partly because traditional teaching concerning coronary blood flow delivery to the left ventricular myocardium emphasized the primacy of the diastolic phase of the cardiac cycle. However, myocardial bridging is not always a benign finding, with recent reports suggesting an association with myocardial ischemia, infarction, vasospasm, cardiac arrythmias, and sudden death.

Use of calcium channel antagonists in myocardial revascularization procedures.

Calcium channel antagonists possess a number of properties that may be beneficial after revascularization procedures. Therefore, we present an overview of the use of these drugs after percutaneous intervention in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT), and compare the results in CAVEAT with those in published randomized trials. Also reviewed are the use of calcium channel antagonists to control perioperative hypertension, reduce myocardial necrosis, and prevent arrhythmias during cardiopulmonary bypass.

Relation between activated clotting time during angioplasty and abrupt closure.

BACKGROUND: The purpose of this study was to determine whether the degree of heparin anticoagulation during coronary angioplasty, as measured by the activated clotting time, is related to the risk of abrupt vessel closure. METHODS AND RESULTS: Sixty-two cases of in- and out-of-laboratory abrupt closure in patients in whom intraprocedure activated clotting times were measured were identified from a population of 1290 consecutive patients who underwent non-emergency coronary angioplasty. This group was compared with a matched control population of 124 patients who did not experience abrupt closure. Relative to the control population, patients who experienced abrupt closure had significantly lower initial (median, 350 seconds [25th to 75th percentile, 309 to 401 seconds] versus 380 seconds [335 to 423 seconds], P = .004) and minimum (345 seconds [287 to 387 seconds] versus 370 seconds [321 to 417 seconds], P = .014) activated clotting times. Higher activated clotting times were not associated with an increased likelihood of major bleeding complications. Within this population, a strong inverse linear relation existed between the activated clotting time and the probability of abrupt closure. CONCLUSIONS: This study demonstrates a significant inverse relation between the degree of anticoagulation during angioplasty and the risk of abrupt closure. A minimum target activated clotting time could not be identified; rather, the higher the intensity of anticoagulation, the lower the risk of abrupt closure.

A meta-analysis of randomized trials of calcium antagonists to reduce restenosis after coronary angioplasty.

The usefulness of calcium antagonists to reduce restenosis after coronary angioplasty remains uncertain despite 5 randomized trials involving 919 patients. Review and meta-analysis of these trials are performed to provide insight into whether calcium antagonists reduce angiographic restenosis. In aggregate, these trials suggest that patients treated with calcium antagonists had approximately a 30% reduction in the odds of angiographic restenosis (odds ratio = 0.68; 95% confidence interval of 0.49 to 0.94, p = 0.03) compared with control patients. Given the relatively low toxicity and cost of these agents, this reduction in angiographic restenosis may translate into a meaningful clinical benefit. A large, randomized clinical trial should be performed to confirm these findings before widespread adoption of this treatment strategy.

Intracranial hemorrhage risk and new thrombolytic therapies in acute myocardial infarction.

Thrombolytic therapy for acute myocardial infarction (AMI) has reduced mortality at the expense of additional intracranial hemorrhages. To determine whether this trade-off has been optimized, a decision analysis was performed using pooled data to determine the further reductions in mortality required to justify increased intracranial hemorrhage rates from more potent thrombolytic and adjunctive antithrombotic regimens that intravenous streptokinase. Pooled data from large clinical trials suggest that streptokinase has a 0.07% nonfatal intracranial hemorrhage rate. Approximately 54% of these result in major/moderate disability and 46% in recovery or minor residual. The early mortality rate in all AMI patients treated with thrombolytic therapy is 9.8%; it is 6.8% in patients with inferior wall AMI and 17.9% in elderly patients. If a new thrombolytic regimen provides a 1% absolute reduction in early mortality compared with streptokinase therapy, approximately a > or = 3.2% nonfatal intracranial hemorrhage rate is justified to obtain this survival benefit. For a 10% relative reduction in mortality risk, the maximal acceptable nonfatal intracranial hemorrhage rates are 2.2% for inferior wall AMI, 3.2% for all patients and 5.9% for elderly patients. Whereas intracranial hemorrhage is a catastrophic complication of thrombolytic therapy in the treatment of patients with AMI, thrombolytic regimens that result in significantly higher rates of intracranial hemorrhage than those observed with streptokinase may be preferable at surprisingly smaller additional reductions in mortality. In addition to evaluating new thrombolytic and antithrombotic regimens, this analysis, in conjunction with models that predict patient-specific intracranial hemorrhage risks and mortality benefits from thrombolytic therapy, can provide a framework for matching AMI patients with optimal thrombolytic regimens.