Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial

BACKGROUND: The efficacy of granulocyte colony-stimulating factor (G-CSF) for coronary collateral growth promotion and thus impending myocardial salvage has not been studied so far, to our best knowledge. METHODS AND RESULTS: In 52 patients with chronic stable coronary artery disease, age 62+/-11 years, the effect on a marker of myocardial infarct size (ECG ST segment elevation) and on quantitative collateral function during a 1-minute coronary balloon occlusion was tested in a randomized, placebo-controlled, double-blind fashion. The study protocol before coronary intervention consisted of occlusive surface and intracoronary lead ECG recording as well as collateral flow index (CFI, no unit) measurement in a stenotic and a > or =1 normal coronary artery before and after a 2-week period with subcutaneous G-CSF (10 microg/kg; n=26) or placebo (n=26). The CFI was determined by simultaneous measurement of mean aortic, distal coronary occlusive, and central venous pressure. The ECG ST segment elevation >0.1 mV disappeared significantly more often in response to G-CSF (11/53 vessels; 21%) than to placebo (0/55 vessels; P=0.0005), and simultaneously, CFI changed from 0.121+/-0.087 at baseline to 0.166+/-0.086 at follow-up in the G-CSF group, and from 0.152+/-0.082 to 0.131+/-0.071 in the placebo group (P<0.0001 for interaction of treatment and time). The absolute change in CFI from baseline to follow-up amounted to +0.049+/-0.062 in the G-CSF group and to -0.010+/-0.060 in the placebo group (P<0.0001). CONCLUSIONS: Subcutaneous G-CSF is efficacious during a short-term protocol in improving signs of myocardial salvage by coronary collateral growth promotion.

When drugs disappear from the patient: elimination of intravenous medication by hemodiafiltration

Twenty-three hours after heart transplantation, life-threatening acute right heart failure was diagnosed in a patient requiring continuous venovenous hemodiafiltration (CVVHDF). Increasing doses of catecholamines, sedatives, and muscle relaxants administered through a central venous catheter were ineffective. However, a bolus of epinephrine injected through an alternative catheter provoked a hypertensive crisis. Thus, interference with the central venous infusion by the dialysis catheter was suspected. The catheters were changed, and hemodynamics stabilized at lower catecholamine doses. When the effects of IV drugs are inadequate in patients receiving CVVHDF, interference with adjacent catheters resulting in elimination of the drug by CVVHDF should be suspected.

Gene therapy for immunodeficiency due to adenosine deaminase deficiency

BACKGROUND: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. METHODS: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. RESULTS: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). CONCLUSIONS: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

Arterial blood pressure during early sepsis and outcome

OBJECTIVE: To evaluate the association between arterial blood pressure (ABP) during the first 24 h and mortality in sepsis. DESIGN: Retrospective cohort study. SETTING: Multidisciplinary intensive care unit (ICU). PATIENTS AND PARTICIPANTS: A total of 274 septic patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Hemodynamic, and laboratory parameters were extracted from a PDMS database. The hourly time integral of ABP drops below clinically relevant systolic arterial pressure (SAP), mean arterial pressure (MAP), and mean perfusion pressure (MPP = MAP - central venous pressure) levels was calculated for the first 24 h after ICU admission and compared with 28-day-mortality. Binary and linear regression models (adjusted for SAPS II as a measure of disease severity), and a receiver operating characteristic (ROC) analysis were applied. The areas under the ROC curve were largest for the hourly time integrals of ABP drops below MAP 60 mmHg (0.779 vs. 0.764 for ABP drops below MAP 55 mmHg; P < or = 0.01) and MPP 45 mmHg. No association between the hourly time integrals of ABP drops below certain SAP levels and mortality was detected. One or more episodes of MAP < 60 mmHg increased the risk of death by 2.96 (CI 95%, 1.06-10.36, P = 0.04). The area under the ROC curve to predict the need for renal replacement therapy was highest for the hourly time integral of ABP drops below MAP 75 mmHg. CONCLUSIONS: A MAP level > or = 60 mmHg may be as safe as higher MAP levels during the first 24 h of ICU therapy in septic patients. A higher MAP may be required to maintain kidney function.

Access technique and its problems in parenteral nutrition - Guidelines on Parenteral Nutrition, Chapter 9

Catheter type, access technique, and the catheter position should be selected considering to the anticipated duration of PN aiming at the lowest complication risks (infectious and non-infectious). Long-term (>7-10 days) parenteral nutrition (PN) requires central venous access whereas for PN <3 weeks percutaneously inserted catheters and for PN >3 weeks subcutaneous tunnelled catheters or port systems are appropriate. CVC (central venous catheter) should be flushed with isotonic NaCl solution before and after PN application and during CVC occlusions. Strict indications are required for central venous access placement and the catheter should be removed as soon as possible if not required any more. Blood samples should not to be taken from the CVC. If catheter infection is suspected, peripheral blood-culture samples and culture samples from each catheter lumen should be taken simultaneously. Removal of the CVC should be carried out immediately if there are pronounced signs of local infection at the insertion site and/or clinical suspicion of catheter-induced sepsis. In case PN is indicated for a short period (max. 7-10 days), a peripheral venous access can be used if no hyperosmolar solutions (>800 mosm/L) or solutions with a high titration acidity or alkalinity are used. A peripheral venous catheter (PVC) can remain in situ for as long as it is clinically required unless there are signs of inflammation at the insertion site.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function

OBJECTIVE This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING University Hospital. PATIENTS 35 patients with chronic stable coronary artery disease. INTERVENTION 2-min iCSO. MAIN OUTCOME MEASURES Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place.

Reciprocal relationship between left ventricular filling pressure and the recruitable human coronary collateral circulation

AIMS The aim of our study in patients with coronary artery disease (CAD) and present, or absent, myocardial ischaemia during coronary occlusion was to test whether (i) left ventricular (LV) filling pressure is influenced by the collateral circulation and, on the other hand, that (ii) its resistance to flow is directly associated with LV filling pressure. METHODS AND RESULTS In 50 patients with CAD, the following parameters were obtained before and during a 60 s balloon occlusion: LV, aortic (Pao) and coronary pressure (Poccl), flow velocity (Voccl), central venous pressure (CVP), and coronary flow velocity after coronary angioplasty (V(Ø-occl)). The following variables were determined and analysed at 10 s intervals during occlusion, and at 60 s of occlusion: LV end-diastolic pressure (LVEDP), velocity-derived (CFIv) and pressure-derived collateral flow index (CFIp), coronary collateral (Rcoll), and peripheral resistance index to flow (Rperiph). Patients with ECG signs of ischaemia during coronary occlusion (insufficient collaterals, n = 33) had higher values of LVEDP over the entire course of occlusion than those without ECG signs of ischaemia during occlusion (sufficient collaterals, n = 17). Despite no ischaemia in the latter, there was an increase in LVEDP from 20 to 60 s of occlusion. In patients with insufficient collaterals, CFIv decreased and CFIp increased during occlusion. Beyond an occlusive LVEDP > 27 mmHg, Rcoll and Rperiph increased as a function of LVEDP. CONCLUSION Recruitable collaterals are reciprocally tied to LV filling pressure during occlusion. If poorly developed, they affect it via myocardial ischaemia; if well grown, LV filling pressure still increases gradually during occlusion despite the absence of ischaemia indicating transmission of collateral perfusion pressure to the LV. With low, but not high, collateral flow, resistance to collateral as well as coronary peripheral flow is related to LV filling pressure in the high range.

Sympathetic stimulation using the cold pressor test increases coronary collateral flow

BACKGROUND Little is known about the vasomotor function of human coronary collateral vessels. The purpose of this study was to examine collateral flow under a strong sympathetic stimulus (cold pressor test, CPT). METHODS In 30 patients (62 +/- 12 years) with coronary artery disease, two subsequent coronary artery occlusions were performed with random CPT during one of them. Two minutes before and during the 1 minute-occlusion, the patient's hand was immerged in ice water. For the calculation of a perfusion pressure-independent collateral flow index (CFI), the aortic (Pao), the central venous (CVP) and the coronary wedge pressure (Poccl) were measured: CFI = (Poccl - CVP)/(Pao - CVP). RESULTS CPT lead to an increase in Pao from 98 +/- 14 to 105 +/- 15 mm Hg (p = 0.002). Without and with CPT, CFI increased during occlusion from 14% +/- 10% to 16% +/- 10% (p = 0.03) and from 17% +/- 9% to 19% +/- 9% (p = 0.006), respectively, relative to normal flow. During CPT, CFI was significantly higher at the beginning as well as at the end of the occlusion compared to identical instants without CPT. CFI at the end of the control occlusion did not differ significantly from the CFI at the beginning of occlusion with CPT. CONCLUSIONS During balloon occlusion, collateral flow increased due to collateral recruitment independent of external sympathetic stimulation. Sympathetic stimulation using CPT additionally augmented collateral flow. The collateral-flow-increasing effect of CPT is comparable to the recruitment effect of the occlusion itself. This may reflect a coronary collateral vasodilation mediated by the sympathetic nervous system.

Prognostic relevance of coronary collateral function: confounded or causal relationship?

OBJECTIVE To expand the limited information on the prognostic impact of quantitatively obtained collateral function in patients with coronary artery disease (CAD) and to estimate causality of such a relation. DESIGN Prospective cohort study with long-term observation of clinical outcome. SETTING University Hospital. PATIENTS One thousand one hundred and eighty-one patients with chronic stable CAD undergoing 1771 quantitative, coronary pressure-derived collateral flow index measurements, as obtained during a 1-min coronary balloon occlusion (CFI is the ratio between mean distal coronary occlusive pressure and mean aortic pressure both subtracted by central venous pressure). Subgroup of 152 patients included in randomised trials on the longitudinal effect of different arteriogenic protocols on CFI. INTERVENTIONS Collection of long-term follow-up information on clinical outcome. MAIN OUTCOME MEASURES All-cause mortality and major adverse cardiac events. RESULTS Cumulative 15-year survival rate was 48% in patients with CFI<0.25 and 65% in the group with CFI≥0.25 (p=0.0057). Cumulative 10-year survival rate was 75% in patients without arteriogenic therapy and 88% (p=0.0482) in the group with arteriogenic therapy and showing a significant increase in CFI at follow-up. By proportional hazard analysis, the following variables predicted increased all-cause mortality: age, low CFI, left ventricular end-diastolic pressure and number of vessels with CAD. CONCLUSIONS A well-functioning coronary collateral circulation independently predicts lowered mortality in patients with chronic CAD. This relation appears to be causal, because augmented collateral function by arteriogenic therapy is associated with prolonged survival.

Clinical parameters associated with collateral development in patients with chronic total coronary occlusion

OBJECTIVE Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis. DESIGN Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI). PATIENTS Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed. INTERVENTIONS Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure. RESULTS The mean CFI was 0.39 ± 0.14. After multivariate analysis, β blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient β=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=-0.01, SE=0.005, p=0.03, B=-0.04, SE=0.02, p=0.03 and B=-0.002, SE=0.001, p=0.011). CONCLUSIONS In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of β blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD.

G-CSF induced arteriogenesis in humans: molecular insights into a randomized controlled trial

AIMS Recent data have demonstrated the feasibility of therapeutic induction of coronary collateral growth (arteriogenesis); however, mechanisms of action of such therapeutic collateral stimulation in humans are unknown. The aim of this study was to evaluate potential mechanisms, especially the involvement of arteriogenesis-relevant genes. METHODS AND RESULTS A total of 52 patients were randomized into two groups: subcutaneous G-CSF (10 μg/kg; n=26) or placebo (n=26). Before and after this 2-week treatment, collateral-flow index (CFI) was determined by simultaneous measurement of mean aortic, distal coronary occlusive and central venous pressure. CD34+ endothelial progenitor cells (EPC) and monocytes were quantified before, during and after treatment; gene-expression analysis of monocytes was performed with real-time polymerase chain reaction (RT-PCR). G-CSF lead to a significant increase of EPC and monocytes (4.8 and 2.6 fold, p < 0.05); for both cell types, the extent of increase correlated with CFI increase (r=0.23 and 0.14, p < 0.05). G-CSF also induced a change in gene expression of pro-and anti-arteriogenic genes in monocytes. Among nine assessed genes, three were found to be differentially regulated (IL8, JAK2, and PNPLa4; p < 0.05). CONCLUSIONS The mechanism of induction of collateral growth by G-CSF is related to an increase of EPC and of peripheral monocytes. It also leads to a change toward a pro-arteriogenic gene expression in peripheral monocytes.

The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease

Objective To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD). Methods This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. Results During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by –8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to −0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113). Conclusions Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD.

Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections

BACKGROUND Enterococci are an important cause of central venous catheter (CVC)-associated bloodstream infections (CA-BSI). It is unclear whether CVC removal is necessary to successfully manage enterococcal CA-BSI. METHODS A 12-month retrospective cohort study of adults with enterococcal CA-BSI was conducted at a tertiary care hospital; clinical, microbiological and outcome data were collected. RESULTS A total of 111 patients had an enterococcal CA-BSI. The median age was 58.2 years (range 21 to 94 years). There were 45 (40.5%) infections caused by Entercoccus faecalis (among which 10 [22%] were vancomycin resistant), 61 (55%) by Enterococcus faecium (57 [93%] vancomycin resistant) and five (4.5%) by other Enterococcus species. Patients were treated with linezolid (n=51 [46%]), vancomycin (n=37 [33%]), daptomycin (n=11 [10%]), ampicillin (n=2 [2%]) or quinupristin/dalfopristin (n=2 [2%]); seven (n=6%) patients did not receive adequate enterococcal treatment. Additionally, 24 (22%) patients received adjunctive gentamicin treatment. The CVC was retained in 29 (26.1%) patients. Patients with removed CVCs showed lower rates of in-hospital mortality (15 [18.3%] versus 11 [37.9]; P=0.03), but similar rates of recurrent bacteremia (nine [11.0%] versus two (7.0%); P=0.7) and a similar post-BSI length of hospital stay (median days [range]) (11.1 [1.7 to 63.1 days] versus 9.3 [1.9 to 31.8 days]; P=0.3). Catheter retention was an independent predictor of mortality (OR 3.34 [95% CI 1.21 to 9.26]). CONCLUSIONS To the authors' knowledge, the present article describes the largest enterococcal CA-BSI series to date. Mortality was increased among patients who had their catheter retained. Additional prospective studies are necessary to determine the optimal management of enterococcal CA-BSI.

Hemodynamics and Flow Characteristics of a New Dialysis Port

Renal replacement therapy by hemodialysis requires a permanent vascular access. Implantable ports offer a potential alternative to standard vascular access strategies although their development is limited both in number and extent. We explored the fluid dynamics within two new percutaneous bone-anchored dialysis port prototypes, both by in vitro experiments and computer simulation. The new port is to be fixed to bone and allows the connection of a dialysis machine to a central venous catheter via a built-in valve. We found that the pressure drop induced by the two ports was between 20 and 50 mmHg at 500 ml/min, which is comparable with commercial catheter connectors (15–80 mmHg). We observed the formation of vortices in both geometries, and a shear rate in the physiological range (<10,000s-1), which is lower than maximal shear rates reported in commercial catheters (up to 13,000s-1). A difference in surface shear rate of 15% between the two ports was obtained.

Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach

Definitions of shock and resuscitation endpoints traditionally focus on blood pressures and cardiac output. This carries a high risk of overemphasizing systemic hemodynamics at the cost of tissue perfusion. In line with novel shock definitions and evidence of the lack of a correlation between macro- and microcirculation in shock, we recommend that macrocirculatory resuscitation endpoints, particularly arterial and central venous pressure as well as cardiac output, be reconsidered. In this viewpoint article, we propose a three-step approach of resuscitation endpoints in shock of all origins. This approach targets only a minimum individual and context-sensitive mean arterial blood pressure (for example, 45 to 50 mm Hg) to preserve heart and brain perfusion. Further resuscitation is exclusively guided by endpoints of tissue perfusion irrespectively of the presence of arterial hypotension ('permissive hypotension'). Finally, optimization of individual tissue (for example, renal) perfusion is targeted. Prospective clinical studies are necessary to confirm the postulated benefits of targeting these resuscitation endpoints.