Role of NFkappaB in the mortality of sepsis.

Binding activity for nuclear factor kappa B (NFkappaB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFkappaB binding activity during the observation period (P < 0.001). The increase in NFkappaB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IkappaBalpha was used to investigate the role of members of the NFkappaB family in a mouse model of endotoxemia. In this model, increased NFkappaB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IkappaBalpha given before LPS attenuated renal NFkappaB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFkappaB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFkappaB-dependent stimulation by LPS. Intravenous somatic gene transfer with IkappaBalpha reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.

Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity.

Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression. These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain.

Molecular cloning of genes differentially regulated by TNF-alpha in bovine aortic endothelial cells, fibroblasts and smooth muscle cells.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic-cytokine binding to and thereby stimulating vascular cells. TNF-alpha mediated intermediate stimulation of vascular cells is believed to play a pivotal role in the development of arteriosclerosis. While extensive information has recently become available on gene induction by TNF-alpha, less is known about gene suppression by TNF-alpha in vascular cells. Endothelial cells are the first cell layer within the vessel wall interacting with circulating, cytokine releasing cells. Therefore, they were selected as target for these study. METHODS: A differential screening approach has been used to isolate cDNAs whose abundance was suppressed by incubating bovine aortic endothelial cells (BAEC) for 6 h with 1 nM TNF-alpha. The gene expression of 6 isolated cDNAs after TNF-alpha was investigated by dot blots and nuclear run-on analysis in BAEC. The investigated genes were partially or completely sequenced. Differential expression after TNF-alpha stimulation of BAEC, bovine fibroblasts and vascular smooth muscle cells (SMC) was studied by Northern blots. RNA transcripts of the clone C7 in aortic aneurysms were examined by in situ hybridization. RESULTS: 49 independent cDNAs were isolated by the differential screening approach and 6 clones were further analyzed. These genes were downregulated in a time and dose dependent manner in BAEC. Sequence analysis revealed that 3 cDNAs encoded previously unidentified genes (C1, C5, C7), while 3 encoded known genes: connective tissue growth factor (CTGF; A1), fibronectin (A8) and the mitochondrial genome (B1). A1 and B1 were suppressed in BAEC, fibroblasts and SMC, whereas A8, C1, C5 and C7 were not uniformly downregulated in the investigated cells. C7 RNA transcripts were exclusively induced in the endothelium of an uninflamed aortic aneurysm. The transcripts were undetectable in an inflamed aortic aneurysm and control vessels. CONCLUSIONS: Gene suppression is a prominent feature of the intermediate effect of TNF-alpha on endothelial cells. Differences in the expression of the tested genes in endothelial cells, fibroblasts and vascular smooth muscle cells open possibilities for the study of cellular interactions in the vascular wall in disease situations with high local TNF-alpha concentrations.

High-dose bolus injection of urokinase. Use during cardiopulmonary resuscitation for massive pulmonary embolism.

Bolus administration of high-dose thrombolytic agents has been reported for the treatment of acute pulmonary embolism. We describe the case of a 60-year-old woman who suffered a massive pulmonary embolism with cardiopulmonary arrest 21 h after an exploratory laparotomy. After 20 min of unsuccessful cardiopulmonary resuscitation (CPR), a bolus of 2,000,000 U of urokinase was injected via a peripheral vein. Ten minutes later, the circulatory system stabilized, and the patient survived without subsequent bleeding. In our opinion, bolus lysis made a definitive contribution to the success of the resuscitation. Several other case reports and small series showed successful treatment of pulmonary embolism during similar circumstances using high-dose bolus injection of thrombolytic agents. Mechanical thrombus fragmentation using a pulmonary artery catheter or pulmonary embolectomy has not been shown to be more successful during resuscitation. We conclude that bolus administration of thrombolytic agents during CPR for massive pulmonary thromboembolism may be an acceptable and successful technique, which also is available even in the community hospital setting.

Rescue therapy with C1-esterase inhibitor concentrate after emergency coronary surgery for failed PTCA.

Administration of C1-esterase inhibitor (C1-INH) attenuates myocardial necrosis and sustains normal cardiac performance after myocardial ischemia and reperfusion in animal experiments. We report on our first experience of C1-INH application as rescue therapy in patients undergoing emergency surgical revascularization after failed percutaneous transluminal coronary angioplasty. Three patients were treated, because post-operative hemodynamic stabilization could not be achieved despite prolonged reperfusion periods, high-dose inotropic support, inodilators and aortic counterpulsation. As there was no surgical or medical option remaining, C1-INH was administered starting with a 2000 unit bolus, followed by 1000 U 12 and 24 h after surgery. C1-INH therapy resulted in rapid hemodynamic stabilization of all patients; weaning from aortic counterpulsation and epinephrine support was possible within 1 day. All patients survived and were discharged from hospital. In this group of patients suffering from severe reperfusion injury after coronary surgery, C1-INH seemed to be an effective adjuvant therapy to restore myocardial function by blocking the complement cascade. These results should encourage the performance of controlled studies on the effects of prophylactic C1-INH substitution therapy in patients undergoing coronary surgery at high risk conditions.

Clonidine as a sedative adjunct in intensive care.

A 63-year-old man underwent distal oesophagectomy and proximal gastrectomy. Postoperatively, controlled ventilation was necessary for 53 days because of anastomotic leakage. Multiple sedative regimens proved to be inadequate. By contrast, a fentanyl-midazolam combination with continuous supplementation of clonidine 0.014 micrograms kg-1 min-1 (1.44 mg 70 kg-1 24 h-1) was very effective in terms of sedation and pain relief. During combined fentanyl-midazolam and clonidine infusion, cardiovascular depression gradually developed over several days necessitating the institution of a dobutamine infusion (dose: 8-12 micrograms kg-1 min-1). Four attempts of abrupt clonidine withdrawal were followed by sympathetic overshoot reactions consisting of tachycardia, hypertension, agitation, and sweating. Discontinuation of clonidine was finally possible after a 12-day weaning period.

Serum aluminium levels of intensive care patients treated with two different antacids for prevention of stress ulceration.

We studied the serum aluminum levels of 30 intensive care patients receiving six daily doses of magaldrate (Riopan) or aluminium hydroxide (Trigastril). In both groups we found a significant rise of the serum aluminium concentration (p less than 0.01) following administration of the antacid solutions. Examination on day 9 and 15 the magaldrate group showed significantly (p less than 0.05) lower aluminium levels than the aluminium hydroxide group. An increase up to the critical serum aluminium level of 100 ng/ml occurred in none of the patients that all had normal or slightly impaired renal function. Therefore routine measurements of serum aluminium levels in patients without renal impairment are not considered necessary following antacid therapy. However, we recommend the use of antacids with an aluminium absorption rate as low as possible.

Semi-continuous versus injectate cardiac output measurement in intensive care patients after cardiac surgery.

OBJECTIVE: Commercially available semi-continuous cardiac output (SCCO) monitoring systems are based on the pulsed warm thermodilution technique. There is evidence that SCCO fails to correlate with standard intermittent bolus cardiac output (ICO) in clinical situations with thermal instability in the pulmonary artery. Furthermore, ventilation may potentially influence thermodilution measurements by enhanced respiratory variations in pulmonary artery blood temperature and by cyclic changes in venous return. Therefore, we evaluated the correlation, accuracy and precision of SCCO versus ICO measurements before and after extubation. DESIGN: Prospective cohort study. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS AND PARTICIPANTS: 22 cardiac surgical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: SCCO and ICO data were obtained at nine postoperative time points while the patients were on controlled mechanical ventilation. Further sets of measurements were taken during the weaning phase 20 min before extubation, and 5 min, 20 min and 1 h after extubation. SCCO and ICO measurements yielded 286 data pairs with a range of 1.8-9.9 l/min for SCCO and 1.9-9.8 l/min for ICO. The correlation between SCCO and ICO was highly significant (r = 0.92; p < 0.01), accompanied by a bias of -0.052 l/min and a precision of 0.56 l/min. Correlation, accuracy and precision were not influenced by the mode of respiration. CONCLUSIONS: Our results demonstrate excellent correlation, accuracy and precision between SCCO and ICO measurements in postoperative cardiac surgical ICU patients. We conclude that SCCO monitoring offers a reliable clinical method of cardiac output monitoring in ICU patients following cardiac surgery.

Effects of continuous (CPAP) and bi-level positive airway pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting.

OBJECTIVE: To evaluate the effects of continuous positive airway pressure (CPAP) and bi-level positive airway pressure (Bi-PAP) on extravascular lung water during weaning from mechanical ventilation in patients following coronary artery bypass grafting. DESIGN: Prospective, randomized clinical study. SETTING: Intensive care unit at a university hospital. PATIENTS: Seventy-five patients following coronary artery bypass grafting. INTERVENTIONS: After extubation of the trachea, patients were treated for 30 min with CPAP via face mask (n = 25), with nasal BiPAP (n = 25), or with oxygen administration via nasal cannula combined with routine chest physiotherapy (RCP) for 10 min (n = 25). MEASUREMENTS AND RESULTS: Extravascular lung water (EVLW), pulmonary blood volume index (PBVI) and cardiac index (CI) were obtained during mechanical ventilation (T1), T-piece breathing (T2), interventions (T3), spontaneous breathing 60 min (T4) and 90 min (T5) after extubation of the trachea using a combined dye-thermal dilution method. Changing from mechanical ventilation to T-piece breathing did not show any significant differences in EVLW between the three groups, but a significant increase in PBVI from 155 +/- 5 ml/m2 to 170 +/- 4 ml/m2 could be observed in all groups (p < 0.05). After extubation of the trachea and treatment with BiPAP. PBVI decreased significantly to 134 +/- 6 ml/m2 (p < 0.05). After treatment with CPAP or BiPAP, EVLW did not change significantly in these groups (5.5 +/- 0.3 ml/kg vs 5.0 +/- 0.4 ml/kg and 5.1 +/- 0.4 ml/kg vs 5.7 +/- 0.4 ml/kg). In the RCP-treated group, however, EVLW increased significantly from 5.8 +/- 0.3 ml/kg to 7.1 +/- 0.4 ml/kg (p < 0.05). Sixty and 90 min after extubation, EVLW stayed at a significantly higher level in the RCP-treated group (7.5 +/- 0.5 ml/kg and 7.4 +/- 0.5 ml/kg) than in the CPAP-(5.6 +/- 0.3 ml/kg and 5.9 +/- 0.4 ml/kg) or BiPAP-treated groups (5.2 +/- 0.4 ml/kg and 5.2 +/- 0.4 ml/kg). No significant differences in CI could be observed within the three groups during the time period from mechanical ventilation to 90 min after extubation of the trachea. CONCLUSIONS: Mask CPAP and nasal BiPAP after extubation of the trachea prevent the increase in extravascular lung water during weaning from mechanical ventilation. This effect is seen for at least 1 h after the discontinuation of CPAP or BiPAP treatment. Further studies have to evaluate the clinical relevance of this phenomenon.

Effect of the 21-aminosteroid tirilazad mesylate on leukocyte adhesion and macromolecular leakage during endotoxemia.

BACKGROUND: Interstitial accumulation of leukocytes has been related to the development of multiple organ failure after sepsis. Oxygen radicals are involved in the process of leukocyte adherence to the microvascular wall. This study investigates the effects of the oxygen radical scavenger tirilazad mesylate on leukocyte-endothelial interactions, macromolecular leakage, and microhemodynamics in mesenteric venules during endotoxemia. METHODS: Male Wistar rats were randomly allocated to receive tirilazad mesylate (group A, n = 10), its vehicle (group B, n = 10), or saline 0.9% (group C, n = 10) before a 120-minute infusion of endotoxin (2 mg/kg/hr). Furthermore, a control group without receiving endotoxin (group D, n = 10) was investigated. Leukocyte adherence, emigration of leukocytes, and macromolecular leakage were determined in postcapillary venules of the mesentery by using intravital videomicroscopy. RESULTS: During the administration of endotoxin the number of adherent leukocytes per square millimeter of vessel surface progressively increased in group B (baseline, 431 +/- 35 cells/mm2; 120 minutes, 1121 +/- 71 cells/mm2) and group C (baseline, 398 +/- 44 cells/mm2; 120 minutes, 1290 +/- 116 cells/mm2). In group A no increase in leukocyte adherence was observed after 120 minutes (baseline, 415 +/- 81 cells/mm2; 120 minutes, 638 +/- 87 cells/mm2). In control animals the leukocyte adherence remained unchanged (baseline, 347 +/- 41 cells/mm2; 120 minutes, 507 +/- 75 cells/mm2). After 120 minutes, tirilazad mesylate prevented the increase in leukocyte emigration observed in group B and C. Increased macromolecular leakage during endotoxemia (groups B and C) was not influenced by pretreatment with tirilazad. Tirilazad did not affect the decrease in red cell velocity, volumetric blood flow, and venular shear rate observed during endotoxemia. CONCLUSIONS: This study demonstrates inhibitory effects of tirilazad on endotoxin-induced leukocyte adherence and emigration, suggesting a potential therapeutic role for this substance in the prevention of sepsis-induced multiple organ failure.

Retention of the antibiotic teicoplanin on a hydromer-coated central venous catheter to prevent bacterial colonization in postoperative surgical patients.

OBJECTIVE: Antibiotic-coated intravascular catheters may be an effective means of decreasing bacterial colonization and subsequent catheter-related infection. The present study was designed to investigate the retention of the antibiotic teicoplanin on a hydromer-coated intravenous catheter and the effect of this antibiotic coating on catheter bacterial colonization. DESIGN: A prospective, randomized pilot study. SETTING: Operating rooms (ORs) and an intensive care unit (ICU) at a university hospital. PATIENTS: A consecutive group of 20 male patients undergoing major abdominal surgery. INTERVENTIONS: Control (C; n = 10) or teicoplanin-coated (T; n = 10) single-lumen central venous catheters were inserted before surgery in the OR. Catheters were withdrawn at the discretion of the physicians in the ICU after various periods. MEASUREMENTS: The teicoplanin content of the catheter material was assessed using a bioassay with Bacillus subtilis after complete elution of the antibiotic from the catheter. Bacterial colonization was measured using a quantitative culture technique after the catheter lumen had been flushed and the catheter segments sonicated. MAIN RESULTS: Nearly three-quarters of the initial teicoplanin coating (374 +/- 103 micrograms; mean +/- SD) were released during the first day of catheterization, and after 36 h of intravenous catheterization, no antibiotic was retained on the catheter. No significant difference could be found either in the incidence of bacterial colonization between test (n = 3) and control (n = 4) catheters or in the number of colony-forming units (CFU) on the catheter segments (T, 263 +/- 104 CFU/cm; C, 372 +/- 294 CFU/cm; mean +/- SEM). CONCLUSION: The retention of teicoplanin antibiotic coating on hydromer catheters is only short term if catheters are inserted intravenously. This may limit clinical antibacterial efficacy.

Bolus injection of thrombolytic agents during cardiopulmonary resuscitation for massive pulmonary embolism.

Thrombolytic therapy has proved to be efficacious in the treatment of massive and fulminant pulmonary embolism (PE), but thrombolysis has been considered as contraindicated during cardiopulmonary resuscitation (CPR). This review on the administration of thrombolytic agents in patients who have suffered massive PE necessitating CPR summarises 14 anecdotal reports and three case series involving 34 patients. The case series revealed an overall initial survival rate of 55-100% following bolus administration of thrombolytic agents. In general, bleeding complications were managed conservatively. The establishment of the diagnosis may be feasible using echocardiography or bedside angiography during CPR. However, therapeutic measures should be taken without delay; the patient's history and the clinical picture may thus be the only diagnostic criteria. Even where myocardial infarction is misinterpreted as PE during CPR, bolus injection of a thrombolytic agent can be an appropriate therapeutic option. An alternative may be mechanical catheter fragmentation of the thrombus with subsequent local thrombolysis. Surgery may be restricted to hospitals with ready access to extracorporeal circulation. We conclude that early administration of thrombolytic agents during PE necessitating CPR may help to reduce mortality. We favour the administration of urokinase (2- to 3,000,000-U bolus) or rt-PA.

Changes in intrathoracic fluid volumes during weaning from mechanical ventilation in patients after coronary artery bypass grafting.

PURPOSE: Although it is known that weaning from mechanical ventilation is associated with alterations in intrathoracic pressure, lung volume, and venous return, changes in intrathoracic fluid volumes during weaning are not reported. Especially in patients with impaired cardiac function, the development of pulmonary edema during weaning has been described. Thus, we investigated changes in intrathoracic fluid volumes in patients after coronary artery bypass grafting after changing the ventilatory pattern from mechanical to spontaneous ventilation. MATERIALS AND METHODS: Intrathoracic blood volume index (ITBVI), pulmonary blood volume index (PBVI), and extravascular lung water (EVLW) were calculated during mechanical ventilation (T1), T-piece breathing (T2), and spontaneous breathing after extubation of the trachea (T3) in 72 consecutive patients after coronary artery bypass grafting using a combined dye-thermal dilution method. RESULTS: Changing from mechanical ventilation to T-piece breathing resulted in an increase in ITBVI from 880 +/- 22 mL/m2 to 970 +/- 22 mL/m2 (P < .01), and in PBVI from 162 +/- 6 mL/m2 to 173 +/- 6 mL/m2 (P < .01). After extubation of the trachea, both parameters decreased again (ITBVI, 879 +/- 20 mL/m2; PBVI, 160 +/- 7 mL/m2). EVLW remained unchanged after transition to T-piece breathing (T1, 5.8 +/- 0.3 mL/kg; T2, 6.0 +/- 0.3 mL/kg), but increased to 6.6 +/- 0.5 mL/kg (P < .01) after extubation of the trachea. However, pathological values of EVLW were not observed. CONCLUSIONS: In patients after coronary artery bypass grafting, changes in intrathoracic intravascular fluid volumes during weaning are restricted to the period of T-piece breathing and reflect an increased venous return. The maintenance of EVLW in the normal range during weaning indicates that cardiac function was matched to this elevated preload.

Masking of the symptoms of esophageal and bowel perforation by combination treatment of sepsis with polyvalent immunoglobulins and low-dose hydrocortisone.

Sepsis is usually treated with surgical drainage, antibiotics, oxygenation optimization and volume resuscitation. Recent monoclonal and polyclonal anti-bodies have been used to treat sepsis by neutralizing the endotoxins and cytokines found in septic patients. This method does not significantly reduce mortality except in certain sub-populations of the treatment groups. We introduced a combination approach for sepsis treatment. This adjuvant therapy consists of polyclonal human immunoglobins together with infusion of low-dose hydrocortisone. This paper reports the results of this treatment in two different cases.

[Cognitive function of geriatric ophthalmology patients after local and general anesthesia]. / Untersuchung der kognitiven Funktion bei geriatrischen ophthalmologischen Patienten nach Lokal-bzw. Allgemeinanästhesie.

Since there will be an increase in the number of geriatric patients who undergo surgery and anesthesia over the next few years, studies comparing the effects of general and local anesthesia on cognitive functioning in elderly persons are mandatory. One hundred eleven ophthalmological patients, all over the age of 64 years, were assessed preoperatively, on the first and on the fourth postoperative day using a battery of standardized cognitive tests. Of the initial sample, 47 patients undergoing local and 54 undergoing general anesthesia completed the assessment. The performance of the patients in six tests did not change perioperatively. In both anesthesia groups, two tests revealed a cognitive deficit postoperatively, which only became evident on the first postoperative day. The two other tests showed a significant difference between the two anesthesia groups on the first postoperative day. The performance of patients with general anesthesia decreased transiently and returned to the initial levels within 3 days. We conclude from our results that postoperative cognitive deficits may occur in geriatric patients. However, general anesthesia poses no more risk to cognitive function than local anesthesia.

[Importance of blood transfusion in anemic patients with COPD and unsuccessful weaning from respirator]. / Stellenwert der Bluttransfusion bei schwer vom Respirator entwöhnbaren Patienten mit Anämie und COPD.

BACKGROUND: Imbalance of load-capacity relationship in severe COPD may lead to ventilatory failure. Additionally, in such patients, anemia may aggravate the ventilatory load. In this retrospective study we investigated whether anemia patients undergoing long-term ventilation benefit from transfusion. CASE REPORTS: We studied 5 anemic patients (hemoglobin: 8.7 +/- 0.8 g/dl) with COPD in whom trials of weaning from the ventilator had been unsuccessful. After transferral to our regional weaning centre, blood was transfused to increase the hemoglobin value to approximately 12 g/dl or higher. Subsequently, all patients could be successfully weaned within a short period. CONCLUSION: We conclude that in difficult to wean anemic patients blood transfusion should be considered and may lead to successful weaning.

[Pressure versus volume constant ventilation in chronic ventilatory insufficiency]. / Druck- versus volumenkonstante Beatmung bei der chronisch ventilatorischen Insuffizienz.

BACKGROUND: Volume controlled intermittent ventilation (IPPV) via face mask is a treatment of proven efficacy for chronic respiratory failure (CRF). Pressure support ventilation has recently been introduced in the treatment of CRF. In this study we investigated whether pressure constant ventilation (PCV) via face mask could be an adequate long term alternative to IPPV. PATIENTS AND METHODS: We studied 30 (24 male, age: 52.2 +/- 15.9 years) patients with CRF. We measured the following parameters at baseline, after 1, 2 and 6 months, respectively: blood gas analysis, oxygen saturation, vital capacity, forced exspiratory volume, breathing frequency, tidal volume, inspiratory mouth occlusion pressure, maximal inspiratory pressure, subjective symptom scores and ventilator acceptance scores. In all patients, we attempted to treat with IPPV over 1 month, followed by 1 month's trial of PCV. If PCV, compared to IPPV, was adequate, PCV was continued for a follow-up period of 4 months' duration. If patients deteriorated after PCV they were treated the following 4 months with IPPV. RESULTS: In 28 out of 30 patients CRF improved concerning subjective and objective parameters. After IPPV 18 out of 28 patients changed to PCV, with an equal quality of treatment (PCV-responder). Ten patients were PCV-nonresponders since compared to IPPV the subjective scores deteriorated and the PaCO2 increased again. In all patients of either therapy group, subjective and objective parameters remained constant for another 4 months period. At baseline the PCV-nonresponders had significantly higher degree of hypercapnia and oxygen desaturation; no other parameters were found to be of predictive value concerning the efficacy of PCV. CONCLUSIONS: PCV proved to be an alternative to IPPV in the treatment of chronic respiratory insufficiency in approximately 60% of the patients with CRF. However there is a subgroup with more severe CRF at baseline in whom PCV is inadequate.