Uwe Janssens

Recombinant Hirudin (Lepirudin) Provides Safe and Effective Anticoagulation in Patients With Heparin-Induced Thrombocytopenia A Prospective Study

BACKGROUND The immunological type of heparin-induced thrombocytopenia (HIT) is the most frequent drug-induced thrombocytopenia. This study evaluated the efficacy of recombinant hirudin (r-hirudin or lepirudin), a potent thrombin inhibitor, for anticoagulation in patients with confirmed HIT. METHODS AND RESULTS Eighty-two patients in this prospective, multicenter study received 1 of 4 intravenous r-hirudin regimens: A1, HIT patients with thrombosis (n=51), 0.4-mg/kg bolus and then 0.15 mg. kg-1. h-1; A2, HIT patients with thrombosis receiving thrombolysis (n=5), 0. 2-mg/kg bolus and then 0.1 mg. kg-1. h-1; B, HIT patients without thrombosis (n=18), 0.1 mg. kg-1. h-1; and C, during cardiopulmonary bypass surgery (n=8), 0.25-mg/kg bolus and then 5-mg boluses as needed. Response criteria were increase in platelet count by >/=30% to >10(9)/L and activated partial thromboplastin time (aPTT) values 1.5 to 3.0 times baseline values achieved with a maximum of 2 dose increases. No placebo control was used for ethical reasons. Outcomes of a subset of r-hirudin-treated patients who met predefined inclusion criteria (n=71) were compared with those of a historical control group (n=120) for combined and individual incidences of death, amputations, new thromboembolic complications, and incidences of bleeding. Platelet counts increased rapidly in 88.7% of r-hirudin-treated patients with acute HIT. In regimens A1 and A2, the 25% and 75% quartiles of the aPTT were within the target range at all but 1 time point. The incidence of the combined end point (death, amputation, new thromboembolic complications) was significantly reduced in r-hirudin patients compared with historical control patients (P=0.014). During first selected treatment, the adjusted hazard ratio for r-hirudin patients versus historical control was 0.279 (95% CI, 0.112 to 0.699; P=0.003). Bleeding rates were similar in both groups. CONCLUSIONS r-Hirudin treatment is associated with a rapid and sustained recovery of platelet counts, sufficient aPTT prolongations, and true clinical benefits for patients with HIT.

Lepirudin (Recombinant Hirudin) for Parenteral Anticoagulation in Patients With Heparin-Induced Thrombocytopenia

BACKGROUND We prospectively investigated lepirudin for further parenteral anticoagulation in patients with heparin-induced thrombocytopenia (HIT). METHODS AND RESULTS Patients with confirmed HIT (n=112) received lepirudin according to need for 2 to 10 days (longer if necessary): A1, treatment: 0.4 mg/kg IV bolus, followed by 0.15 mg. kg(-1). h(-1) intravenous infusion, n=65; A2, treatment in conjunction with thrombolysis: 0.2 mg/kg, followed by 0.10 mg. kg(-1). h(-1), n=4; and B, prophylaxis: 0.10 mg. kg(-1). h(-1), n=43. Outcomes from 95 eligible lepirudin-treated patients were compared with those of historical control patients (n=120). Complete laboratory response (activated partial thromboplastin time ratio >1.5 with </=2 dose increases and platelet count normalization by day 10) was achieved in 65 lepirudin-treated patients (69.1%; 95% CI, 59. 3% to 78.3%). At 2 weeks after cessation of lepirudin, 11 patients died (9.8%), 10 underwent limb amputation (8.9%), and 20 suffered a new thromboembolic complication (17.9%). The average combined event rate per patient-day decreased from 5.1% in the pretreatment period to 1.5% in the treatment period. Thirty-five days after HIT confirmation, fewer lepirudin-treated patients than historical control patients had experienced >/=1 outcome (cumulative incidence 30.9% versus 52.1%; relative risk [RR] 0.71; P=0.12, log-rank test). Bleeding events were more frequent in the lepirudin group than the historical control group (cumulative incidence at 35 days, 44.6% versus 27.2%; RR 2.57; P=0.0001, log-rank test). No difference was observed in bleeding events requiring transfusion (cumulative incidence at 35 days, 12.9% versus 9.1%; RR 1.66; P=0.23, log-rank test); no intracranial bleeding was observed in the lepirudin group. CONCLUSIONS Lepirudin effectively prevents death, limb amputations, and new thromboembolic complications and has an acceptable safety profile in HIT patients. Treatment should be initiated as soon as possible if HIT is suspected.

HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis

Background—HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. Methods and Results—Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24±0.09 to 0.87±0.11 mL · min−1 · g−1 in untreated mice (P <0.005; n=12), while remaining unaltered (1.21±0.08 mL · min−1 · g−1 at baseline and 1.15±0.1 mL · min−1 · g−1 20 hours after CLP, P =NS, n=12) in CLP mice treated with simvastatin]. Untreated CLP mice remained refractory to β-stimulation, whereas the responsiveness to dobutamine was restored by treatment with simvastatin. Susceptibility of coronary flow to endothelial nitric oxide synthase (eNOS) stimulation by bradykinin was close to 3 times as pronounced in untreated CLP mice as in untreated sham-operated mice, indicating a high level of eNOS activation secondary to sepsis. In addition, treatment with simvastatin reversed inflammatory alterations in CLP mice, namely, increased monocyte adhesion to endothelium. Conclusions—Simvastatin, which is well established in the treatment of lipid disorders and coronary artery disease, might have the additional potential of being an effective agent in sepsis treatment.

Massive pulmonary embolism: percutaneous emergency treatment by pigtail rotation catheter.

OBJECTIVES This study was designed to assess the feasibility, efficacy and safety of mechanical fragmentation of pulmonary emboli using a new rotational pigtail catheter system. BACKGROUND Acute massive pulmonary embolism associated with right ventricular dysfunction is frequently lethal, despite high-dose thrombolytic therapy. Adjunctive catheter fragmentation may prevent a fatal outcome. METHODS In 20 patients (age 58.9+/-10.5 years) with severe hemodynamic impairment, massive pulmonary emboli were fragmented by mechanical action of the rotating pigtail. Fifteen patients received thrombolysis after embolus fragmentation or no thrombolysis at all (noninterference group). RESULTS Prefragmentation pulmonary arterial occlusion was 68.6 +/- 11.3% for both lungs. Pulmonary placement and navigation of the fragmentation catheter was easy and rapid. Fragmentation time was 17+/-8 min. The noninterference group showed a decrease pre- to postfragmentation of shock index from 1.28+/-0.53 to 0.95+/-0.38 (p = 0.011), mean pulmonary artery pressure from 31+/-5.7 to 28+/-7.5 mm Hg (p = 0.02) and a recanalization by fragmentation of 32.9+/-11.8% (mean angiographic score per treated lung from 7.4 to 5.0). Overall mortality was 20%. CONCLUSIONS Fragmentation by pigtail rotation catheter provided for a rapid and safe improvement of the hemodynamic situation and an average recanalization of about one-third of the pulmonary embolic occlusion. The method appears useful especially in high-risk patients threatened by right ventricular failure, to accelerate thrombolysis, and as a minimal-invasive alternative to surgical embolectomy.

Assessment of Myocardial Reperfusion by Intravenous Myocardial Contrast Echocardiography and Coronary Flow Reserve After Primary Percutaneous Transluminal Coronary Angiography in Patients With Acute Myocardial Infarction

Background—This study investigated whether the extent of perfusion defect determined by intravenous myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction (AMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) relates to coronary flow reserve (CRF) for assessment of myocardial reperfusion and is predictive for left ventricular recovery. Methods and Results—Twenty-five patients with first AMI underwent intravenous MCE with NC100100 with intermittent harmonic imaging before PTCA and after 24 hours. MCE before PTCA defined the risk region and MCE at 24 hours the “no-reflow” region. The no-reflow region divided by the risk region determined the ratio to the risk region. CFR was assessed immediately after PTCA and 24 hours later. Left ventricular wall motion score indexes were calculated before PTCA and after 4 weeks. CFR at 24 hours defined a recovery (CFR ≥1.6; n=17) and a nonrecovery group (CFR <1.6; n=8). Baseline CFR did not differ between groups. M...

brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure.

OBJECTIVES The goal of this study was to determine if brain natriuretic peptide (BNP) levels are associated with exercise capacity in patients with chronic heart failure (HF). BACKGROUND Plasma levels of BNP are increased subject to the degree of systolic and diastolic left ventricular dysfunction in patients with chronic HF. Exercise testing is useful to assess functional capacity and prognosis in chronic HF. METHODS We prospectively studied 70 consecutive patients with chronic HF (60.3 +/- 10.4 years, 51 men) referred for cardiopulmonary exercise testing. Resting BNP was obtained after 10 min of supine rest before symptom-limited bicycle exercise testing. RESULTS In patients with chronic HF, BNP levels correlated with oxygen uptake (VO(2)), both at anaerobic threshold (VO(2)AT: r = -0.54, p < 0.001) and peak exercise (peak VO(2): r = -0.56, p < 0.001). Impairment of ventilatory efficiency (EqCO(2): r = 0.43, p < 0.001) and maximum exercise level (W % predicted: r = -0.44, p < 0.05) correlated less well with BNP. There was a significant inverse correlation between left ventricular ejection fraction and BNP (r = -0.50, p < 0.05). Brain natriuretic peptide discriminated well chronic HF patients with a peak VO(2) <10 ml/min/kg (area under the receiver operating characteristic [ROC] 0.93) or <14 ml/min/kg (area under the ROC 0.72). A BNP >316 pg/ml was associated with a risk ratio of 6.8 (95% confidence interval, 2.3 to 19.8) for a reduced exercise capacity with a peak VO(2) <14 ml/min/kg. CONCLUSIONS Brain natriuretic peptide is clearly associated with exercise capacity in chronic HF. Brain natriuretic peptide levels show a significant correlation with the impairment of VO(2) at peak exercise and anaerobic threshold. Brain natriuretic peptide is able to differentiate between chronic HF patients with moderately and severely impaired exercise capacity.

Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism

BACKGROUND Plasma levels of brain natriuretic peptide (BNP) are increased in patients with left heart failure. In patients with severe pulmonary embolism (PE), primary right ventricular (RV) dysfunction is frequent. Little is known about BNP secretion in acute RV failure. METHODS We prospectively studied 50 consecutive patients with confirmed PE (age range, 57 +/- 19 years; 36 men). PE was confirmed with pulmonary angiography, spiral computed tomography, or echocardiography and subsidiary analyses. On admission, echocardiography and BNP measurements were performed in all patients. RESULTS Patients without RV dysfunction had significantly lower BNP levels than patients with RV dysfunction (55 +/- 69 pg/mL vs 340 +/- 362 pg/mL, P <.001). There was a significant correlation between RV end-diastolic diameter and BNP (r = 0.43, P <.05). BNP discriminated patients with or without RV dysfunction (area under the receiver operating characteristic curve, 0.78; 95% CI, 0.64-0.92). A BNP >90 pg/mL was associated with a risk ratio of 28.4 (95% CI, 3.22-251.12) for the diagnosis of RV dysfunction. All patients without LV systolic dysfunction who had syncope necessitating cardiopulmonary resuscitation had normal BNP levels. Patients with RV dysfunction had significantly more in-hospital complications (cardiogenic shock, inotropic therapy, mechanical ventilation). However, BNP levels were not predictive of mortality or in-hospital complications. CONCLUSIONS BNP levels are frequently increased in patients with PE who have RV dysfunction, whereas patients without RV dysfunction show reference range BNP levels in the absence of left ventricular dysfunction. In acute PE, BNP elevation is highly predictive of RV dysfunction, but not of in-hospital complications and mortality.

Health-related quality of life before, 1 month after, and 9 months after intensive care in medical cardiovascular and pulmonary patients.

ObjectiveAssessment of health-related quality of life before, 1 month after, and 9 months after an intensive care unit stay using an established generic instrument, the Medical Outcome Survey Short Form-36 (SF-36). DesignProspective, observational study. SettingUniversity hospital medical intensive care unit. PatientsTwo hundred forty-five patients with predominantly cardiovascular and pulmonary disorders. InterventionsNone. Measurements and Main ResultsDemographic data, Simplified Acute Physiology Score (SAPS) II, and Sepsis-Related Organ Failure Assessment (SOFA) were obtained. All adult survivors staying in the intensive care unit for >24 hrs were eligible. Pre-intensive care unit status was obtained for 245 patients (179 males, mean age 64 yrs, mean intensive care unit stay 3 days, SAPS II 26 ± 10), and 153 patients completed all three questionnaires. In this cohort, none of the eight health dimensions of the SF-36 showed impaired functioning after 9 months compared with baseline values. Physical and emotional role deteriorated after 1 month but returned to baseline thereafter. Notably, the mental health summary scale did not change during the course of the study, whereas the physical health summary scale consistently improved over time. Patients older than the median of 66 yrs rated their physical functioning lower. No association with SAPS II or SOFA and SF-36 was found. ConclusionQuality of life after intensive care unit is a dynamic process, with some functions improving shortly after intensive care unit discharge and others deteriorating but returning at least to baseline values later on. In this patient population, the SF-36 was independent from measures of severity of illness or morbidity. Health-related quality of life represents a feasible method to collect patients’ individual views in contrast to surrogate measures of outcome.

Evaluation of the SOFA score: a single-center experience of a medical intensive care unit in 303 consecutive patients with predominantly cardiovascular disorders

Objective: To evaluate the use of the Sequential Organ Failure Assessment (SOFA) score, the total maximum SOFA (TMS) score, and a derived variable, the ΔSOFA (TMS score minus total SOFA score on day 1) in medical, cardiovascular patients as a means for describing the incidence and severity of organ dysfunction and the prognostic value regarding outcome. Design: Prospective, clinical study. Setting: Medical intensive care unit in a university hospital. Patients: A total of 303 consecutive patients were included (216 men, 87 women; mean age 62 ± 12.6 years; SAPS II 26.2 ± 12.7). They were evaluated 24 h after admission and thereafter every 24 h until ICU discharge or death between November 1997 and March 1998. Readmissions and patients with an ICU stay shorter than 12 h were excluded. Main outcome measure: Survival status at hospital discharge, incidence of organ dysfunction/failure. Interventions: Collection of clinical and demographic data and raw data for the computation of the SOFA score every 24 h until ICU discharge. Measurements and main results: Length of ICU stay was 3.7 ± 4.7 days. ICU mortality was 8.3 % and hospital mortality 14.5 %. Nonsurvivors had a higher total SOFA score on day 1 (5.9 ± 3.7 vs. 1.9 ± 2.3, p < 0.001) and thereafter until day 8. High SOFA scores for any organ system and increasing number of organ failures (SOFA score ≥ 3) were associated with increased mortality. Cardiovascular and neurological systems (day 1) were related to outcome and cardiovascular and respiratory systems, and admission from another ICU to length of ICU stay. TMS score was higher in nonsurvivors (1.76 ± 2.55 vs. 0.58 ± 1.39, p < 0.01), and ΔSOFA/total SOFA on day 1 was independently related to outcome. The area under the receiver-operating characteristic curve was 0.86 for TMS, 0.82 for SOFA on day 1, and 0.77 for SAPS II. Conclusions: The SOFA, TMS, and ΔSOFA scores provide the clinician with important information on degree and progression of organ dysfunction in medical, cardiovascular patients. On day 1 both SOFA score and TMS score had a better prognostic value than SAPS II score. The model is closely related to outcome and identifies patients who are at increased risk for prolonged ICU stay.

Health care costs, long-term survival, and quality of life following intensive care unit admission after cardiac arrest

IntroductionThe purpose of this study was to investigate the costs and health status outcomes of intensive care unit (ICU) admission in patients who present after sudden cardiac arrest with in-hospital or out-of-hospital cardiopulmonary resuscitation.MethodsFive-year survival, health-related quality of life (Medical Outcome Survey Short Form-36 questionnaire, SF-36), ICU costs, hospital costs and post-hospital health care costs per survivor, costs per life year gained, and costs per quality-adjusted life year gained of patients admitted to a single ICU were assessed.ResultsOne hundred ten of 354 patients (31%) were alive 5 years after hospital discharge. The mean health status index of 5-year survivors was 0.77 (95% confidence interval 0.70 to 0.85). Women rated their health-related quality of life significantly better than men did (0.87 versus 0.74; P < 0.05). Costs per hospital discharge survivor were 49,952 €. Including the costs of post-hospital discharge health care incurred during their remaining life span, the total costs per life year gained were 10,107 €. Considering 5-year survivors only, the costs per life year gained were calculated as 9,816 € or 14,487 € per quality-adjusted life year gained. Including seven patients with severe neurological sequelae, costs per life year gained in 5-year survivors increased by 18% to 11,566 €.ConclusionPatients who leave the hospital following cardiac arrest without severe neurological disabilities may expect a reasonable quality of life compared with age- and gender-matched controls. Quality-adjusted costs for this patient group appear to be within ranges considered reasonable for other groups of patients.