Andja Bojic

Cardiac Toxicity of Sunitinib and Sorafenib in Patients With Metastatic Renal Cell Carcinoma

PURPOSE Sunitinib and sorafenib are tyrosine kinase inhibitors (TKIs) that have considerable efficacy in metastatic renal cell carcinoma. TKI-associated cardiotoxicity was reported in approximately 10% of the patients. Detailed cardiovascular monitoring during TKI treatment may reveal early signs of myocardial damage. PATIENTS AND METHODS In this observational, single-center study, all patients intended for TKI treatment were analyzed for coronary artery disease (CAD) risk factors, history or evidence of CAD, hypertension, rhythm disturbances, and heart failure. Monitoring included assessment of symptoms, ECGs, and biochemical markers (ie, creatine kinase-MB, troponin T). Echocardiography was performed at baseline in selected patients and in all patients who experienced a cardiac event. A cardiac event was defined as the occurrence of increased enzymes if normal at baseline, symptomatic arrhythmia that required treatment, new left ventricular dysfunction, or acute coronary syndrome. RESULTS A total of 86 patients were treated with either sunitinib or sorafenib. Among 74 eligible patients, 33.8% experienced a cardiac event, 40.5% had ECG changes, and 18% were symptomatic. Seven patients (9.4%) were seriously compromised and required intermediate care and/or intensive care admission. All patients recovered after cardiovascular management (ie, medication, coronary angiography, pacemaker implantation, heart surgery) and were considered eligible for TKI continuation. Statistically, there was no significant survival difference between patients who experienced a cardiac event and those who did not experience a cardiac event. CONCLUSION Our observations indicate that cardiac damage from TKI treatment is a largely underestimated phenomenon but is manageable if patients have careful cardiovascular monitoring and cardiac treatment at the first signs of myocardial damage.

Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1): A Randomized, Double-Blind, Placebo-Controlled, Single-Dose Study

BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (−12 mm Hg [95% CI, −22 to −1]; P = .03) and right ventricular end-diastolic area (−5.6 cm2 [95% CI, −11 to −0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience

Background Acute myeloid leukemia is a life-threatening disease associated with high mortality rates. A substantial number of patients require intensive care. This investigation analyzes risk factors predicting admission to the intensive care unit in patients with acute myeloid leukemia eligible for induction chemotherapy, the outcome of these patients, and prognostic factors predicting their survival. Design and Methods A total of 406 consecutive patients with de novo acute myeloid leukemia (15–89 years) were analyzed retrospectively. Markers recorded at the time of diagnosis included karyotype, fibrinogen, C-reactive protein, and Charlson comorbidity index. In patients requiring critical care, the value of the Simplified Acute Physiology Score II, the need for mechanical ventilation, and vasopressor support were recorded at the time of intensive care unit admission. The independent prognostic relevance of the parameters was tested by multivariate analysis. Results Sixty-two patients (15.3%) required intensive care, primarily due to respiratory failure (50.0%) or life-threatening bleeding (22.6%). Independent risk factors predicting intensive care unit admission were lower fibrinogen concentration, the presence of an infection, and comorbidity. The survival rate was 45%, with the Simplified Acute Physiology Score II being the only independent prognostic parameter (P<0.05). Survival was inferior in intensive care patients compared to patients not admitted to an intensive care unit. However, no difference between intensive care and non-intensive care patients was found concerning continuous complete remission at 6 years or survival at 6 years in patients who survived the first 30 days after diagnosis (non-intensive care patients: 28%; intensive care patients: 20%, P>0.05). Conclusions Ongoing infections, low fibrinogen and comorbidity are predictive for intensive care unit admission in acute myeloid leukemia. Although admission was a risk factor for survival, continuous complete remission and survival of patients alive at day 30 were similar in patients who were admitted or not admitted to an intensive care unit.

Continuous lateral rotation therapy to prevent ventilator-associated pneumonia

Objective: To investigate the impact of prophylactic continuous lateral rotation therapy on the prevalence of ventilator-associated pneumonia, duration of mechanical ventilation, length of stay, and mortality in critically ill medical patients. Design: Prospective, randomized, clinical study. Setting: Three medical intensive care units of an university tertiary care hospital. Patients: Patients were randomized to continuous lateral rotation therapy or standard care if they were mechanically ventilated for <48 hrs and free from pneumonia. Primary study end point was development of ventilator-associated pneumonia. Ventilator-associated pneumonia was defined as infiltrate on the chest radiograph plus newly developed purulent tracheal secretion plus increasing signs of inflammation. The diagnosis had to be confirmed microbiologically and required the growth of a pathogen >104 colony-forming units/mL in bronchoalveolar lavage. Radiologists were blinded to randomization whereas clinical outcome assessors were not. Interventions: Rotation therapy was performed continuously in a specially designed bed over an arc of 90°. Additional measures to prevent ventilator-associated pneumonia were equally standardized in both groups including semirecumbent position. Measurements and Main Results: Ventilator-associated pneumonia frequency during the intensive care unit stay was 11% in the rotation group and 23% in the control group (p = .048), respectively. Duration of ventilation (8 ± 5 vs. 14 ± 23 days, p = .02) and length of stay (25 ± 22 days vs. 39 ± 45 days, p = .01) were significantly shorter in the rotation group. In a forward stepwise logistic regression model including the continuous lateral rotation therapy, gender, Lung Injury Score, and Simplified Acute Physiology Score II, continuous lateral rotation therapy just failed to reach statistical significance with respect to development of ventilator-associated pneumonia (p = .08). Intolerance to continuous lateral rotation therapy during the weaning phase was observed in 29 patients (39%). Mortality was comparable in both groups. Conclusions: Ventilator-associated pneumonia prevalence was significantly reduced by continuous lateral rotation therapy. Continuous lateral rotation therapy led to shorter ventilation time and length of stay. Continuous lateral rotation therapy should be considered in ventilated patients at risk for ventilator-associated pneumonia as a feasible method exerting additive effects to other preventive measures.

Jaundice increases the rate of complications and one‐year mortality in patients with hypoxic hepatitis

Hypoxic hepatitis (HH) is the most frequent cause of acute liver injury in critically ill patients. No clinical data exist about new onset of jaundice in patients with HH. This study aimed to evaluate the incidence and clinical effect of jaundice in critically ill patients with HH. Two hundred and six consecutive patients with HH were screened for the development of jaundice during the course of HH. Individuals with preexisting jaundice or liver cirrhosis at the time of admission (n = 31) were excluded from analysis. Jaundice was diagnosed in patients with plasma total bilirubin levels >3 mg/dL. One‐year‐survival, infections, and cardiopulmonary, gastrointestinal (GI), renal, and hepatic complications were prospectively documented. New onset of jaundice occurred in 63 of 175 patients with HH (36%). In patients who survived the acute event of HH, median duration of jaundice was 6 days (interquartile range, 3‐8). Patients who developed jaundice (group 1) needed vasopressor treatment (P < 0.05), renal replacement therapy (P < 0.05), and mechanical ventilation (P < 0.05) more often and had a higher maximal administered dose of norepinephrine (P < 0.05), compared to patients without jaundice (group 2). One‐year survival rate was significantly lower in group 1, compared to group 2 (8% versus 25%, respectively; P < 0.05). Occurrence of jaundice was associated with an increased frequency of complications during follow‐up (54% in group 1 versus 35% in group 2; P < 0.05). In particular, infections as well as renal and GI complications occurred more frequently in group 1 during follow‐up. Conclusion: Jaundice is a common finding during the course of HH. It leads to an increased rate of complications and worse outcome in patients with HH. (HEPATOLOGY 2012)

Extracorporeal CO2 removal as bridge to lung transplantation in life-threatening hypercapnia

In patients awaiting lung transplantation (LTX), adequate gas exchange may not be sufficiently achieved by mechanical ventilation alone if acute respiratory decompensation arises. We report on 20 patients with life‐threatening hypercapnia who received extracorporeal CO2 removal (ECCO2‐R) by means of the interventional lung assist (ILA®, Novalung) as bridge to LTX. The most common underlying diagnoses were bronchiolitis obliterans syndrome, cystic fibrosis, and idiopathic pulmonary fibrosis, respectively. The type of ILA was pumpless arteriovenous or pump‐driven venovenous (ILA activve®, Novalung) in 10 patients each. ILA bridging was initiated in 15 invasively ventilated and five noninvasively ventilated patients, of whom one had to be intubated prior to LTX. Hypercapnia and acidosis were effectively corrected in all patients within the first 12 h of ILA therapy: PaCO2 declined from 109 (70–146) to 57 (45–64) mmHg, P < 0.0001; pH increased from 7.20 (7.06–7.28) to 7.39 (7.35–7.49), P < 0.0001. Four patients were switched to extracorporeal membrane oxygenation due to progressive hypoxia or circulatory failure. Nineteen patients (95%) were successfully transplanted. Hospital and 1‐year survival was 75 and 72%, respectively. Bridging to LTX with ECCO2‐R delivered by arteriovenous pumpless or venovenous pump‐driven ILA is feasible and associated with high transplantation and survival rates.

First experience with a new miniaturized pump-driven venovenous extracorporeal CO2 removal system (iLA Activve): a retrospective data analysis.

iLA Activve is a new minimally invasive device for extracorporeal CO2 removal (ECCO2-R) using a miniaturized pump, a special gas exchange membrane, and a double-lumen cannula. We retrospectively analyzed our experiences in 12 patients with hypercapnic respiratory failure undergoing ECCO2-R. Indication for ECCO2-R was hypercapnia due to terminal lung failure during bridging to lung transplantation, pneumonia, and chronic obstructive lung disease or asthma. The median duration of ECCO2-R was 8 days (range 2–30). Seven patients were successfully weaned and five died. Patients with primarily hypoxic lung failure were significantly longer ventilated before ECCO2-R and had a higher mortality rate. Complications were retroperitoneal hematoma after cannulation in one patient and repeated system changes because of clotting in two patients. We observed effective CO2 removal in all patients, with significant reduction in ventilation pressures and minute volumes at median blood flow rates of 1.2–1.4 L/min. The iLA Activve system using venous double-lumen cannulas proved to be an effective method for ECCO2-R. Invasiveness of ventilation could be reduced. Additional severe impairment of oxygenation and prolonged mechanical ventilation before ECCO2-R are factors of adverse prognosis. The use of ECCO2-R should be thoroughly reconsidered in these cases.

Automated red blood cell exchange as an adjunctive treatment for severe Plasmodium falciparum malaria at the Vienna General Hospital in Austria: a retrospective cohort study.

BackgroundSevere falciparum malaria is associated with considerable rates of mortality, despite the administration of appropriate anti-malarial treatment. Since overall survival is associated with total parasite biomass, blood exchange transfusion has been proposed as a potential method to rapidly reduce peripheral parasitaemia. However, current evidence suggests that this treatment modality may not improve outcome. Automated red blood cell exchange (also referred to as “erythrocytapheresis”) has been advocated as an alternative method to rapidly remove parasites from circulating blood without affecting patients’ volume and electrolyte status. However, only limited evidence from case reports and case series is available for this adjunctive treatment. This retrospective cohort study describes the use of automated red blood cell exchange for the treatment of severe malaria at the Medical University of Vienna.MethodsEpidemiologic data for imported malaria cases in Austria are reported and data of patients treated for malaria at the General Hospital/Medical University of Vienna were extracted from electronic hospital records.ResultsBetween 2000 and 2010, 146 patients were hospitalized at the Medical University of Vienna due to malaria and 16 of those were classified as severe malaria cases. Eleven patients of this cohort were potentially eligible for an adjunctive treatment with automated red blood cell exchange. Five patients eventually underwent this procedure within a period of seven hours (range: 3–19 hours) after hospital admission. Six patients did not undergo this adjunctive treatment following the decision of the treating physician. The procedure was well tolerated in all cases and rapid reduction in parasite counts was achieved without occurrence of haemodynamic complications. One patient died within seven days, whereas four patients survived without any sequelae.Discussion and conclusionAutomated red blood cell exchange was a safe and efficient procedure to rapidly clear peripheral parasitaemia. Whether the fast reduction in parasite biomass may ultimately improve patient survival remains however unclear. Randomized controlled trials are needed to conclusively appreciate the value of this adjunctive treatment.

Catastrophic graft-versus-host disease after lung transplantation proven by PCR-based chimerism analysis

Acute graft‐versus‐host disease (GvHD) is a rare complication after solid organ transplantation. We describe a 52‐year‐old female developing neutropenia and fever 48 days after single lung transplantation for chronic obstructive pulmonary disease. Bone marrow (BM) biopsy suggested drug‐induced marrow failure, so immunosuppression was reduced. Five days later a maculopapular skin rash was observed, progressing to a generalized erythema with desquamation. Skin biopsy was suspectable for GvHD, so immunosuppression was re‐initiated. PCR‐based chimerism analysis of BM revealed 78% donor cells. Intensified immunosuppression resulted in temporary improvement, but BM aplasia recurred and the patient experienced severe GvHD of gut and liver. Despite extensive immunosuppression the patient died from multi‐organ failure 99 days after transplantation. This report describes the occurrence of neutropenia as an early presenting sign of acute GvHD after lung transplantation. We therefore recommend incorporating GvHD in the differential diagnosis of neutropenia after solid organ transplantation, calling for early chimerism analyses.

Influence of different oxygenator types on changing frequency, infection incidence, and mortality in ARDS patients on veno-venous ECMO

Purpose Veno-venous extracorporeal membrane oxygenation (vv-ECMO) is pivotal in the treatment of patients suffering from acute respiratory distress syndrome (ARDS). Comparative data with different oxygenator models have not yet been reported. The aim of this retrospective investigation was therefore to assess whether different oxygenator types might influence changing frequency, infection incidence, and mortality in patients on vv-ECMO. Methods 42 patients undergoing vv-ECMO between 1998 and 2009 were identified. In 20 out of these patients, a polypropylene (PP) microporous hollow fiber membrane oxygenator, and in 22 patients a nonmicroporous polymethylpentene (PMP) diffusion membrane oxygenator was used. Infection incidence, changing frequency, and mortality were documented. Results In the PMP group, an oxygenator change was necessary less often than in the PP group (p<0.001). The incidence of bacterial, viral, or fungal growth was similar in the groups, thus independent of the frequency of oxygenator change. Irrespective of the groups, the occurrence of Candida sp. tended to correlate with death (p = 0.06). In general, there was a trend towards a higher infection incidence in the subgroup with pulmonary ARDS (p = 0.07). Moreover, infection incidence was associated with a longer ICU stay (p = 0.03) and longer ECMO therapy (p = 0.03). ICU mortality was lower in the PMP group than in the PP group, although not statistically significant (p = 0.10). Conclusions The PMP oxygenator membranes showed benefits with regards to changing frequency, but not infection incidence, length of ICU stay, and length of ECMO therapy. There was a trend towards a lower ICU mortality in patients with PMP oxygenators.