Florian Thalhammer

Outcome and prognostic factors in critically ill cancer patients admitted to the intensive care unit

Objective: To assess survival in cancer patients admitted to an intensive care unit (ICU) with respect to the nature of malignancy, cause of ICU admittance, and course during ICU stay as well as to evaluate the prognostic value of the Acute Physiology and Chronic Health Evaluation (APACHE) III score. Design: Retrospective cohort study. Setting: ICU at a university cancer referral center. Patients: A total of 414 cancer patients admitted to the ICU during a period of 66 months. Interventions: None. Measurements: Charts of the patients were analyzed with respect to underlying disease, cause of admission, APACHE III score, need and duration of mechanical ventilation, neutropenia and development of septic shock, as well as ICU survival and survival after discharge. Mortality data were compared with two control groups: 1362 patients admitted to our ICU suffering from diseases other than cancer and 2,776 cancer patients not admitted to the ICU. Main Results: ICU survival was 53%, and 1‐yr survival was 23%. The 1‐yr mortality rate was significantly lower in both control groups. Patients admitted after bone marrow transplantation had the highest mortality. In a multivariate analysis, prognosis was negatively influenced by respiratory insufficiency, the need of mechanical ventilation, and development of septic shock during the ICU stay. Admission after cardiopulmonary resuscitation yielded high ICU mortality but a relatively good long‐term prognosis. Admission after surgery and as a result of acute hemorrhage was associated with a good prognosis. Age, neutropenia, and underlying disease did not influence outcome significantly. Admission APACHE III scores were significantly higher in nonsurvivors but failed to predict individual outcome satisfactorily. All patients with APACHE III scores of >80 died at the ICU. Conclusion: A combination of factors must be taken into account to estimate a critically ill cancer patients prognosis in the ICU. The APACHE III scoring system alone should not be used to make decisions about therapy prolongation. Admission to the ICU worsens the prognosis of a cancer patient substantially; however, as ICU mortality is 47%, comparable with severely ill noncancer patients, general reluctance to admit cancer patients to an ICU does not seem to be justified.

Impaired Target Site Penetration of Vancomycin in Diabetic Patients following Cardiac Surgery

ABSTRACT Soft tissue infections constitute a serious complication following surgery in diabetic patients and frequently require the administration of vancomycin. However, despite antibiotic treatment, mortality of patients with postoperative infections remains high and might be related to an impaired penetration of anti-infective agents to target tissues. Therefore, the present study was designed to measure vancomycin tissue concentrations in six diabetic and six nondiabetic patients after cardiac surgery. Vancomycin was administered as a continuous intravenous infusion at an infusion rate of 80 to 120 mg/h. Vancomycin concentrations in soft tissues and plasma were measured in all patients during steady state as “therapeutic window” concentrations in plasma by microdialysis on day 8 ± 4 after initiation of vancomycin treatment. Vancomycin tissue concentrations in diabetic patients were significantly lower than in nondiabetics (3.7 mg/liter versus 11.9 mg/liter; P = 0.002). The median vancomycintissue/vancomycinplasma concentration ratio was 0.1 in diabetic patients and 0.3 in nondiabetics (P = 0.002). Our study demonstrated that vancomycin penetration into target tissues is substantially impaired in diabetic patients versus nondiabetics. Insufficient tissue concentrations could therefore possibly contribute to failure of antibiotic treatment and the development of antimicrobial resistance in diabetic patients.

Anakinra in two adolescent female patients suffering from colchicine-resistant familial Mediterranean fever: effective but risky.

Sir, Mutations in the pyrin gene (MEFV) cause the inflammatory disorder familial Mediterranean fever (FMF) [1]. Most of the patients are treated with colchicine for the prevention of both attacks and secondary amyloidosis. Clinical failure of colchicine treatment is seen in 5 to 10% of patients. Patients who are non-responders suffer a lot despite taking painkillers. Quite often patients are unable to manage daily life because of the disease. No treatment recommendations exist for these cases [2]. Recently, two case reports concerning treatment of colchicine-resistant FMF patients with anakinra were published [3,4]. Anakinra is an interleukin-1 (Il-1) receptor antagonist. Il-1 is a major proinflammatory cytokine that is increased in activity by pyrin, which is shown to be elevated in FMF [5,6]. Since knowledge about the efficacy and tolerance of anakinra is rare we herein present two case studies of patients treated with it. Case 1: A 29-year old Turkish woman with positive personal and family FMF history was visiting our outpatient clinic in March 2007 because of recurrent FMF attacks associated with severe abdominal pain and fever. FMF was previously diagnosed in this patient in Turkey when she was 13 years of age. She had been taking colchicine tablets for several years but in the last year the attack rate had increased and she had typical symptoms every week. During the onset of symptoms she took a large amount of different painkillers, which had no effect. Despite an increased dosage of colchicine (1·5 mg d –1 ), she had elevated inflammation signs [C-reactive protein (CRP): 90·5 mg L –1 , normal: 0–10 mg L –1 ; serum amyloid A (SAA): 626 mg L –1 , normal: < 5 mg L –1 ]. Her serum creatinine level was 0·71 mg dL –1 and no proteinuria was detected. Because of her poor quality of life caused by the recurrent attacks we decided to try anakinra treatment. After informing the patient about the potential side effects and the empirical aspects of the therapy, treatment was started with 100 mg anakinra administered subcutaneously every day. Before administration a quantiFERON-TB Gold test was performed which showed a negative result. After eight days of anakinra treatment the patient was symptom free and after three weeks the inflammatory parameters almost normalised (Fig. 1). The administration of colchicine was not interrupted at any time point. Three weeks after the start of treatment, administration of anakinra was stopped because the patient was feeling well and it was assumed that continuing with colchicine would prolong the attack rate. After 4 days the patient came to our outpatient department again and was complaining of severe abdominal pain. The inflammation parameters were also elevated. Administration of anakrina was restarted and recovery was achieved within a few days concomitant with a decrease in the inflammation parameters. Colchicine was stopped at this time point since efficacy was missing. During the following 3 months an ‘on and off treatment’ with anakrina took place. The first time the application was stopped because the patient could not tolerate any further injections due to severe pain at the site of the injection. Her symptoms and inflammation parameters returned very quickly afterwards. The patient then decided to restart anakinra because the severity of her pain due to FMF persistently increased. Since the patient’s insurance company refused to pay for this treatment, anakinra therapy was stopped until this problem was resolved. Vienna General Hospital, Medical University of Vienna, Vienna, Austria (R. Gattringer, H. Lagler, K. B. Gattringer, S. Knapp, H. Burgmann, S. Winkler, W. Graninger, F. Thalhammer).

Influence of vancomycin on renal function in critically ill patients after cardiac surgery: continuous versus intermittent infusion.

Background:Vancomycin is frequently used in clinical practice to treat severe wound and systemic infections caused by Gram-positive bacteria after cardiac surgery. The drug is excreted almost entirely by glomerular filtration and might exhibit nephrotoxic side effects. This study compared the nephrotoxic impact of vancomycin during continuous versus intermittent administration. Methods:The authors analyzed 149 patients admitted to the intensive care unit during a 5-yr period. All patients were treated at the intensive care unit after elective open heart surgery. Thirty patients received a dosage of 1325 ± 603 mg/d vancomycin (range 300–3400 mg/d) by intermittent infusion, and 119 patients received a mean dosage of 1935 ± 688 mg/d (range 352–3411 mg/d) by continuous infusion. Results:Nephrotoxicity occurred in 11 patients (36.7%) in the intermittent treatment group and in 33 patients (27.7%) in the continuous treatment group (P = 0.3; 95% CI = 0.283). Continuous veno-venous hemofiltration after vancomycin administration was required for 9 patients (9 of 30; 30%) in the intermittent treatment group and for 28 (28 of 119; 23.5%) in the continuous treatment group (P = 0.053; 95% CI = 0.256). A change of one unit (1 mg/l) in vancomycin serum concentration (&Dgr;VancoC) induced an average change of 0.04 mg/dl in creatinine (&Dgr;Crea) in the intermittent treatment group versus 0.006 mg/dl in the continuous treatment group (P < 0.001). Conclusions:The data show that both the intermittent and also the continuous application modality of vancomycin are associated with deterioration of renal function in critically ill patients after cardiac surgery. However, continuous infusion showed the tendency to be less nephrotoxic than the intermittent infusion of vancomycin.

Natural Genetic Transformation of Clinical Isolates of Escherichia coli in Urine and Water

ABSTRACT Transfer of plasmid-borne antibiotic resistance genes in Escherichia coli wild-type strains is possible by transformation under naturally occurring conditions in oligotrophic, aquatic environments containing physiologic concentrations of calcium. In contrast, transformation is suppressed in nitrogen-rich body fluids like urine, a common habitat of uropathogenic strains. Current knowledge indicates that transformation of these E. coli wild-type strains is of no relevance for the acquisition of resistance in this clinically important environment.

Pharmacokinetics of Meropenem in Patients with Renal Failure and Patients Receiving Renal Replacement Therapy

Meropenem is a well established carbapenem antibacterial with a wide spectrum of activity against Gram-positive and Gram-negative bacteria, including β-lactamase producers and Pseudomonas aeruginosa. Because of its clinical and bacteriological efficacy, meropenem is an important antimicrobial drug in the treatment of serious infections in adults and in children.Meropenem is predominately excreted unchanged in the urine, and thus dosage adjustments are necessary in patients with renal insufficiency and those undergoing intermittent haemodialysis (IHD) or various forms of continuous renal replacement therapy (CRRT), such as continuous venovenous haemodialysis, continuous venovenous haemodiafiltration (CVVHDF), continuous venovenous haemofiltration (CVVHF) or continuous ambulatory peritoneal dialysis (CAPD).The half-life of meropenem (approximately 1 hour in healthy volunteers) is prolonged up to 13.7 hours in anuric patients with end-stage renal disease. In patients receiving renal replacement therapy, half-life is influenced by drug-specific factors as well by membrane and treatment modalities (IHD, CRRT or CAPD). Plasma meropenem concentrations reach a peak of between 53 and 62 mg/L after the administration of meropenem 1g intravenously to healthy volunteers, up to 53 mg/L after meropenem 0.5g in haemodialysis patients, and between 18 and 45 mg/L after meropenem 1g during CRRT in critically ill patients.Approximately 50% of meropenem is eliminated by IHD, 25 to 50% by CVVHF and 13 to 53% by CVVHDF. Such differences are not negligible and demonstrate the great influence of the treatment modality on the elimination of the drug during renal replacement therapy. Thus, physicians run the risk of underdosing with this antimicrobial drug because of the quite different recommendations in the literature. Because of the excellent tolerability profile of meropenem, such underadministration should be avoided.

Serum protein concentrations in Plasmodium falciparum malaria.

In patients with uncomplicated Plasmodium falciparum infection cytokine-mediated serum protein levels of C-reactive protein (CRP), coeruloplasmin (COE), beta 2-microglobulin (B2M), alpha 1-acid glycoprotein (AAG), alpha 1-antitrypsin (AAT), haptoglobin (HPT), prealbumin (PRE), retinol binding protein (RBP), albumin (ALB) and transferrin (TRF) were measured in an endemic area of the Amazonian rain forest. Semi-immune (SI) and nonimmune (NI) patients were investigated. In both patient groups the serum concentrations of CRP, COE and B2M were elevated on admission. In addition AAG and AAT concentrations were increased in NI patients compared to control subjects. Significantly lower serum concentrations of HPT, PRE, RBP, ALB and TRF were seen in both patient groups during the acute phase of the disease, and were more pronounced in NI patients. After a 28-day follow-up, AAT and B2M were normal in SI patients but HPT, AAT and B2M were still significantly altered in NI patients.

Hepatotoxicity of antibacterials: pathomechanisms and clinical data.

Drug-induced hepatotoxicity is a frequent cause of liverdisease and acute liver failure, particularly in patients treatedwith multiple drugs. Several antibacterial drugs have thepotential to cause severe liver injury and failure. This articleaims to increase the awareness and understanding of druginducedliver injury (DILI) due to antibacterial drugs. Itreviews the pattern of antibacterial DILI and provides detailson molecular mechanisms and toxicogenomics, as well asclinical data based on epidemiology studies. Certain antibacterialdrugs are more frequently linked to hepatotoxicity thanothers. Therefore, the hepatotoxic potential of tetracyclines,sulfonamides, tuberculostatic agents, macrolides, quinolones,and beta-lactams are discussed in more detail. Efforts toimprove the early detection of DILI and the acquisition ofhigh-quality epidemiological data are pivotal for increasedpatient safety.

How to Calculate Clearance of Highly Protein-Bound Drugs during Continuous Venovenous Hemofiltration Demonstrated with Flucloxacillin

Background: Flucloxacillin is an important antimicrobial drug in the treatment of infections with Staphylococcus aureus and therefore is often used in staphylococcal infections. Furthermore, flucloxacillin has a high protein binding rate as for example ceftriaxone or teicoplanin – drugs which have formerly been characterized as not being dialyzable. Methods: The pharmacokinetic parameters of 4.0 g flucloxacillin every 8 h were examined in 10 intensive care patients during continuous venovenous hemofiltration (CVVH) using a polyamide capillary hemofilter. In addition, the difficulty of calculating the hemofiltration clearance of a highly protein-bound drug is described. Results: Flucloxacillin serum levels were significantly lowered (56.9 ± 24.0%) even though only 15% of the drug was detected in the ultrafiltrate. Elimination half-life, total body clearance and sieving coefficient were 4.9 ± 0.7 h, 117.2 ± 79.1 ml/min and 0.21 ± 0.09, respectively. These discrepancies can be explained by the high protein binding of flucloxacillin, the adsorbing property of polyamide and the equation in order to calculate hemofiltration clearance. The unbound fraction of a 4.0 g flucloxacillin dosage facilitates time above the minimum inhibitory concentration (T > MIC) of 60% only for strains up to a minimum inhibitory concentration (MIC) of 0.5 mg/l. Conclusion: Based on the data of this study, we conclude that intensive care patients with staphylococcal infections on CVVH should be treated with 4.0 g flucloxacillin every 8 h which was safe and well tolerated. Moreover, further studies with highly protein-bound drugs are recommended to check the classical ‘hemodialysis’ equation as the standard equation in calculating the CVVH clearance of highly protein-bound drugs.

Disseminated intravascular coagulation (DIC) and rhabdomyolysis in fulminant varicella infection: Case report and review of the literature

SummaryPrimary infection with varicella-zoster virus usually is a mild, self-limiting childhood illness. However, certain rare but potentially life-threatening complications can be associated with the disease. Adults and immunosuppressed patients are at increased risk for these events. We report a case of a patient on chronic immunosuppressants with fulminant varicella infection complicated by rhabdomyolysis and disseminated intravascular coagulation. Mechanisms of muscle damage in viral diseases might be direct invasion of skeletal muscle and/or induction of harmful cytokines. Aggressive fluid therapy, alkalinization of urine and supportive measures correcting electrolyte imbalances, hypothermia and hypoxemia should result, in preservation or complete restoration of renal function. Disseminated intravascular coagulation occurs in conjunction with various diseases and may range from mild laboratory abnormalities to fulminant lethal thrombosis and bleeding. Apart from elimination of the causative process therapeutic strategies are still highly disputed.