Emile F. Schippers

Infectious Complications of Central Venous Catheters Increase the Risk of Catheter-Related Thrombosis in Hematology Patients: A Prospective Study

PURPOSE We studied whether the risk of central venous catheter (CVC) -related thrombosis increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Secondly, we determined whether thrombosis can be predicted or excluded by CVC lock fluid surveillance cultures. PATIENTS AND METHODS In a prospective setting, 105 consecutive patients were carefully examined for CVC-related infection and thrombosis. In all patients, microbial surveillance cultures of CVC lock fluid were taken every other day. All patients with clinical suspicion of CVC-related thrombosis underwent Doppler ultrasound or additional venography. RESULTS The cumulative incidence of CVC-related infection was 24% (25 of 105 patients). Clinically manifest thrombosis occurred in 13 (12%) of 105 patients. In patients with CVC-related infection, the risk of thrombosis increased markedly in comparison to those without infection (relative risk, 17.6; 95% CI, 4.1 to 74.1). In patients having two or more positive subsequent CVC lock fluid cultures with identical micro-organisms, 71.4% developed thrombosis, as compared with 3.3% in patients with negative or a single positive culture. CONCLUSION The risk of clinically manifest thrombosis is increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Surveillance culturing of CVC lock fluid may be clinically useful in estimating the risk for thrombosis and the instigation of focused early intervention.

No effect of preoperative selective gut decontamination on endotoxemia and cytokine activation during cardiopulmonary bypass: A randomized, placebo-controlled study

Background Cardiopulmonary bypass predisposes the splanchnic region to inadequate perfusion and increases in gut permeability. Related to these changes, circulating endotoxin has been shown to rise during cardiac surgery, and may contribute to cytokine activation, high oxygen consumption, and fever (“postperfusion syndrome”). To a large extent, free endotoxin in the gut is a product of the proliferation of aerobic Gram-negative bacteria and may be reduced by nonabsorbable antibiotics. Objective. To evaluate the effect of preoperative selective gut decontamination (SGD) on the incidence of endotoxemia and cytokine activation in patients undergoing open heart surgery. Design Prospective, randomized, placebo-controlled double-blind trial. Setting Tertiary-care university teaching hospital. Intervention Preoperative administration for 5 to 7 days of oral nonabsorbable antibiotics (polymyxin B and neomycin) vs. placebo. The efficacy of SGD was assessed by culture of rectal swabs. Patients Forty-four patients (median age 65 yrs, 29 males) were included in a pilot study to establish the sampling points of perioperative measurements. Seventy-eight consecutive patients (median age 65 yrs, 55 males) were enrolled for the prospective study; of these, 51 were randomly allocated to take SGD (n = 24) or placebo (n = 27); 27 were included in a control group (no medication). Measurements and Results SGD but not placebo effectively reduced the number of rectal swabs that grew aerobic Gram-negative bacteria (27% vs. 93%, respectively;p < .001). SGD did not affect the occurrence of perioperative endotoxemia, nor did it reduce the tumor necrosis factor-&agr;, interleukin-10, or interleukin-6 concentrations (p > .20), as determined before surgery, upon aorta declamping, 30 mins into reperfusion, or 2 hrs after surgery. Also, SGD did not alter the incidence of postoperative fever or clinical outcome measures such as duration of artificial ventilation and intensive care unit and hospital stay. Conclusion SGD effectively reduces the aerobic Gram-negative bowel flora in cardiac surgery patients but fails to affect the incidence of perioperative endotoxemia and cytokine activation during cardiopulmonary bypass and the occurrence of a postperfusion syndrome.

Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in Gram-negative sepsis

Gram‐negative sepsis is a major death cause in intensive care units. Accumulating evidence indicates the protective role of plasma lipoproteins such as high‐density lipoprotein (HDL) in sepsis. It has recently been shown that septic HDL is almost depleted from apolipoprotein CI (apoCI), suggesting that apoCI may be a protective factor in sepsis. Sequence analysis revealed that apoCI possesses a highly conserved consensus KVKEKLK binding motif for lipopolysaccharide (LPS), an outer‐membrane component of Gram‐negative bacteria. Through avid binding to LPS involving this motif, apoCI improved the presentation of LPS to macrophages in vitro and in mice, thereby stimulating the inflammatory response to LPS. Moreover, apoCI dose‐dependently increased the early inflammatory response to Klebsiella pneumoniae‐induced pneumonia, reduced the number of circulating bacteria, and protected mice against fatal sepsis. Our data support the hypothesis that apoCI is a physiological protector against infection by enhancing the early inflammatory response to LPS and suggest that timely increase of apoCI levels could be used to efficiently prevent and treat early sepsis.—Berbée, J. F. P., van der Hoogt, C. C., Kleemann, R., Schippers, E. F., Kitchens, R. L., van Dissel, J. T., Bakker‐Woudenberg, I. A. J. M., Havekes, L. M., Rensen, P. C. N. Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in Gram‐negative sepsis. FASEB J. 20, E1560 –E1569 (2006)

Oral valganciclovir as pre-emptive therapy has similar efficacy on cytomegalovirus DNA load reduction as intravenous ganciclovir in allogeneic stem cell transplantation recipients.

The efficacy and safety of oral valganciclovir was compared to ganciclovir i.v. in pre-emptive treatment of cytomegalovirus (CMV) in T-cell-depleted allogeneic stem cell transplant (allo-SCT) recipients. A therapeutic guideline was developed to allow the safe application of valganciclovir in allo-SCT recipients requiring CMV therapy. In total, 107 consecutive transplant recipients were evaluated. Cytomegalovirus DNA load in plasma was monitored longitudinally; details on antiviral therapy and treatment responses were analyzed retrospectively. Fifty-seven CMV treatment episodes were recorded in 34 patients: 20 with valganciclovir (900 mg twice-daily) and 37 with ganciclovir (5 mg/kg twice-daily). Median CMV DNA load reduction was 0.079 and 0.069 log10 copies/ml/day in the ganciclovir and valganciclovir group, respectively. Good response on CMV DNA load (reduction below 3.0 log10 copies/ml) was observed in 75.7% of ganciclovir and 80.0% of valganciclovir treatment episodes. Severe adverse effects were not observed and CMV-related disease did not occur. However, the percentage of patients receiving erythrocyte transfusion was higher in the group of patients receiving ganciclovir as compared to valganciclovir (41 versus 20%, P=0.116). In conclusion, pre-emptive treatment with valganciclovir and ganciclovir, led to similar reduction of CMV DNA load. Oral valganciclovir is an attractive and safe alternative for pre-emptive CMV treatment in T-cell-depleted allo-SCT recipients.

Prevention of Coagulase-Negative Staphylococcal Central Venous Catheter–Related Infection Using Urokinase Rinses: A Randomized Double-Blind Controlled Trial in Patients With Hematologic Malignancies

PURPOSE Fibrin deposition at the intraluminal surface of the indwelling part of the central venous catheter (CVC) surface increases the risk of CVC-related coagulase-negative staphylococci (CoNS) infection. Therefore, repetitive enzymatic dissolution of fibrin by urokinase might reduce the risk of CVC-related infection. We undertook this study to investigate whether three times weekly urokinase rinsing of CVC reduces the incidence or severity of CVC-related infections by CoNS in patients undergoing intensive cytotoxic treatment for hematologic malignancies. PATIENTS AND METHODS In a double-blind setting, all consecutive patients with a CVC were randomly allocated to receive either urokinase rinses (5 mL of 5,000 U/mL) or placebo (saline), both three times weekly. RESULTS The percentage of patients with at least one positive culture with CoNS was lower in patients receiving urokinase compared with patients receiving placebo (26% v 42%, respectively; relative risk [RR] = 0.61; 95% CI, 0.39 to 0.94). Major CVC-related CoNS infection occurred less frequently in patients receiving urokinase versus placebo (1.2% v 14.1%, respectively; RR = 0.09; 95% CI, 0.01 to 0.50). Secondary complications, including CVC-related thrombosis, were observed less frequently in the urokinase group compared with the placebo group (1.3% v 9.0%, respectively; RR = 0.14; 95% CI, 0.02 to 0.82). No severe bleeding complications attributable to urokinase were observed. CONCLUSION Three times weekly urokinase rinsing reduces the incidence of CVC-related CoNS infection in patients treated with intensive cytotoxic therapy for hematologic malignancies, with acceptable safety.

Postoperative pro-adrenomedullin levels predict mortality in thoracic surgery patients: comparison with Acute Physiology and Chronic Health Evaluation IV Score*.

Objectives:Risk assessment in ICU patients using commonly used prognostic models may be influenced using different data definitions and by errors in data collection. We investigated whether a set of biomarkers (procalcitonin, MR-pro-adrenomedullin, CT-pro-endothelin-1, CT-pro-arginine vasopressin, and MR-pro-atrial natriuretic peptide), alone or as a panel, could be useful in postoperative risk assessment for hospital mortality in comparison with the Acute Physiology and Chronic Health Evaluation IV score. Design:In a prospective observational cohort study, we analyzed 800 consecutive patients undergoing elective cardiac surgery. We assessed biomarker levels on admission to the ICU and every 6 hours thereafter for 24 hours. For every postoperative time point and for every biomarker, we determined the predictive value for hospital mortality and made a comparison with the Acute Physiology and Chronic Health Evaluation IV score. Setting:Intensive care of an academic referral hospital. Patients:A total of 800 consecutive patients undergoing elective cardiac surgery. Interventions:None. Measurements and Main Results:MR-pro-adrenomedullin is a good predictor of mortality (c-statistic at time point 6 hr after admission to the ICU, 0.940; 95% CI, 0.918–0.956) and performed better than the Acute Physiology and Chronic Health Evaluation IV score (c-statistic, 0.842; 95% CI, 0.811–0.868). The c-statistic did not change significantly on the time points 6, 12, and 18 hours after admission. Using a cutoff value for proadrenomedullin taken 6 hours after admission on ICU (time point 2) of 3.2 nmol/L sensitivity was 81.8% and specificity 93.9%, the positive likelihood ratio was 13.3, positive predictive value was 31.0%, and negative predictive value was 99.4%. Patients with a MR-pro-adrenomedullin above this cutoff level had an odds ratio of 68.9 (95% CI, 22.2–213.1) for not surviving their hospital stay. The other biomarkers had less predictive power. Conclusions:In elective cardiac surgery, MR-pro-adrenomedullin measured between 6 and 18 hours after admission to the ICU is a better predictor of hospital mortality in comparison with the Acute Physiology and Chronic Health Evaluation IV score.

A case of simultaneous primary HIV-1 and CMV infections

HIV-1 and cytomegalovirus (CMV) share common routes of transmission and most HIV-infected persons are also infected by CMV. Primary infections by HIV-1 as well as by CMV may result in similar flu-like illnesses and can also present clinically as distinct mononucleosis-like syndromes. Symptoms include fever, malaise, myalgias, arthralgias, rash, headache, lethargy, sore throat, nausea, vomiting, diarrhea, and weight loss. Although both these primary infections can cause severe symptoms, these infections often pass asymptomatically or cause only mild disease. Patients with severe disease have been described in simultaneously co-infected patients (Berger et al., 1996; Bonetti et al., 1989; Raffi et al., 1990; Schindler and Neftel, 1990). We describe a patient presenting with an acute retroviral illness directly followed by an acute primary CMV infection. This is to our knowledge the first case in which close monitoring of serological and viral load measurements have been performed. A 55-year-old previously healthy man was send to our hospital with a 3-day history of a ulcerative skin eruption, a genital ulcer, headache, sore throat, and painful inguinal lymph node enlargements. He stated having infrequent, unprotected homosexual contacts, the last contact being 4 weeks before presentation. On physical examination, the temperature was 37.3 ◦C. Painful enlarged inguinal lymph nodes were found. Examination of the skin and genitalia revealed widespread nodular and papular lesions some of which showed central hemorrhagic necrosis and ulceration. Differential diagnosis of the skin eruption was secondary syphilis, leukaemia cutis, pityriasis lichenoides et varioliformis acuta and primary HIV-1 infection. Laboratory tests revealed the following values: haemoglobin 9.5 mmol/l; WBC count 4.1 × 109/l; platelet count 86 × 109/l; serum

Cytokine response to endotoxin in individuals heterozygous for the Δ32 mutation of chemokine receptor CCR5

Studies of mice with a targeted disruption of the CCR5 gene suggest that the CC chemokine receptor 5 (CCR5) is a determinant of the cytokine response to endotoxin. In humans, a naturally occurring mutation of the CCR5 gene is a 32-basepair (bp) deletion which precludes the translation of the gene into a functional transmembrane protein. To evaluate the cytokine phenotype of heterozygosity for the 32 deletion, we studied the endotoxin-stimulated release of tumor necrosis factor-alpha, Interleukin (IL)-6, IL-8, IL-10, and IL-12 in whole blood ex-vivo of healthy volunteers and patients undergoing elective cardiac bypass surgery. This operation represents a major surgical trauma associated with ischemia-reperfusion-injury and triggers a profound inflammatory response. In these patients, cytokine plasma concentrations were measured during and after cardiac surgery. No difference was found between the frequencies of the observed and expected CCR5 genotypes in the groups of individuals studied. Furthermore, no significant difference in ex-vivo or peri- and postoperative cytokine plasma concentrations was detected between CCR5 wild-type homozygotes and individuals carrying one defective CCR5 allele. Our results indicate that heterozygosity for the 32bp deletion of CCR5 is not associated with an altered cytokine response to endotoxin or to a major surgical trauma when compared with individuals homozygous for the wild-type allele.