Francesco Bruno

High Dose, Extended-Interval Colistin Administration in Critically Ill Patients: Is this the Right Dosing Strategy? A Preliminary Study

In critically ill patients with otherwise untreatable nosocomial infection due to gram-negative bacteria susceptible only to colistin, a high-dose, extended-interval colistin dosing regimen is, according to the pharmacokinetic/pharmacodynamic behavior of the drug, associated with low renal toxicity and high efficacy.

Cardiorespiratory Effects of Positive End-expiratory Pressure during Progressive Tidal Volume Reduction (Permissive Hypercapnia) in Patients with Acute Respiratory Distress Syndrome

Background In patients with acute respiratory distress syndrome (ARDS), the ventilatory approach is based on tidal volume (VT) of 10-15 ml/kg and positive end-expiratory pressure (PEEP). To avoid further pulmonary injury, decreasing VT and allowing PaCO2 to increase (permissive hypercapnia) has been suggested. Effects of 10 cmH sub 2 O of PEEP on respiratory mechanics, hemodynamics, and gas exchange were compared during mechanical ventilation with conventional (10-15 ml/kg) and low (5-8 ml/kg) VT.

A comparison between fenoldopam and low-dose dopamine in early renal dysfunction of critically ill patients*

Objective:Fenoldopam mesylate is a selective dopamine-1 agonist, with no effect on dopamine-2 and &agr;1 receptors, producing a selective renal vasodilation. This may favor the kidney oxygen supply/demand ratio and prevent acute renal failure. The aim of the study was to investigate if fenoldopam can provide greater benefit than low-dose dopamine in early renal dysfunction of critically ill patients. Design:Prospective, multiple-center, randomized, controlled trial. Setting:University and city hospital intensive care units. Patients:One hundred adult critically ill patients with early renal dysfunction (intensive care unit stay <1 wk, hemodynamic stability, and urine output ≤0.5 mL/kg over a 6-hr period and/or serum creatinine concentration ≥1.5 mg/dL and ≤ 3.5 mg/dL). Interventions:Patients were randomized to receive 2 &mgr;g/kg/min dopamine (group D) or 0.1 &mgr;g/kg/min fenoldopam mesylate (group F). Drugs were administered as continuous infusion over a 4-day period. Measurements and Main Results:Systemic hemodynamic and renal function variables were recorded daily. The two groups were well matched at enrollment for illness severity and hemodynamic and renal dysfunction. No differences in heart rate or systolic, diastolic, or mean arterial pressure were observed between groups. Fenoldopam produced a more significant reduction in creatinine values compared with dopamine after 2, 3, and 4 days of infusion (change from baseline at time 2, −0.32 vs. −0.03 mg/dL, p = .047; at time 3, −0.45 vs. −0.09 mg/dL, p = .047; and at time 4, −.041 vs. −0.09 mg/dL, p = .02, in groups F and D, respectively). The maximum decrease in creatinine compared with baseline was significantly greater in group F than group D (−0.53 ± 0.47 vs. −0.34 ± 0.38 mg/dL, p = .027). Moreover, 66% of patients in group F had a creatinine decrease >10% of the baseline value at the end of infusion, compared with only 46% in dopamine group (chi-square = 4.06, p = .04). Total urinary output during drug infusion was not significantly different between groups. After 1 day, urinary output was lower in group F compared with group D (p < .05). Conclusions:In critically ill patients, a continuous infusion of fenoldopam at 0.1 &mgr;g/kg/min does not cause any clinically significant hemodynamic impairment and improves renal function compared with renal dose dopamine. In the setting of acute early renal dysfunction, before severe renal failure has occurred, the attempt to reverse renal hypoperfusion with fenoldopam is more effective than with low-dose dopamine.

Use of N-terminal pro-brain natriuretic peptide to detect acute cardiac dysfunction during weaning failure in difficult-to-wean patients with chronic obstructive pulmonary disease.

Objective: To evaluate the utility of serial measurements of plasma N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) to detect acute cardiac dysfunction during weaning failure in difficult to wean patients with chronic obstructive pulmonary disease. Design: Prospective observational cohort study. Setting: A 14‐bed general intensive care unit in a university hospital. Patients: Nineteen patients mechanically ventilated for chronic obstructive pulmonary disease exacerbation who were difficult to wean. Interventions: None. Measurements and Main Results: Cardiac and hemodynamic variables, arterial and central venous blood gas, breathing pattern, respiratory mechanics, indexes of oxygen cost of breathing, and plasma levels of NT‐proBNP were measured and analyzed immediately before (baseline) and at the end of a spontaneous breathing trial. Eight of 19 patients (42%) were identified with acute cardiac dysfunction at the end of the weaning trial. Baseline NT‐proBNP levels were significantly higher (median 5000, interquartile range 4218 pg/mL) in these patients than in patients without evidence of acute cardiac dysfunction (median 1705, interquartile range 3491 pg/mL). Plasma levels of NT‐proBNP increased significantly at the end of the spontaneous breathing trial only in patients with acute cardiac dysfunction (median 12,733, interquartile range 16,456 pg/mL, p < .05). The elevation in NT‐proBNP at the end of the weaning trial had a good diagnostic performance in detecting acute cardiac dysfunction, as estimated by area under the receiver operating characteristic curve analysis (area under the curve 0.909, se 0.077, 95% confidence interval 0.69–0.98; p < .0001, cutoff = 184.7 pg/mL). Conclusions: Serial measurements of NT‐proBNP plasma levels provided a noninvasive manner to detect acute cardiac dysfunction during an unsuccessful weaning trial in difficult to wean patients with chronic obstructive pulmonary disease. The utility of this test as a complement of the standard clinical monitoring of the weaning trial deserves further investigation.

Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice.

Summary A combination of low doses of ziconotide and morphine, administered intrathecally, allows safe and rapid control of oral opioid–refractory malignant pain. ABSTRACT Ziconotide is a nonopioid intrathecal analgesic drug used to manage moderate to severe chronic pain. The aim of this work is to assess the safety and efficacy of intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral opioids. Patients with malignant pain refractory to high oral opioids doses with a mean visual analogue scale of pain intensity (VASPI) score of ⩾70 mm were enrolled. An IT combination therapy was administered: Ziconotide was started at a dose of 2.4 μg/day, followed by increases of 1.2 μg/day at intervals of at least 7 days, and an initial IT daily dose of morphine was calculated based on its oral daily dose. Percentage change in VASPI scores from baseline was calculated at 2 days, at 7 days, and weekly until the first 28 days. The mean percentage change of VASPI score from baseline was used for efficacy assessment. Safety was monitored based on adverse events and routine laboratory values. Twenty patients were enrolled, with a mean daily VASPI score at rest of 90 ± 7. All had a disseminated cancer with bone metastases involving the spine. The percentage changes in VASPI mean scores from baseline to 2 days, 7 days, and 28 days were 39 ± 13% (95% confidence interval [CI] = 13.61–64.49, P < .001), 51 ± 12% (95% CI = 27.56–74.56, P < .001), and 62 ± 13% (95% CI = 36.03–87.89%, P < .001), respectively. Four patients experienced mild adverse events related to the study drugs. In conclusion, an IT combination of low doses of ziconotide and morphine allows safe and rapid control of oral opioid–refractory malignant pain.

Zygomycosis in Italy: a Survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology)

Abstract The aims of the study were to analyze the clinical and epidemiological characteristics and treatments for patients who developed zygomycosis enrolled in italy during the european Confederation of medical mycology survey. This prospective multicenter study was performed between 2004 and 2007 at 49 italian Departments. 60 cases of zygomycosis were enrolled: the median age was 59.5 years (range 1-87), with a prevalence of males (70%). The majority of cases were immunocompromised patients (42 cases, 70%), mainly hematological malignancies (37). Among non-immunocompromised (18 cases, 30%), the main category was represented by patients with penetrating trauma (7/18, 39%). The most common sites of infection were sinus (35%) with/without CNS involvement, lung alone (25%), skin (20%), but in 11 cases (18%) dissemination was observed. According to EORTC criteria, the diagnosis of zygomycosis was proven in 46 patients (77%) and in most of them it was made in vivo (40/46 patients, 87%); in the remaining 14 cases (23%) the diagnosis was probable. 51 patients received antifungal therapy and in 30 of them surgical debridement was also performed. The most commonly used antifungal drug was liposomal amphotericin b (L- AmB), administered in 44 patients: 36 of these patients (82%) responded to therapy. Altogether an attributable mortality rate of 32% (19/60) was registered, which was reduced to 18% in patients treated with L-AmB (8/44). Zygomycosis is a rare and aggressive filamentous fungal infection, still associated with a high mortality rate. This study indicates an inversion of this trend, with a better prognosis and significantly lower mortality than that reported in the literature. It is possible that new extensive, aggressive diagnostic and therapeutic procedures, such as the use of L-AmB and surgery, have improved the prognosis of these patients.

Inspiratory effort and measurement of dynamic intrinsic PEEP in COPD patients: effects of ventilator triggering systems.

ObjectiveTo investigate effects of ventilator triggering systems (pressure and flow triggering: PT and FT) on measurement of dynamic intrinsic PEEP (PEEPidyn) and patient-ventilator interaction in patients with chronic obstructive pulmonary disease during weaning from mechanical ventilation.DesignProspective study.SettingMedical/surgical intensive care unit of an academic hospital.Patients and participants6 COPD patients with acute respiratory failure ready to wean.MeasurementsWe measured flow, airway opening, esophageal and gastric pressures. Minute ventilation, breathing pattern and pressure time product (PTP) of the respiratory muscles and of the diaphragm were obtained during spontaneous ventilation through a mechanical ventilator (Puritan-Bennett 7200ae). Two triggering systems, namely PT and FT, were evaluated.ResultsThe inspiratory muscles effort necessary to overcome the triggering system overestimated PEEPidyn measurement of an amount equal to 49±2 and 58±3% during respectively pressure and flow triggering. FT increased tidal volume and minute ventilation and decrease PTP/b and PTP/min of the respiratory muscles and diaphragm.ConclusionsTo correctly measure PEEPidyn, the inspiratory effort produced to overcome PEEPi and to trigger the ventilator must be discriminated. Application of flow triggering requires less effort to initiate inspiration and provide a positive end-expiratory pressure level that is able to unload the respiratory muscles by reducing PEEPi. With flow triggering higher minute ventilation are obtained in COPD patients during the weaning phase.

Colistin-associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study

BACKGROUND Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy. METHODS A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach. RESULTS Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001). CONCLUSIONS In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin.

Low respiratory rate plus minimally invasive extracorporeal Co2 removal decreases systemic and pulmonary inflammatory mediators in experimental Acute Respiratory Distress Syndrome.

Objective:The Acute Respiratory Distress Syndrome Network protocol recommends limiting tidal volume and plateau pressure; it also recommends increasing respiratory rate to prevent hypercapnia. We tested a strategy that combines the low tidal volume with lower respiratory rates and minimally invasive CO2 removal. Subjects:Ten lung-damaged pigs (instilled hydrochloride). Interventions:Two conditions randomly applied in a crossover fashion: the Acute Respiratory Distress Syndrome Network protocol and the Acute Respiratory Distress Syndrome Network protocol plus lower respiratory rate plus minimally invasive Co2 removal. A similar arterial Co2 partial pressure was targeted in the two conditions. Measurements and Main Results:Physiological parameters, computed tomography scans, plasma and bronchoalveolar lavage concentrations of interleukin-1&bgr;, interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-&agr;. During the lower respiratory rate condition, respiratory rate was reduced from 30.5 ± 3.8 to 14.2 ± 3.5 (p < 0.01) breaths/min and minute ventilation from 10.4 ± 1.6 to 4.9 ± 1.7 L/min (p < 0.01). The extracorporeal device removed 38.9% ± 6.1% (79.9 ± 18.4 mL/min) of CO2 production. During the lower respiratory rate condition, interleukin-6, interleukin-8, and tumor necrosis factor-&agr; concentrations were significantly lower in plasma; interleukin-6 and tumor necrosis factor-&agr; concentrations were lower in bronchoalveolar lavage, whereas the concentrations of the other cytokines remained unchanged. Conclusion:The strategy of lower respiratory rate plus minimally invasive extracorporeal CO2 removal was feasible and safe and, as compared with the Acute Respiratory Distress Syndrome Network protocol, reduced the concentrations of some, but not all, of the tested cytokines without affecting respiratory mechanics, gas exchange, and hemodynamics.

Candida Colonization Index in Patients Admitted to an ICU

Multiple-site colonization with Candida spp. is commonly recognized as a risk factor for invasive fungal infection in critically ill patients. We carried out a study to determine the relationship between Candida colonization and invasive infection in neurological patients admitted to an ICU. At admission (T0) and every three days for two weeks, different samples (pharynx swab, tracheal secretions, stomach contents, etc.) were collected for mycological surveillance. Candida mannan antigen and Candida anti-mannan antibodies were assayed. The Colonization Index (CI) and Corrected Colonization Index were calculated for each time point. Of all patients 70% was already colonized by Candida spp. at T0 and six of them had CI ≥ 0.5. Three patients developed candidemia; they had CI ≥ 0.5 before infection. Positive values of Candida mannan antigen and anti-mannan antibodies were found only in the patients with candidemia. The sensitivity and specificity of the Candida mannan test were 66.6% and 100%, respectively, while the sensitivity and specificity of the anti-mannan antibody test were 100%. In accordance with other authors, we find the surveillance cultures are useful to monitor the Candida colonization in ICU patients. In addition, the sequential observation of anti-mannan antibodies could contribute to early diagnosis of candidiasis more than Candida mannan antigen in immunocompetent patients.