F. Javier Belda

Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration

BACKGROUND Anidulafungin is indicated as a first-line treatment for invasive candidiasis in critically ill patients. In the intensive care unit, sepsis is the main cause of acute renal failure, and treatment with continuous renal replacement therapy (CRRT) has increased in recent years. Antimicrobial pharmacokinetics is affected by CRRT, but few studies have addressed the optimal dosage for anidulafungin during CRRT. PATIENTS AND METHODS We included 12 critically ill patients who received continuous venovenous haemodiafiltration to treat acute renal failure. Anidulafungin was infused on 3 consecutive days, starting with a loading dose (200 mg) on Day 1, and doses of 100 mg on Days 2 and 3. Blood and ultradiafiltrate samples were collected on Day 3 (during steady-state) before, and at regular intervals after, the infusion had started. Anidulafungin concentrations were determined with HPLC. RESULTS On Day 3, peak plasma concentrations with the 100 mg dose were 6.2 ± 1.7 mg/L and 7.1 ± 1.9 mg/L in the arterial and venous samples, respectively. The mean, pre-filter trough concentration was 3.0 ± 0.6 mg/L. The mean AUC0-24 values for plasma anidulafungin were 93.9 ± 19.4 and 104.1 ± 20.3mg·h/L in the arterial and venous samples, respectively. There was no adsorption to synthetic surfaces, and the anidulafungin concentration in the ultradiafiltrate was below the limit of detection. CONCLUSION The influence of CRRT on anidulafungin elimination appeared to be negligible. Therefore, we recommend no adjustments to the anidulafungin dose for patients receiving CRRT.

Postoperative Pulmonary Dysfunction and Mechanical Ventilation in Cardiac Surgery

Postoperative pulmonary dysfunction (PPD) is a frequent and significant complication after cardiac surgery. It contributes to morbidity and mortality and increases hospitalization stay and its associated costs. Its pathogenesis is not clear but it seems to be related to the development of a systemic inflammatory response with a subsequent pulmonary inflammation. Many factors have been described to contribute to this inflammatory response, including surgical procedure with sternotomy incision, effects of general anesthesia, topical cooling, and extracorporeal circulation (ECC) and mechanical ventilation (VM). Protective ventilation strategies can reduce the incidence of atelectasis (which still remains one of the principal causes of PDD) and pulmonary infections in surgical patients. In this way, the open lung approach (OLA), a protective ventilation strategy, has demonstrated attenuating the inflammatory response and improving gas exchange parameters and postoperative pulmonary functions with a better residual functional capacity (FRC) when compared with a conventional ventilatory strategy. Additionally, maintaining low frequency ventilation during ECC was shown to decrease the incidence of PDD after cardiac surgery, preserving lung function.

Perioperative hyperoxia: the debate is only getting started.

I N this issue of ANESTHESIOLOGY, Stæhr et al. 1 report the lack of effect of perioperative hyperoxia on preventing surgical site infection (SSI) in obese patients undergoing laparotomy. The study was a secondary analysis of data from the PROXI Trial, a Danish multicenter study of 1,400 patients undergoing elective or emergency laparotomy who were randomized to receive a 30% or 80% oxygen concentration intraoperatively and for the first 2 h after surgery. Although no significant reduction in the frequency of SSI was observed in the high-concentration group in that trial, it was hypothesized that the results for the subpopulation of 213 obese patients (body mass index 30 kg/m, 15% of the sample) might be different. However, on reanalysis the researchers again found no significant differences in the rates of SSI or pulmonary complications. Surgical site infection, which accounts for 15–20% of all healthcare-associated infections, is the second most common preventable adverse outcome of major surgery. The incidence of SSI, which differs according to surgical procedure, is highest for gastrointestinal interventions. If we are to decrease the SSI rates in the various surgical settings and attenuate the consequences, it will be necessary to identify risk factors as a first step. Age, duration of surgery, hypoalbuminemia, obesity, diabetes mellitus, and a history of chronic obstructive pulmonary disease are some of the predictors that have been linked with SSI. Obesity is associated with a higher incidence of SSI. Glance et al. recently studied a population of 310,208 patients in the American College of Surgeons National Surgical Quality Improvement Program database, more than 95,000 of whom were overweight. Obese and morbidly obese patients with metabolic syndrome (obesity, hypertension, and diabetes), who accounted for 19% of all the obese patients in the study, had higher risk of postoperative complications, including death and SSI, in comparison with normal-weight and obese patients without metabolic syndrome. In addition, percentage of body fat and thickness of subcutaneous fat have been shown to be better predictors of SSI than body mass index, suggesting that obesity is not a homogeneous clinical state and body mass index may be too simplistic a measure for this complex illness. In other words, individuals classified as obese may be more or less healthy and have different levels of risk. In recent years, interest has grown in identifying factors amenable to management to reduce the risk of SSI, and anesthesiologists may have partial control over some of them. Measures such as the avoidance of hypothermia and the careful timing and selection of antibiotics seem to be effective in preventing SSI. The rationale for proposing hyperoxia as another manageable factor for preventing SSI is well established. Neutrophils safeguard against infection through nonspecific phagocytosis and elimination of bacteria from wounds; the oxygen tension in subcutaneous tissue is critical for these functions. Tissue oxygen tension and concentration have been shown to predict SSI after colorectal surgery, and supplemental oxygen (e.g., 80%) can double oxygen partial pressure in tissue. In vitro studies have shown that hyperoxia exerts significant influence on multiple cellular and immune system parameters, improving the functional capacity of the innate immune response as reflected by increasing concentrations of reactive oxygen species, a major component of the bactericidal defense. Adequate wound oxygen tension is also important in the development of collagen and epithelium required for healing. Hyperoxia increases the availability of molecular oxygen to tissues by increasing oxygen dissolved in plasma and enhancing the driving force between capillary blood and cells. Achieving a subcutaneous oxygen tension greater than 90 mmHg seems to protect against infection, and at least 40 mmHg would be needed to support the leukocyte-mediated oxidative burst and collagen formation. Good capillary perfusion of tissue also determines cell oxygenation, and helpful actions that can be managed by anesthesiologists are fluid replacement and the avoidance of vasoconstriction triggered by activation of the sympathetic nervous system by hypothermia and pain. However, all actions intended to increase cell oxygen tension can be offset if tissue perfusion is compromised (e.g., in diabetes or peripheral vascular disease) or when the oxygen pressure gradient along the axial capillary drops rapidly. The results of the clinical translation of this rationale, in controlled trials testing perioperative hyperoxia, have been mixed. Two randomized trials comparing 30% and 80% oxygen in a total of almost 800 patients undergoing colorectal surgery reported significant reductions in the rate of SSI. A large trial to test the effect of nitrous oxide on events after major surgery indirectly compared high (80%) and low (30%) oxygen concentrations and found significantly fewer cases of SSI in patients breathing the high concentration. In contrast, 165 patients undergoing major

The accuracy of the anesthetic conserving device (AnaConDa©) as an alternative to the classical vaporizer in anesthesia.

BACKGROUND: The Anesthetic Conserving Device—AnaConDa® (ACD)—has been compared with a conventional vaporizer. However, the accuracy of the administered concentration of volatile anesthetics was not examined. In the present study we measured the accuracy of the ACD when used as a portable vaporizer. METHODS: This prospective study included 30 ASA I–III patients scheduled for elective surgery under general anesthesia. The patients were randomly organized into 3 groups of 10 patients per group. In each group, the sevoflurane infusion rate was adjusted to deliver 1.0 vol%, 1.5 vol%, and 2.0 vol% alveolar concentration. Hemodynamic data, bispectral index, and end-tidal sevoflurane concentrations were recorded every 2 minutes. RESULTS: We analyzed 801 data points from 30 patients. The mean difference between the end-tidal sevoflurane concentration and the target concentration was −11.0 ± 9.3% of the target when the target was 1.0 vol%, −5.4 ± 6.4% when the target was 1.5 vol%, and −4.0 ± 7.4% when the target was 2.0 vol%. No significant differences were found in the error at the different target concentrations. CONCLUSIONS: We found that the ACD may be a valid alternative to the conventional vaporizer. The ACD is very simple to use, delivery rate needs to be adjusted only once per hour, and the anesthetic savings are independent of the circuit characteristics and fresh gas flow rate.

Adaptive support ventilation for gynaecological laparoscopic surgery in Trendelenburg position: bringing ICU modes of mechanical ventilation to the operating room.

Background and objective The aim of the present study was to test the efficacy of adaptive support ventilation (ASV) to automatically adapt the ventilatory settings to the changes in the respiratory mechanics that occur during pneumoperitoneum and Trendelenburg position in gynaecological surgeries. Methods We prospectively studied 22 ASA I women scheduled for gynaecological laparoscopic surgery in the Trendelenburg position. After intravenous induction of general anaesthesia, patients were ventilated with ASV, a closed-loop mode of mechanical ventilation based on the Otis formula, designed to automatically adapt the ventilatory settings to changes in the patients respiratory system mechanics, while maintaining preset minute ventilation. Respiratory mechanics variables, ventilatory setting parameters and analysis of blood gases were recorded at three time points: 5 min after induction (baseline), 15 min after pneumoperitoneum and Trendelenburg positioning (Pneumo-Trend) and 15 min after pneumoperitoneum withdrawal (final). Results A reduction of 44.4% in respiratory compliance and an increase of 29.1% in airway resistance were observed during the Pneumo-Trend period. Despite these changes in respiratory mechanics, minute ventilation was kept constant. ASV adapted the ventilatory settings by automatically increasing inspiratory pressure by 3.2 ± 0.9 cmH2O (+19%), P < 0.01, respiratory rate by 1.3 ± 0.5 breaths per minute (+9%) and the inspiratory to total time ratio (Ti/Ttot) by 43.3%. At final time, these parameters returned towards their baseline values. Adequate gas exchange was maintained throughout all periods. PaCO2 increased moderately (+13%) from 4.4 ± 0.6 (baseline) to 5.0 ± 0.9 kPa (Pneumo-Trend), P < 0.01; and decreased slightly at final time (4.7 ± 0.8 kPa), P < 0.05. Clinicians intervention was needed in only one patient who showed a moderate hypercapnia (PaCO2 6.9 kPa) during pneumoperitoneum. Conclusion In healthy women undergoing gynaecologic laparoscopy, ASV automatically adapted the ventilatory settings to the changes in the respiratory mechanics, keeping constant the preset minute ventilation, providing an adequate exchange of respiratory gases and obviating clinicians interventions.

WHO Needs High FIO2

World Health Organization and the United States Center for Disease Control have recently recommended the use of 0.8 FIO2 in all adult surgical patients undergoing general anaesthesia, to prevent surgical site infections. This recommendation has arisen several discussions: As a matter of fact, there are numerous studies with different results about the effect of FIO2 on surgical site infection. Moreover, the clinical effects of FIO2 are not limited to infection control. We asked some prominent authors about their comments regarding the recent recommendations.

Pharmacokinetics of anidulafungin during albumin dialysis

In the ICU setting, current guidelines recommend echi-nocandins as the first-line treatment for invasive candi-diasis [1]. Albumin dialysis (AD) has been used in theICU as supportive therapy for hepatic failure, but thistechnique can significantly enhance drug elimination [2].We prescribed anidulafungin for suspected invasivecandidiasis in a patient with severe liver failure treatedwith AD and measured the plasma concentrations of thedrug using high-performance liquid chromatography.This study (GEF-ANI-2010-02) was approved by thelocal ethics committee (INCLIVA, Institute of Research,Valencia, Spain) and written informed consent wasobtained from the patient’s next of kin. An adult patientwas admitted to our ICU with acute liver failure aftermajor hepatectomy for metastasis. The patient was givenanidulafungin (200 mg loading dose on day 1, followedby 100 mg daily) for suspected invasive candidiasis. Onthe fourth day, the patient developed encephalopathyand complained of increasing pruritus. AD using theMolecular Adsorbent Recirculating System (GambroHospal AG, Zurich, Switzerland) was therefore startedwhile waiting for liver function to improve. Arterialblood, urine, and dialysate samples were collected atdifferent times after the first AD session was initiated:before starting the fourth anidulafungin infusion and at0.5, 1, 1.5, 2, 4, 6, and 8 hours after starting the infusion.The last samples (8 hours) were obtained when AD wasfinished. Anidulafungin was well tolerated withoutrelevant adverse effects.The following pharmacokinetic parameters were calcu-lated: area under the concentration curve from 0 to 8 hoursusing the linear trapezoidal rule, and the eliminationhalf-life with noncompartmental analysis. The values forthe peak plasma concentration, the through plasma con-centration, and the time to reach the peak plasma concen-tration were calculated from the observed values (Figure 1).Plasma, urine, and dialysate samples were analysed.The limit of quantification was 0.5 mg/l. No anidulafun-gin levels were measurable in the ultradiafiltrate andurine samples. The peak plasma concentration with the100 mg dose on day 4 was 9.45 mg/l (Figure 1).Only two reports regarding the use of antifungals duringAD were found in the literature, demonstrating that theinfluence of this technique on drug elimination appeared tobe negligible [3,4]. We report the first pharmacokineticstudy of anidulafungin during AD. Although the mainlimitation of our study is the enrolment of only one patientand the sampling being no more than 8 hours, AD appearsto have little influence on the pharmacokinetics of anidula-fungin and an adjustment of the drug dose is probably notrequired. However, further research is needed to confirmour findings.

Extravascular Lung Water Does Not Increase in Hypovolemic Patients after a Fluid-Loading Protocol Guided by the Stroke Volume Variation

Introduction. Circulatory failure secondary to hypovolemia is a common situation in critical care patients. Volume replacement is the first option for the treatment of hypovolemia. A possible complication of volume loading is pulmonary edema, quantified at the bedside by the measurement of extravascular lung water index (ELWI). ELWI predicts progression to acute lung injury (ALI) in patients with risk factors for developing it. The aim of this study was to assess whether fluid loading guided by the stroke volume variation (SVV), in patients presumed to be hypovolemic, increased ELWI or not. Methods. Prospective study of 17 consecutive postoperative, fully mechanically ventilated patients diagnosed with circulatory failure secondary to presumed hypovolemia were included. Cardiac index (CI), ELWI, SVV, and global end-diastolic volume index (GEDI) were determined using the transpulmonary thermodilution technique during the first 12 hours after fluid loading. Volume replacement was done with a strict hemodynamic protocol. Results. Fluid loading produced a significant increase in CI and a decrease in SVV. ELWI did not increase. No correlation was found between the amount of fluids administered and the change in ELWI. Conclusion. Fluid loading guided by SVV in hypovolemic and fully mechanically ventilated patients in sinus rhythm does not increase ELWI.

Pharmacokinetics of anidulafungin during venovenous extracorporeal membrane oxygenation

Echinocandins are currently considered the first-line treatment for invasive candidiasis (IC) in the intensive care unit (ICU) [1, 2]. However, extracorporeal membrane oxygenation (ECMO), a rescue therapy used in patients with severe acute respiratory distress syndrome (ARDS) [3], could alter the pharmacokinetics of certain drugs [4]. We prescribed anidulafungin for suspected IC in a patient with severe ARDS on ECMO and measured the plasma concentrations of the drug using high-performance liquid chromatography (HPLC).

Optimal doses of caspofungin during continuous venovenous hemodiafiltration in critically ill patients

The aim of the present study was to describe the pharmacokinetics of caspofungin in 12 critically ill adult patients with suspected or proven invasive candidiasis who were receiving continuous venovenous hemodiafiltration (CVVHD). CVVHD was performed using a polysulfone hemofilter (Fresenius, Germany). Caspofungin was administered at usual doses. Pre-filter and post-filter blood, ultradiafiltrate, and urine samples were collected at steady state on day 3 or later, before the dose infusion started, and 0.5, 1, 1.5, 2, 4, 6, 8, and 24 h after the infusion ended. The drug concentrations were measured by high performance liquid chromatograpy (HPLC) and the following pharmacokinetic parameters were calculated: area under the concentration-time curve (AUC0-24h), elimination t1/2, volume of distribution (Vd), clearance, trough concentration (Ctrough), and maximum concentration (Cmax). The results of our study are summarized in Tables 1 and 2 and Fig. 1. Caspofungin was negligible in the ultradiafiltrate and urine samples, confirming the lack of drug elimination through hemofiltration or hemodialysis. Similar findings were previously described by Weiler et al. [1]. Additionally, the mean concentration of caspofungin was slightly higher in the post-filter line than in the pre-filter line (Fig. 1), allowing us to rule out the adsorption to the filter hypothesized in other studies with echinocandins [2, 3]. In four patients (33%), the trough concentration of caspofungin was lower than the MIC90s published for Candida and Aspergillus spp., including Candida parapsilosis (2 mg/L) [4]. On the other hand, among echinocandins, micafungin has been associated with 1 log kill/24 h in a murine model of disseminated candidiasis when an AUC/MIC of 865, 450, or 1185 is achieved for Candida albicans, Candida glabrata, or C. parapsilosis, respectively [5]. Taking into account a MIC of 0.1 mg/L [4], and using the target pharmacokinetics/pharmacodynamics (PK/PD) described for micafungin, we would have reached this concentration in only nine patients (75%, AUC > 86.5 mg h/L) for C. albicans and four patients (33%, AUC > 118.5 mg h/L) for C. parapsilosis but all patients for C. glabrata (AUC > 45 mg h/L) (Table 2). These data suggest that caspofungin dosing could be insufficient in some critically ill patients. In conclusion, CVVHD appears to have a negligible effect on caspofungin clearance. However, the licensed regimen of caspofungin was not adequate to reach the PK/PD targets in some critically ill patients, regardless of the use of CVVHD. Nevertheless, future studies are needed to confirm these findings.