Population Pharmacokinetic Model and Optimal Sampling Strategies for Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis.

Candida bloodstream infections are associated with high attributable mortality, where early initiation of adequate antifungal therapy is important to increase survival in critically ill patients. The exposure variability of micafungin, a first-line agent used for the treatment of invasive candidiasis, in critically ill patients is significant, potentially resulting in underexposure in a substantial portion of these patients. The objective of this study was to develop a population pharmacokinetic model including appropriate sampling strategies for assessing micafungin drug exposure in critically ill patients to support adequate area under the concentration-time curve (AUC) determination. A two-compartment pharmacokinetic model was developed using data from intensive care unit (ICU) patients (n = 19), with the following parameters: total body clearance (CL), volume of distribution of the central compartment (V1), inter-compartmental clearance (CL12), and volume of distribution of the peripheral compartment (V2). The final model was evaluated with bootstrap analysis and the goodness-of-fit plots for the population and individual predicted micafungin plasma concentrations. Optimal sampling strategies (with sampling every hour, 24 h per day) were developed with 1- and 2-point sampling schemes. Final model parameters (±SD) were: CL = 1.03 (0.37) (L/h/1.85 m2), V1 = 0.17 (0.07) (L/kg LBMc), CL12 = 1.80 (4.07) (L/h/1.85 m2), and V2 = 0.12 (0.06) (L/kg LBMc). Sampling strategies with acceptable accuracy and precision were developed to determine the micafungin AUC. The developed model with optimal sampling procedures provides the opportunity to achieve quick optimization of the micafungin exposure from a single blood sample using Bayesian software and may be helpful in guiding early dose decision-making.

Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients.

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (Cmin). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

Short- and long-term complications of surgical and percutaneous dilatation tracheotomies: a large single-centre retrospective cohort study.

OBJECTIVES: The aim of this study was to determine and compare the incidence of long- and short-term complications of percutaneous dilatation tracheotomies (PDT) and surgical tracheotomies (ST). DESIGN: A single-centre retrospective study. PARTICIPANTS: 305 patients undergoing a tracheotomy (PDT or ST) in the University Medical Center Groningen from 2003 to 2013 were included. Data were gathered from patient files. MAIN OUTCOME MEASURES: Short-term and long-term complications including tracheal stenosis. RESULTS: The incidence of short- and long-term complications, including tracheal stenosis, was similar in both groups. Analysis of a small high-risk subgroup showed no difference in long-term complications. CONCLUSIONS: The rate of short- and long-term complications, including tracheal stenosis, is equal in PDT and ST. PDT is a safe alternative for ST in selected patients.

Times are A-Changin': self-poisoning and ICU admissions in the northern part of the Netherlands.

INTRODUCTION: We noticed that fewer patients with self-poisoning were transferred from the ED to the Intensive Care Unit (ICU) than previously. To objectify this, we evaluated ED and ICU admissions in two time periods. METHODS: The number of admissions was collected during 1994-1998 and 2010-2014. As a sample survey, full records of patients with an intoxication from January 2010 till December 2010 were studied. RESULTS: From 2010-2014 26 patients/year were admitted from the ED to the ICU; from 1994-1998 51 patients/year (p=0.0001). In 2010, 270 patients presented to our ED; 31 were admitted to the ICU; 1 patient died. Time spent in the ED was 236 min for patients who went home, 290 min for patients who went to a nursing ward and 185 minutes for patients transferred to the ICU. CONCLUSION: We found indeed fewer ICU admissions in recent years. Changing work routines - a longer observation period in the ED, causing a workload shift from the ICU to the ED, more than changing patient or drug characteristics, may be the cause for this development.

A Systematic Review of the Effects of Hyperoxia in Acutely Ill Patients: Should We Aim for Less?

INTRODUCTION: Despite widespread and liberal use of oxygen supplementation, guidelines about rational use of oxygen are scarce. Recent data demonstrates that current protocols lead to hyperoxemia in the majority of the patients and most health care professionals are not aware of the negative effects of hyperoxemia. METHOD: To investigate the effects of hyperoxemia in acutely ill patients on clinically relevant outcomes, such as neurological and functional status as well as mortality, we performed a literature review using Medline (PubMed) and Embase. We used the following terms: hyperoxemia OR hyperoxemia OR ["oxygen inhalation therapy" AND (mortality OR death OR outcome OR survival)] OR [oxygen AND (mortality OR death OR outcome OR survival)]. Original studies about the clinical effects of hyperoxemia in adult patients suffering from acute or emergency illnesses were included. RESULTS: 37 articles were included, of which 31 could be divided into four large groups: cardiac arrest, traumatic brain injury (TBI), stroke, and sepsis. Although a single study demonstrated a transient protective effect of hyperoxemia after TBI, other studies revealed higher mortality rates after cardiac arrest, stroke, and TBI treated with oxygen supplementation leading to hyperoxemia. Approximately half of the studies showed no association between hyperoxemia and clinically relevant outcomes. CONCLUSION: Liberal oxygen therapy leads to hyperoxemia in a majority of patients and hyperoxemia may negatively affect survival after acute illness. As a clinical consequence, aiming for normoxemia may limit negative effects of hyperoxemia in patients with acute illness.

Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis.

The estimated attributable mortality rate for invasive candidiasis (IC) in the intensive care unit (ICU) setting varies from 30 to 40%. Physiological changes in critically ill patients may affect the distribution and elimination of micafungin, and therefore, dosing adjustments might be mandatory. The objective of this study was to determine the pharmacokinetic parameters of micafungin in critically ill patients and assess the probability of target attainment. Micafungin plasma concentrations were measured to estimate the pharmacokinetic properties of micafungin. MIC values for Candida isolates were determined to assess the probability of target attainment for patients. Data from 19 patients with suspected or proven invasive candidiasis were available for analysis. The median area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24) was 89.6 mg · h/liter (interquartile range [IQR], 75.4 to 113.6 mg · h/liter); this was significantly lower than the median micafungin AUC0-24 values of 152.0 mg · h/liter (IQR, 136.0 to 162.0 mg · h/liter) and 134.0 mg · h/liter (IQR, 118.0 to 148.6 mg · h/liter) in healthy volunteers (P = <0.0001 and P = <0.001, respectively). All Candida isolates were susceptible to micafungin, with a median MIC of 0.016 mg/liter (IQR, 0.012 to 0.023 mg/liter). The median AUC0-24/MIC ratio was 5,684 (IQR, 4,325 to 7,578), and 3 of the 17 evaluable patients (17.6%) diagnosed with proven invasive candidiasis did not meet the AUC/MIC ratio target of 5,000. Micafungin exposure was lower in critically ill patients than in healthy volunteers. The variability in micafungin exposure in this ICU population could be explained by the patients' body weight. Our findings suggest that healthier patients (sequential organ failure assessment [SOFA] score of <10) weighing more than 100 kg and receiving 100 mg micafungin daily are at risk for inappropriate micafungin exposure and potentially inadequate antifungal treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT01716988.).

Incidence, timing and outcome of AKI in critically ill patients varies with the definition used and the addition of urine output criteria.

BACKGROUND: Acute kidney injury (AKI) is a serious complication of critical illness with both attributed morbidity and mortality at short-term and long-term. The incidence of AKI reported in critically ill patients varies substantially with the population evaluated and the definitions used. We aimed to assess which of the AKI definitions (RIFLE, AKIN or KDIGO) with or without urine output criteria recognizes AKI most frequently and quickest. Additionally, we conducted a review on the comparison of incidence proportions of varying AKI definitions in populations of critically ill patients. METHODS: We included all patients with index admissions to our intensive care unit (ICU) from January 1st, 2014 until June 11th, 2014 to determine the incidence and onset of AKI by RIFLE, AKIN and KDIGO during the first 7 days of ICU admission. We conducted a sensitive search using PubMed evaluating the comparison of RIFLE, AKIN and KDIGO in critically ill patients RESULTS: AKI incidence proportions were 15, 21 and 20% respectively using serum creatinine criteria of RIFLE, AKIN and KDIGO. Adding urine output criteria increased AKI incidence proportions to 35, 38 and 38% using RIFLE, AKIN and KDIGO definitions. Urine output criteria detected AKI in patients without AKI at ICU admission in a median of 13 h (IQR 7-22 h; using RIFLE definition) after admission compared to a median of 24 h using serum creatinine criteria (IQR24-48 h). In the literature a large heterogeneity exists in patients included, AKI definition used, reference or baseline serum creatinine used, and whether urine output in the staging of AKI is used. CONCLUSION: AKIN and KDIGO criteria detect more patients with AKI compared to RIFLE criteria. Addition of urine output criteria detect patients with AKI 11 h earlier than serum creatinine criteria and may double AKI incidences in critically ill patients. This could explain the large heterogeneity observed in literature.

Abdominal Compartment Syndrome and Intra-abdominal Ischemia in Patients with Severe Acute Pancreatitis.

INTRODUCTION: Severe acute pancreatitis may be complicated by intra-abdominal hypertension (IAH), abdominal compartment syndrome (ACS), and intestinal ischemia. The aim of this retrospective study is to describe the incidence, treatment, and outcome of patients with severe acute pancreatitis and ACS, in particular the occurrence of intestinal ischemia. METHODS: The medical records of all patients admitted with severe acute pancreatitis admitted to the ICU of a tertiary referral center were reviewed. The criteria proposed by the World Society of the Abdominal Compartment Syndrome (WSACS) were used to determine whether patients had IAH or ACS. RESULTS: Fifty-nine patients with severe acute pancreatitis were identified. Intra-abdominal pressure (IAP) measurements were performed in 29 patients (49.2 %). IAH was present in all patients (29/29). ACS developed in 13/29 (44.8 %) patients. Ten patients with ACS underwent decompressive laparotomy. A large proportion of patients with ACS had intra-abdominal ischemia upon laparotomy: 8/13 (61.5 %). Mortality was high in both the ACS group and the IAH group. CONCLUSION: This study confirms that ACS is common in severe acute pancreatitis. Intra-abdominal ischemia occurs in a large proportion of patients with ACS. Swift surgical intervention may be indicated when conservative measures fail in patients with ACS. National and international guidelines need to be updated so that routine IAP measurements become standard of care for patients with severe acute pancreatitis in the ICU.

Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Glucocorticosteroids (steroids) are widely used for sepsis patients. However, the potential benefits and harms of both high and low dose steroids remain unclear. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis (TSA) might shed light on this clinically important question. METHODS: A systematic review was conducted according to a published protocol and The Cochrane Handbook methodology including meta-analyses, TSA of randomised clinical trials, and external validity estimation (GRADE). Randomised clinical trials evaluating steroids were included for sepsis patients (systemic inflammatory response syndrome, sepsis, severe sepsis or septic shock) aged >18 years. Cochrane Central Register of Controlled Trials (CENTRAL), PubMed/Medline, Embase, Web of Science and Cinahl were searched until 18 February 2015. No language restrictions were applied. Primary outcomes were mortality at longest follow-up and serious adverse events. RESULTS: A total of 35 trials randomising 4682 patients were assessed and reviewed in full text. All trials but two had high risk of bias. No statistically significant effect was found for any dose of steroids versus placebo or no intervention on mortality at maximal follow-up [relative risk (RR) 0.89; TSA adjusted confidence interval (CI) 0.74-1.08]. Two trials with low risk of bias also showed no statistically significant difference (random-effects model RR 0.38, 95% CI 0.06-2.42). Similar results were obtained in subgroups of trials stratified according to high (>500 mg) or low (≤ 500 mg) dose hydrocortisone (or equivalent) (RR 0.87; TSA-adjusted CI 0.38-1.99; and RR 0.90; TSA-adjusted CI 0.49-1.67, respectively). There were also no statistically significant effects on serious adverse events other than mortality (RR 1.02; TSA-adjusted CI 0.7-1.48). The effects did not vary according to the degree of sepsis. TSA showed that many more randomised patients are needed before definitive conclusions may be drawn. CONCLUSION: Evidence to support or negate the use of steroids in any dose in sepsis patients is lacking. The results of ongoing and future well-designed, large randomised clinical trials are needed.

Interplay of co-inherited diseases can turn benign syndromes in a deadly combination: haemoglobinopathy and bilirubin transport disorder.

We present a case about a 25-year-old male patient suffering from a rare genetic disorder called Mizuho haemoglobin. He was admitted to the Intensive Care Unit with acute liver and renal failure. During admission he also developed a cardiac tamponade twice. Finally he received a liver transplantation. Hereafter the patient stabilised and his liver and renal functions improved. His symptoms could not be explained solely by his known disease. After searching the literature, similarities between his symptoms and a rare complication of sickle cell disease were found. Molecular diagnostics showed that the patient also suffered from Gilbert's syndrome. Due to his chronic haemolysis, symptoms of this other disease were masked. This stresses the importance of always looking for other causes if symptoms or changes cannot be explained by a known rare disorder.

Burden of highly resistant microorganisms in a Dutch intensive care unit.

BACKGROUND: The occurrence of highly resistant microorganisms (HRMOs) is a major threat to critical care patients, leading to worse outcomes, need for isolation measures, and demand for second-line or rescue antibiotics. The aim of this study was to quantify the burden of HRMOs in an intensive care unit (ICU) for adult patients in a university hospital in the Netherlands. We evaluated local distribution of different HRMO categories and proportion of ICU-imported versus ICU- acquired HRMOs. Outcome of HRMO-positive patients versuscontrols was compared. METHODS: In this prospective single-centre study, culture results of all ICU patients during a four-month period were recorded, as well as APACHE scores, ICU mortality and length of stay (LOS) in the ICU. RESULTS: 58 of 962 (6.0%) patients were HRMO positive during ICU stay. The majority (60%) of those patients were HRMO positive on ICU admission. HRMO-positive patients had significantly higher APACHE scores, longer LOS and higher mortality compared with controls. CONCLUSIONS: Our study suggests that a large part of antibiotic resistance in the ICU is imported. This underscores the importance of a robust surveillance and infection control program throughout the hospital, and implies that better recognition of those at risk for HRMO carriage before ICU admission may be worthwhile. Only a small minority of patients with HRMO at admission did not have any known risk factors for HRMO.

An upper gastrointestinal ulcer still bleeding after endoscopy: what comes next?

INTRODUCTION: Recurrent bleeding from an upper gastrointestinal ulcer when endoscopy fails is a reason for radiological or surgical treatment, both of which have their advantages and disadvantages. CASE: Based on a patient with recurrent gastrointestinal bleeding, we reviewed the available evidence regarding the efficacy and safety of surgical treatment and embolisation, respectively. DISCUSSION: Transarterial embolisation (TAE) and surgical treatment are both options for recurrent gastrointestinal bleeding when endoscopy fails. Both therapies have serious complications and a risk of rebleeding. Choosing the therapy depends on the capability of the patient to tolerate haemodynamic instability, resuscitation and hypotension. CONCLUSION: Choosing between TAE and surgery depends a great deal on the case presented, haemodynamic stability and the skills and tools available at that moment.

"Acute liver failure": the heart may be the matter.

Hypoxic hepatitis secondary to heart failure is a known and treatable cause of liver failure. The diagnosis may be difficult, especially when symptoms of heart failure are absent. We present two patients who were transferred to our hospital with the diagnosis of acute liver failure to be screened for a liver transplantation. Both patients had increased serum levels ofaminotransferases, lactic acidosis, coagulation disorders, and non-specific clinical symptoms. Echocardiography revealed right ventricular dysfunction. Treatment with inotropes resulted in a fast normalization of liver enzymes, acidosis and coagulation, confirming the diagnosis hypoxic hepatitis. In conclusion, when the cause of acute liver dysfunction is unclear, hypoxic hepatitis due to heart failure should be considered and echocardiography should be performed, even when symptoms are non-specific for heart failure.

Validation of a transcutaneous CO(2) monitor in adult patients with chronic respiratory failure.

BACKGROUND: Home mechanical ventilation is usually started in hospital as arterial blood gas sampling is deemed necessary to monitor CO(2) and O(2) adequately during institution of ventilatory support. A non-invasive device to reliably measure CO(2) transcutaneously would alleviate the need for high care settings for measurement and open the possibility for home registration. OBJECTIVES: In this study we investigated whether the TOSCA® transcutaneous CO(2) (PtcCO(2)) measurements, performed continuously during the night, reliably reflect arterial CO(2) (PaCO(2)) measurements in adults with chronic respiratory failure. METHODS: Paired measurements were taken in 15 patients hospitalised to evaluate their blood gas exchange. Outcomes were compared 30 min, 2, 4, 6 and 8 h after attaching the sensor to the earlobe. A maximum difference of 1.0 kPa and 95% limits of agreement (LOA) of 1 kPa between CO(2) pressure measurements, following the analysis by Bland and Altman, were determined as acceptable. RESULTS: Mean PtcCO(2) was 0.4 kPa higher (LOA -0.48 to 1.27 kPa) than mean PaCO(2) after 30 min. These figures were 0.6 kPa higher (LOA -0.60 to 1.80 kPa) after 4 h, with a maximum of 0.72 kPa (LOA 0.35 to 1.79 kPa) after 8 h. The corresponding values for changes in PtcCO(2) versus PaCO(2) were not significant (ANOVA). CONCLUSIONS: PtcCO(2) measurement, using TOSCA, is a valid method showing an acceptable agreement with PaCO(2) during 8 h of continuous measurement. Therefore, this device can be used to monitor CO(2) adequately during chronic ventilatory support.

Cardiac assessment of patients with late stage Duchenne muscular dystrophy.

Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, but is hampered by scoliosis and poor echocardiographic acoustic windows in adult DMD patients. Multigated cardiac radionuclide ventriculography (MUGA) does not suffer from these limitations. N-terminal proBNP (NTproBNP) has shown to be a diagnostic factor for heart failure. We present our initial experience with plasma NT-proBNP measurement in the routine screening and diagnosis of cardiomyopathy in adult mechanically ventilated DMD patients.Methods. Retrospective study, 13 patients. Echocardiography classified left ventricular (LV) function as preserved or depressed. NT-proBNP was determined using immunoassay. LV ejection fraction (LVEF) was determined using MUGA.Results. Median (range) NT-proBNP was 73 (25 to 463) ng/l. Six patients had an NT-proBNP >125 ng/l. Seven patients showed an LVEF <45% on MUGA. DMD patients with depressed LV function (n=4) as assessed by echocardiography had significantly higher median NT-proBNP than those (n=9) with preserved LV function: 346 (266 to 463) ng/l versus 69 (25 to 257) ng/l (p=0.003). NT-proBNP significantly correlated with depressed LV function on echocardiogram and with LVEF determined by MUGA.Conclusion. Although image quality of MUGA is superior to echocardiography, the combination of echocardiography and NT-proBNP achieves similar results in the evaluation of left ventricular function and is less time consuming and burdensome for our patients. We advise to add NT-proBNP to echocardiography in the routine cardiac assessment of DMD patients. (Neth Heart J 2009;17:232-7.).

Nocturnal non-invasive ventilation in addition to rehabilitation in hypercapnic patients with COPD.

BACKGROUND: Long-term non-invasive positive pressure ventilation (NIPPV) might improve the outcomes of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) with chronic respiratory failure. A study was undertaken to investigate whether nocturnal NIPPV in addition to pulmonary rehabilitation improves health-related quality of life, functional status and gas exchange compared with pulmonary rehabilitation alone in patients with COPD with chronic hypercapnic respiratory failure. METHODS: 72 patients with COPD were randomly assigned to nocturnal NIPPV in addition to rehabilitation (n = 37) or rehabilitation alone (n = 35). Outcome measures were assessed before and after the 3-month intervention period. RESULTS: The Chronic Respiratory Questionnaire total score improved 15.1 points with NIPPV + rehabilitation compared with 8.7 points with rehabilitation alone. The difference of 7.5 points was not significant (p = 0.08). However, compared with rehabilitation alone, the difference in the fatigue domain was greater with NIPPV + rehabilitation (mean difference 3.3 points, p<0.01), as was the improvement in the Maugeri Respiratory Failure questionnaire total score (mean difference -10%, p<0.03) and its cognition domain (mean difference -22%, p<0.01). Furthermore, the addition of NIPPV improved daytime arterial carbon dioxide pressure (mean difference -0.3 kPa; p<0.01) and daily step count (mean difference 1269 steps/day, p<0.01). This was accompanied by an increased daytime minute ventilation (mean difference 1.4 l; p<0.001). CONCLUSION: Non-invasive ventilation augments the benefits of pulmonary rehabilitation in patients with COPD with chronic hypercapnic respiratory failure as it improves several measures of health-related quality of life, functional status and gas exchange.

[Serious intoxication with hydroxychloroquine, with haemodynamic instability: a case report supporting treatment with diazepam]. / Ernstige intoxicatie met hydroxychloroquine, met hemodynamische instabiliteit: casuistische ondersteuning voor behandeling met diazepam.

A 37-year-old woman was admitted to the emergency room because of an autointoxication with hydroxychloroquine, leading to haemodynamic instability. Treatment consisted of the rapid administration of intravenous diazepam, after which the hypotension recovered rapidly even though no vasoactive medication was given. Treatment with diazepam has been advised in the Netherlands for many years in case of severe hydroxychloroquine intoxication, despite the fact that convincing evidence for its use is lacking. On the basis of the experience with the relevant cases, the administration of diazepam, 2 mg/kg initially followed by 2 mg/kg/24 hours as a continuous infusion, should certainly be considered for supportive treatment in the ICU in case of severe haemodynamic instability.