Intraperitoneal vancomycin concentrations during peritoneal dialysis-associated peritonitis: correlation with serum levels

♦ Background: For the treatment of peritoneal dialysis–associated peritonitis (PDP), it has been suggested that serum concentrations of vancomycin be kept above 12 mg/L – 15 mg/L. However, studies correlating vancomycin concentrations in serum and peritoneal dialysate effluent (PDE) during active infection are sparse. We undertook the present study to investigate this issue and to determine whether achieving the recommended serum level of vancomycin results in therapeutic levels intraperitoneally.♦ Methods: We studied patients treated with intraperitoneal (IP) vancomycin for non-gram-negative PDP. We gave a single dose (approximately 30 mg/kg) at presentation, and we subsequently measured vancomycin levels in PDE on day 5; we wanted to determine if efflux of vancomycin from serum to PDE during a 4-hour dwell was consistent and resulted in therapeutic levels.♦ Results: Of the 48 episodes of PDP studied, serum vancomycin concentrations exceeding 12 mg/L were achieved in 98% of patients, but in 11 patients (23%), a PDE vancomycin level below 4 mg/L—the minimal inhibitory concentration (MIC) of many gram-positive organisms—was observed at the end of a 4-hour dwell on day 5. The correlation between the concentrations of vancomycin in serum and PDE (from efflux of antibiotic over 4 hours) was statistically significant, but poor (R² = 0.18).♦ Conclusions: Our data support the International Society for Peritoneal Dialysis statement that adequate serum vancomycin concentrations can be achieved with intermittent dosing (single dose every 5 days), but cannot guarantee therapeutic PDE levels in the treatment of PDP. Intermittent dosing of vancomycin may not consistently result in PDE concentrations markedly greater than MIC of many important pathogens. Although the clinical significance of this finding remains to be determined, it may be preferable to give smaller but more frequent doses of PDE vancomycin (continuous dosing) for adults with PDP (as is currently recommended for children).     

The good and the bad of diabetes mellitus in the critically ill

Diabetes mellitus is increasingly prevalent and associated with significant end organ damage that one may presume to impact upon critical illness. However, Siegelaar and colleagues present data that suggest, excepting those patients admitted to a cardiac intensive care unit, the presence of diabetes mellitus is not associated with increased mortality in critically ill patients. It is not possible to unpick how unmeasured parameters such as glycaemic control, the nature of whether type I or type II, or concomitant drug therapy confound the results. Nevertheless, the results are consistent with many risk-adjustment models used in the critically ill, and clinical practice that tolerates mild hyperglycaemia. Is it even possible that diabetes mellitus is protective?The prevalence of diabetes mellitus is increasing, in part due to aging, obesity, and lower levels of physical activity. The findings of Siegelaar and colleagues presented in the previous issue of Critical Care challenge current beliefs but are also relevant to all [1]. Advanced diabetes is associated with end organ damage that is likely to impact upon critically ill patients - nephropathy, autonomic neuropathy, and small-vessel and large-vessel disease. Thus many believe that diabetes is associated with increased mortality and morbidity in patients admitted to an intensive care unit (ICU). Moreover, studies have demonstrated that not addressing severe hyperglycaemia (>10 mmol/l) in critically ill patients is associated with higher mortality [2,3].Siegelaar and colleagues use meta-analysis techniques to examine the relationship between mortality and diabetes mellitus in patients admitted to an ICU. Pooling data from 141 studies and nearly 12.5 million patients, they demonstrate that, outside the cardiothoracic ICU, diabetes mellitus is not associated with an increased risk of mortality. Their findings were consistent whether mortality was considered at ICU discharge, hospital discharge, or 28/30 days.The value of the study lies in the large number of patients included, sourced from a broad range of publications most of which were not specific to patients with diabetes mellitus. Moreover, the Forest plots demonstrate consistency between studies. However, unmeasured con-founders may influence their results. Whilst a sensitivity analysis using risk-adjusted mortality from five studies encompassing ~15% of the patients demonstrates a similar result, the model is not comprehensive. For example, patients with diabetes mellitus may receive inhibitors of the renin-angiotensin system, HMG-CoA reductase inhibitors, peroxisome proliferator-activated receptor gamma agonists, and aspirin. All of these treatments have been postulated to affect outcome in critically ill patients [4-6]. The study is limited also by considering diabetes mellitus as a homogeneous entity rather than a diagnosis that encompasses two different pathophysiologies and widely ranging therapies and qualities of glycaemic control. How all these parameters impact upon outcome is not explored.The authors'' results are mirrored in current risk-adjustment models. In the cardiothoracic setting, the presence of diabetes mellitus has been used as a risk factor for perioperative mortality in the Parsonnet score [7] but not the EuroSCORE tools [8]. Cardiac revascularisation of patients with diabetes mellitus is complicated by poorer targets and microvascular disease. By contrast, diabetes mellitus does not form part of standard ICU risk-prediction models such as the Acute Physiology and Chronic Health Evaluation score and the Simplified Acute Physiology Score [9-12].Why does the presence of diabetes mellitus not matter outside the cardiothoracic ICU? As the authors point out, the higher incidence of sepsis in patients with diabetes mellitus may imply a protective effect. Certainly, targeting mild hyperglycaemia in all patients seems preferable to strict normoglycaemia control [13]. The effects of insulin may be detrimental in the critically ill [14]. Insulin is anti-inflammatory [15] and switches cells to preferentially metabolise glucose rather than free fatty acids. Alternatively, patients with diabetes mellitus may be taking protective medications or have become accustomed to mild hyperglycaemia, a prooxidant status, or increased levels of advanced glycated end products - all implicated in the pathogenesis of systemic inflammation.Since few would have cited diabetes mellitus as a contributory reason for defining an ICU admission as futile, Siegelaar and colleagues'' study does not change our clinical practice. Nevertheless, the suggestion of a potential protective effect for diabetes mellitus merits further investigation. Unpicking this hypothesis may reveal new therapeutic strategies that we can exploit in other patient populations.     

Red blood cell substitutes

Soluble polymerized haemoglobin (polyhaemoglobin) is now in a phase III clinical trials. Patients have received up to 20 units (10 litres) in trauma surgery and other surgery. Polyhaemoglobin can be stored for more than 1 year. Haemoglobin solutions have no blood group antigen and can be used as a 'universal donor' oxygen carrier. They can also be sterilized. With a circulation half-life of 24 hours they are undergoing trials for peri-operative use. For conditions with potential for ischaemia-reperfusion injuries, a new polyhaemoglobin-superoxide dismutase-catalase, which can reduce oxygen radicals, is being developed. Recombinant human haemoglobin has been tested in clinical trials, and a new type of recombinant human haemoglobin that has low affinity for nitric oxide is being developed for clinical trials. To increase the circulation time, artificial red blood cells have been prepared with a bilayer lipid membrane (haemoglobin liposomes) or with a biodegradable polymer membrane-like polylactide (haemoglobin nanocapsules). Synthetic chemicals such as perfluorochemicals are also being developed and tested in clinical trials as red blood cell substitutes.     

Lipoprotein-cholesterol analysis during screening: accuracy and reliability

OBJECTIVE: To evaluate the accuracy and reliability of lipoprotein-cholesterol measurements obtained during screening. DESIGN: Cross-sectional study. PARTICIPANTS: From November 1989 to January 1990, 154 adults were screened. MEASUREMENTS: Split venous samples from fasting participants were analyzed for total cholesterol, triglyceride, and high-density-lipoprotein (HDL) cholesterol with screening and standardized laboratory methods. Low-density-lipoprotein (LDL)-cholesterol levels were calculated using the Friedewald equation. Split venous samples from nonfasting participants were analyzed for total cholesterol. Capillary blood samples were analyzed for total cholesterol with the screening method. MAIN RESULTS: Total cholesterol measurements in screening venous blood samples were 5.4% and 3.8% lower than the laboratory values in samples from fasting and nonfasting participants, respectively. Triglyceride and HDL-cholesterol values in venous samples obtained from fasting participants were, on average, 9.8% and 11.2% lower than the respective laboratory measurements. Screening HDL-cholesterol values varied, differing from the laboratory values by as much as 40% in 95% of participants. In fasting participants, total cholesterol in capillary samples averaged 5.5% higher than in venous samples; in nonfasting participants the capillary samples were 3.1% higher. Screening for either total cholesterol or LDL cholesterol identified 93% of the persons with LDL-cholesterol values of 3.36 mmol/L (130 mg/dL) or higher. CONCLUSIONS: Total cholesterol can be reliably measured in samples from fasting or nonfasting persons. The values in capillary blood samples were slightly higher than those in venous samples. Screening HDL-cholesterol values were too variable to establish the HDL-cholesterol level reliably. Participants with high LDL-cholesterol levels were identified as accurately by measuring total cholesterol only when compared with calculating the LDL-cholesterol level from total cholesterol, triglyceride, and HDL-cholesterol concentrations.     

Fibrinopeptide A and the phosphate content of fibrinogen in venous thromboembolism and disseminated intravascular coagulation

Concentrations of plasma fibrinopeptide A (FPA) were measured by radioimmunoassay in 50 patients with venous thromboembolism or disseminated intravascular coagulation or both. A consistent discrepancy was observed in values obtained with two anti-FPA antisera. Analysis of extracts from plasma of these patients by high-performance liquid chromatography (HPLC) revealed the presence of a phosphorylated and an unphosphorylated form of the A peptide. Differences in concentrations of FPA measured with the two antisera could be accounted for by their different reactivity with phosphorylated FPA (FPA-P). The differences were abolished by treatment with alkaline phosphatase. A good correlation was observed between the FPA-P content of free A- peptide material and of fibrinogen in plasma as determined by HPLC (r = .88, P less than .001, n = 11). In patients with elevated FPA levels, the mean FPA-P content of fibrinogen was significantly higher (P less than .002, n = 13) than in patients with normal FPA levels (n = 8) and in healthy controls (n = 14). Phosphorus in fibrinogen did not correlate with fibrinogen degradation products or fibrinogen levels and became normal on adequate anticoagulation. Therefore, blood-clotting activation may lead to a high phosphate content of fibrinogen and of free FPA in plasma.     

Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects

Long-term treatment with ibuprofen twice daily, at doses that achieve peak plasma concentration (Cmax) >50 microg/ml, slows progression of lung disease in patients with cystic fibrosis (CF). Previous data suggest that Cmax >50 microg/ml is associated with a reduction in neutrophil (PMN) migration into the lung and that lower concentrations are associated with an increase in PMN migration. To estimate the threshold concentration at which ibuprofen is associated with a decrease in PMN migration in vivo, we measured the PMN content of oral mucosal washes in 35 healthy (age 19-40 years) and 16 CF (age 18-32 years) subjects who took ibuprofen twice daily for 10 days in doses that achieved Cmax 8 to 90 microg/ml. Cmax >50 microg/ml was associated with a 31 +/- 7% (mean +/- S.E.M.) reduction in PMNs in CF (n = 11, p < 0.001) and 25 +/- 6% reduction in PMNs in healthy subjects (n = 16, p < 0.001). Increasing concentrations above 50 microg/ml was not associated with a greater decrease in PMNs. The reduction in PMN migration was consistently present 12 h after a dose, but not after 24 h. Cmax <50 microg/ml was associated with an increase in PMNs of approximately 40%. These results suggest that Cmax >50 microg/ml and twice daily dosing of ibuprofen are required to decrease PMN migration, and reinforce the current recommendation that pharmacokinetics should be performed in CF patients prescribed ibuprofen.     

MDS clinical diagnostic criteria for Parkinson's disease

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances. © 2015 International Parkinson and Movement Disorder Society     

Patient characteristics,anaesthetic workload and techniques in the UK: an analysis from the 7th National Audit Project (NAP7) activity survey

Detailed contemporary knowledge of the characteristics of the surgical population, national anaesthetic workload, anaesthetic techniques and behaviours are essential to monitor productivity, inform policy and direct research themes. Every 3–4 years, the Royal College of Anaesthetists, as part of its National Audit Projects (NAP), performs a snapshot activity survey in all UK hospitals delivering anaesthesia, collecting patient-level encounter data from all cases under the care of an anaesthetist. During November 2021, as part of NAP7, anaesthetists recorded details of all cases undertaken over 4 days at their site through an online survey capturing anonymous patient characteristics and anaesthetic details. Of 416 hospital sites invited to participate, 352 (85%) completed the activity survey. From these, 24,177 reports were returned, of which 24,172 (99%) were included in the final dataset. The work patterns by day of the week, time of day and surgical specialty were similar to previous NAP activity surveys. However, in non-obstetric patients, between NAP5 (2013) and NAP7 (2021) activity surveys, the estimated median age of patients increased by 2.3 years from median (IQR) of 50.5 (28.4–69.1) to 52.8 (32.1–69.2) years. The median (IQR) BMI increased from 24.9 (21.5–29.5) to 26.7 (22.3–31.7) kg.m^–2. The proportion of patients who scored as ASA physical status 1 decreased from 37% in NAP5 to 24% in NAP7. The use of total intravenous anaesthesia increased from 8% of general anaesthesia cases to 26% between NAP5 and NAP7. Some changes may reflect the impact of the COVID-19 pandemic on the anaesthetic population, though patients with confirmed COVID-19 accounted for only 149 (1%) cases. These data show a rising burden of age, obesity and comorbidity in patients requiring anaesthesia care, likely to impact UK peri-operative services significantly.