Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients.

INTRODUCTION: Acute kidney injury (AKI) is a common and serious complication increasing morbidity and mortality from all causes of hospital admission. We have previously shown that AKI decreases midazolam metabolism, a substrate of the cytochrome P450 3A (CYP3A) enzymes and our primary aim was to determine if this effect is dependent on the severity of AKI. We also present preliminary data on the functional impact of different genotypes of CYP3A. METHODS: Critically ill patients at risk of AKI and admitted to a general intensive care unit were categorised after initial resuscitation according to the RIFLE criteria for AKI. Midazolam (1mg) was administered and the serum concentration of midazolam measured at 4 h. Samples were taken for CYP3A genotyping. RESULTS: Seventy-three patients were assigned to categories R, I and F of the RIFLE criteria or C (controls). Midazolam concentrations (ng mL(-1)) increased significantly (p = 0.002) as the severity of AKI worsened [control 3.1 (1.4-5.9), risk 4.7 (1.3-10.3), injury 3.9 (2.0-11.1) and failure 6.8 (2.2-113.6)] and were predicted by the duration of AKI (p = 0.000) and γ-glutamyl transferase (p = 0.005) concentrations. Increasing BMI negatively predicted the midazolam concentration (p = 0.001). Preliminary data suggest this effect is diminished if the patient expresses functional CYP3A5. CONCLUSION: Increasing severity and duration of AKI are associated with decreased midazolam elimination. We propose that this is caused by impaired CYP3A activity secondary to AKI. The exact mechanism remains to be elucidated. This may have important implications for our drug treatment of critically ill patients.

Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Hyperglycaemia is associated with poor outcomes from pneumonia, myocardial infarction and stroke, but the effect of blood glucose on outcomes from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) has not been established. Recent UK guidelines do not comment on measurement or control of blood glucose in AECOPD. A study was therefore undertaken to determine the relationship between blood glucose concentrations, length of stay in hospital, and mortality in patients admitted with AECOPD. METHODS: Data were retrieved from electronic records for patients admitted with AECOPD with lower respiratory tract infection in 2001-2. The patients were grouped according to blood glucose quartile (group 1, <6 mmol/l (n = 69); group 2, 6.0-6.9 mmol/l (n = 69); group 3, 7.0-8.9 mmol/l (n = 75); and group 4, >9.0 mmol/l (n = 71)). RESULTS: The relative risk (RR) of death or long inpatient stay was significantly increased in group 3 (RR 1.46, 95% CI 1.05 to 2.02, p = 0.02) and group 4 (RR 1.97, 95% CI 1.33 to 2.92, p < 0.0001) compared with group 1. For each 1 mmol/l increase in blood glucose the absolute risk of adverse outcomes increased by 15% (95% CI 4 to 27), p = 0.006. The risk of adverse outcomes increased with increasing hyperglycaemia independent of age, sex, a previous diagnosis of diabetes, and COPD severity. Isolation of multiple pathogens and Staphylococcus aureus from sputum also increased with increasing blood glucose. CONCLUSION: Increasing blood glucose concentrations are associated with adverse clinical outcomes in patients with AECOPD. Tight control of blood glucose reduces mortality in patients in intensive care or following myocardial infarction. A prospective study is now required to determine whether control of blood glucose can also improve outcomes from AECOPD.

Glucose in bronchial aspirates increases the risk of respiratory MRSA in intubated patients.

BACKGROUND: The risk of nosocomial infection is increased in critically ill patients by stress hyperglycaemia. Glucose is not normally detectable in airway secretions but appears as blood glucose levels exceed 6.7-9.7 mmol/l. We hypothesise that the presence of glucose in airway secretions in these patients predisposes to respiratory infection. METHODS: An association between glucose in bronchial aspirates and nosocomial respiratory infection was examined in 98 critically ill patients. Patients were included if they were expected to require ventilation for more than 48 hours. Bronchial aspirates were analysed for glucose and sent twice weekly for microbiological analysis and whenever an infection was suspected. RESULTS: Glucose was detected in bronchial aspirates of 58 of the 98 patients. These patients were more likely to have pathogenic bacteria than patients without glucose detected in bronchial aspirates (relative risk 2.4 (95% CI 1.5 to 3.8)). Patients with glucose were much more likely to have methicillin resistant Staphylococcus aureus (MRSA) than those without glucose in bronchial aspirates (relative risk 2.1 (95% CI 1.2 to 3.8)). Patients who became colonised or infected with MRSA had more infiltrates on their chest radiograph (p<0.001), an increased C reactive protein level (p<0.05), and a longer stay in the intensive care unit (p<0.01). Length of stay did not determine which patients acquired MRSA. CONCLUSION: The results imply a relationship between the presence of glucose in the airway and a risk of colonisation or infection with pathogenic bacteria including MRSA.

New insights into the glucose oxidase stick test for cerebrospinal fluid rhinorrhoea.

Rhinorrhoea is a clinical sign of cerebrospinal fluid (CSF) leakage in patients with skull fracture, but can also be attributable to respiratory secretions or tears. Laboratory tests confirming the presence of CSF are not sufficiently rapid to support clinical decision making in the emergency department and may not be universally available. Detection of glucose in nasal discharge was traditionally used to diagnose CSF leak at the bedside, but has fallen into disuse as it has poor positive predictive value. We propose an algorithm to improve the diagnostic value of this test taking into consideration factors we have found to affect the glucose concentration of respiratory secretions. In patients at risk of CSF leak, nasal discharge is likely to contain CSF if glucose is present in the absence of visible blood, if blood glucose is <6 mmol x L(-1), and if there are no symptoms of upper respiratory tract infection.

In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens.

Understanding estrogen's regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17beta-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17beta-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17beta-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17beta-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.

The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure.

We have investigated the effect of N-acetylcysteine on hemodynamic variables, oxygen delivery (DO2), oxygen consumption (VO2), and oxygen extraction in patients with fulminant hepatic failure using independent methods of determining DO2 and VO2, thereby eliminating the effect of mathematical coupling, which may have biased previous studies. In 11 patients with severe fulminant hepatic failure, we documented the hemodynamic effects of N-acetylcysteine during the first 5 hours of a standard infusion regime and simultaneously measured VO2 using a method based on respiratory gas analysis. We related physiological changes to plasma N-acetylcysteine concentrations, and compared this group with 7 patients who received placebo infusions. A variable hemodynamic response to N-acetylcysteine was observed that did not differ significantly in comparison with the placebo group, and did not correlate with plasma drug concentrations. The most significant relationship observed between DO2 and VO2 in any patient predicted a 13-mL x min(-1) x m(-2) increase in VO2 when DO2 increased by 100 mL x min(-1) x m(-2); in 8 patients, VO2 was independent of DO2 over the range observed. In the group that received N-acetylcysteine, a small (mean 6 [SD 6] mL x min(-1) x m[-2]) increase in VO2 occurred in comparison with baseline after 1 hour of infusion (P < .01), but changes were not significantly different from the placebo group and were not sustained. N-Acetylcysteine infusion did not increase oxygen extraction or result in an improvement in whole-blood lactate levels or base excess during the study period. We conclude that N-acetylcysteine infusion does not result in clinically relevant improvements in global VO2, or in clinical markers of tissue hypoxia in patients with severe fulminant hepatic failure.

Cerebral blood flow and metabolism in patients with chronic liver disease undergoing orthotopic liver transplantation.

Changes in cerebral hemodynamics and metabolism associated with anesthesia and liver transplantation may present particular hazards for patients with cirrhosis. Fifteen patients undergoing liver transplantation were studied, 7 of whom had encephalopathy. Cerebral blood flow (CBF) was measured at the start of surgery, during veno-venous bypass and post reperfusion, using a method based on the Kety-Schmidt method. Cerebral metabolism was assessed by measuring the cerebral metabolic rate for oxygen (CMRO2) and the lactate oxygen index (LOI). The cerebral vascular reactivity to carbon dioxide (CO2) was studied during the preanhepatic and post reperfusion phases. During the preanhepatic period, the median CBF was 44 mL/100 g/min at an arterial carbon dioxide tension (PaCO2) of 3.8 kPa. After reperfusion the CBF increased (P < .02) to 102 mL/100 g/min, the arterial hydrogen ion concentration increased from 39 nmol/L to 53 nmol/L (P < .02) and the jugular venous oxygen saturation from 74% to 89% (P < .02). CBF was similar in patients with and without encephalopathy. The cerebral vascular reactivity to CO2 remained intact, although after reperfusion, the CBF for a given PaCO2 was greater, and the slope of the CBF/CO2 response curve diminished. The CMRO2 was normal in patients without encephalopathy. In the encephalopathic patients, the CMRO2 was low during all stages of transplantation (0.54, 0.86, 1.24 mL/100 g/min, respectively). Patients with encephalopathy may be at increased risk of hypoxemic brain injury during transplantation. To minimize this possibility, more detailed neurological monitoring may be useful.

Surgical face masks are effective in reducing bacterial contamination caused by dispersal from the upper airway.

We have studied the effectiveness of surgical face masks in reducing bacterial contamination of a surface, produced by dispersal of organisms from the upper airway. Twenty-five volunteers were asked to speak at blood agar plates positioned in close proximity to the mouth, initially whilst not wearing a face mask and then wearing a surgical face mask over the mouth and nose. A fresh face mask almost completely abolished bacterial contamination of agar plates 30 cm from the mouth. After 15 min there was an increase in the level of contamination which was statistically insignificant.

Cleft palate. Selected case studies.

These case studies provide small, selected samples of the results of assessments of articulation skills and their phonologic applications and give some information related to velopharyngeal function during speech. These illustrations were based chiefly on perceptual assessment of speech because this type of assessment is used routinely by SLPs, and does not require instrumentation. Indicators for referral and communication to a cleft palate team were derived from the perceptual evaluation. Other articles in this issue discuss procedures for evaluation in considerable detail. Early identification of possible velopharyngeal problems and early referral to a cleft palate team can help to resolve speech, language, and hearing disorders related to cleft palate and velopharyngeal dysfunction. People who comprise cleft palate and craniofacial teams are most likely to have the experience, and the special instrumentation necessary, to make a definitive diagnosis. The team's comprehensive multidisciplinary evaluation should lead to thorough consideration of the many factors that are important for treatment planning. The information and services provided by the team will assist the audiologist and SLP in the conduct of their services for these clients. In this way, the communication disorders specialist becomes an affiliate of the team. The affiliate not only acts as a referent, but also may provide the necessary longitudinal services. The best interests of the client are promoted by ongoing communication between the team and the affiliates of the team.

Stereospecific effects of a kappa-opiate antagonist on the actions of morphine in morphine-tolerant rats.

The effects of kappa-opiate receptor antagonist, MR 2266 and its dextro isomer, MR 2267 on morphine-induced analgesia and changes in colonic temperature were determined in morphine-naive and morphine-tolerant male Sprague-Dawley rats. Intraperitoneal administration of morphine (8 mg/kg) produced analgesia and hyperthermia in morphine-naive rats. MR 2266 (0.3-3.0 mg/kg) antagonized morphine-induced analgesia and hyperthermia in morphine-naive rates but MR 2267 was inactive. Subcutaneous implantation of six morphine pellets during a 7 day period induced tolerance to the analgesic and hyperthermic effects of morphine in the rat. MR 2266 also antagonized morphine analgesia and hyperthermia in morphine-tolerant rats, however, MR 2267 had no effect. A high dose (3 mg/kg) of MR 2266 produced an intense hypothermic response in morphine-tolerant rats. Previously we have shown that kappa-opiate receptor agonists antagonize morphine analgesia in morphine-naive rats but potentiate it in morphine-tolerant rats. The results of the present studies indicate that the antagonist of kappa-opiate receptors, on the other hand, antagonize morphine effects in both morphine-naive and morphine-tolerant rats in a stereospecific manner.

A comparative study of four methods of evaluating velopharyngeal adequacy.

Forty-eight subjects with repaired palatal clefts were divided into three major groups on the basis of speech symptoms and were examined for velopharyngeal valving integrity by means of the R-D nasal manometer, pressure-flow techniques, the Hunter oral manometer, and videofluoroscopy. Videofluoroscopy appeared to provide data that most nearly agreed with predictions of valving made from speech. The Hunter oral manometer was the least useful of the four techniques.

Perceptual evaluation of velopharyngeal competency.

Eight public school speech/language pathologists estimated velopharyngeal competence on the basis of perceptual evaluation of speech characteristics of 24 subjects. These evaluations were made from tape-recorded speech samples. After orientation to a system for scoring speech characteristics associated with velopharyngeal incompetence they reevaluated the same 24 subjects. The evaluations were found to improve significantly with orientation and to correlate well with experts' live evaluations as well as evaluations based on instrumentation which included telefluorography, manometric and pressure-flow data. It was concluded that speech-language pathologists, who by nature of their education and training have expertise in identification of speech deviations, can apply their skills effectively in identifying velopharyngeal incompetence. Further it was suggested that orientation to a system for weighing speech characteristics related to velopharyngeal competency can improve their estimates.

Shaping behavior in voice therapy.

This study demonstrates the process of learning and shaping of behavior which occurs during a program of therapy for individuals with hyperfunctional hoarse voice quality. First a therapy program delineating the techniques and criteria to be used was written. The program was presented during 16 individual half-hour sessions over an eight-week period to three clients known to have vocal nodules. The clients' responses were charted at various points from audiotape recordings of each therapy session using a modification of the Boone-Prescott analysis system, to obtain data to demonstrate the learning processes. It was concluded that: (1) the client's behaviors in this vocal rehabilitation program reflected a learning process; (2) facilitating techniques were used to modify or shape behavior through successive approximations to the terminal goal; (3) self-evaluation is an important factor needed to bring about successful changes in behavior; (4) analysis of client's behaviors in relation to the learning process can aid in evaluating the effectiveness of the facilitating techniques; and (5) from such evaluation intraclient and interclient program changes are derived hopefully resulting in a greater success rate and maximum benefits from time spent in therapy.

A telefluoroscopic study of lingual contacts made by persons with palatal defects.

Telefluoroscopic tapes were viewed to obtain evaluations of lingual contacts during the production of six consonant sounds by 69 subjects who had a history of cleft palate or velopharyngeal inadequacy. Using phonetic textbook descriptions of normal lingual contacts as standards, these observed contacts were judged to be either normal or deviant in placement, and direction of deviation was noted. Clinical records of subjects afforded medical and surgical histories as well as evaluations of the subjects' intelligibility, nasal resonance and nasal emission at the time of the taping. Evaluations of velopharyngeal adequacy made from these tapes were also available. Based on the results of this study it was concluded that some but not all speakers who have a history of palatal problems use deviant lingual contacts to produce consonant sounds. The use of deviant lingual contacts does not appear to be related to the type of palatal problem, but is significantly related to the adequacy of the velopharyngeal mechanism for speech. Those with adequate mechanisms show the least use of deviant lingual contacts, subjects with borderline adequacy show a greater use, and those with inadequate closure show the greatest use of deviant contacts. There is a significant relationship between the use of deviant lingual contacts and the presence of abnormal intelligibility and abnormal nasal resonance. The tendency toward the use of deviant lingual contacts by those with velopharyngeal insufficiency suggests that these are compensations for the inadequate valving. These compensations may increase both the intelligibility and nasal resonance problems caused by the inadequate valving. Subjects who achieved adequacy of velopharyngeal mechanism for speech before the age of mastery of consonant sounds showed significantly less tendency to use deviant contacts than those who never attained adequacy. This was reflected in intelligible speech and less tendency toward abnormal nasal resonance. It is suggested that when velopharyngeal adequacy cannot be achieved through early surgical intervention, speech therapy may be indicated to promote the development of potentially adequate articulatory patterns and to discourage the development of compensatory mechanisms.