The Relationship Between Sedatives, Sedative Strategy, and Healthcare-Associated Infection: A Systematic Review.

BACKGROUND Healthcare-associated infections (HAIs) cause significant morbidity in critically ill patients. An underappreciated but potentially modifiable risk factor for infection is sedation strategy. Recent trials suggest that choice of sedative agent, depth of sedation, and sedative management can influence HAI risk in mechanically ventilated patients. OBJECTIVE To better characterize the relationships between sedation strategies and infection. METHODS Systematic literature review. RESULTS We found 500 articles and accepted 70 for review. The 3 most common sedatives for mechanically ventilated patients (benzodiazepines, propofol, and dexmedetomidine) have different pharmacologic and immunomodulatory effects that may impact infection risk. Clinical data are limited but retrospective observational series have found associations between sedative use and pneumonia whereas prospective studies of sedative interruptions have reported possible decreases in bloodstream infections, pneumonia, and ventilator-associated events. CONCLUSION Infection rates appear to be highest with benzodiazepines, intermediate with propofol, and lowest with dexmedetomidine. More data are needed but studies thus far suggest that a better understanding of sedation practices and infection risk may help hospital epidemiologists and critical care practitioners find new ways to mitigate infection risk in critically ill patients. Infect Control Hosp Epidemiol 2016;1-9.

Hemorheological in vitro action of propofol on erythrocytes from healthy donors and diabetic patients.

Drugs used during anesthesia might induce disturbance on microcirculation due to their systemic cardiovascular actions and to direct hemorheological effects. A comparative investigation of the hemorheological alterations related to in vitro propofol treatment of red blood cells (RBCs) from healthy and diabetic volunteers is presented here. Viscoelasticity and aggregation of RBCs from type 2 diabetic patients (DBT) and healthy donors (HD) were studied from RBCs incubated with propofol near steady-state concentration. 'S parameter', which measures the aggregation degree, was obtained using digital analysis of microscopic images. Erythrocyte viscoelasticity parameters were determined using an Erythrocyte Rheometer. Results obtained from DBT samples showed an increase of 10% or more in aggregation due to the propofol action. The phase shift between erythrocyte response and oscillating shear stress applied at 1 Hz was altered by propofol treatment of erythrocyte from HD and DBT. Propofol could produce slight alterations in the rheological behavior of erythrocyte from HD and DBT, at concentrations near those of steady state. Moreover, this anesthetic could induce an adverse effect in DBT, particularly on erythrocyte aggregation. The observed hemorheologic alteration would increase the possibility of microcapillary obstruction. Hence, this type of study [0] would prove relevant to avoid possible postoperative complications.

Development of a homogeneous immunoassay for the detection of zolpidem in urine.

Sleep disorders are common conditions that affect about 40 million people in the U.S every year, the most common of which is insomnia, which is characterized by difficulty falling or staying asleep. Zolpidem (Ambien) is a non-benzodiazepine prescription drug that is used to treat insomnia and is often preferred over the commonly used benzodiazepines due to a lesser side effect profile. This is because the non-benzodiazepine binding is more selective to GABA-A receptors versus the non-selective binding of benzodiazepines. With the increasing popularity of non-benzodiazepines, drug abuse and driving-while-impaired cases involving sleep-inducing drugs have risen. Therefore, a highly sensitive and rapid homogeneous immunoassay (EMIT-type assay) has been developed for the detection of zolpidem in urine. The zolpidem antibody is highly specific and does not cross-react with other newer sleep aids such as zopiclone and zaleplon. This assay has a detection limit of 5 ng/mL for zolpidem in urine. Further evaluation of this assay using liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis of authentic urine samples demonstrated that the accuracy of the assay is greater than 90%. Because this assay is designed to measure the non-conjugated drug in urine, it resulted in simplification for gas chromatography-MS or LC-MS-MS confirmation methods that do not require urine hydrolysis before solid-phase extraction or liquid-liquid extraction.

Sedation & immunomodulation.

The management of critically ill patients necessitates the use of sedatives and analgesics to provide patient comfort and cooperation. These drugs exert profound effects on all organ systems, not only the central nervous system, and this article describes the immunologic effects of the commonly used critical care sedatives: propofol, the benzodiazepines, opioids, and alpha(2)-adrenoceptor agonists. Benzodiazepines, opioids, and possibly even propofol worsen outcome in animal models of infection, whereas preliminary evidence suggests that the alpha(2)-adrenoceptor agonist, dexmedetomidine, may improve outcomes in the setting of infection. Given the burden of sepsis and secondary infections in critical care, choice of sedation may need to be carefully considered to preserve immune responses in critically ill patients.

Development of immunoaffinity solid phase microextraction probes for analysis of sub ng/mL concentrations of 7-aminoflunitrazepam in urine.

We report on the development of solid phase microextraction probes for drug analysis, prepared with antibodies specific for benzodiazepines covalently immobilized to the surface. In the technique, immobilized antibody probes are exposed to a sample containing the drug for 30 min. Extracted drugs are subsequently desorbed from the probes in 500 microL of methanolic desorption solution, which is dried, reconstituted in a small volume of injection solution and analysed by LC-MS/MS. The antibodies were characterized both before and after immobilization, to facilitate the rational selection of antibodies for such analyses. Polyclonal and monoclonal antibodies were compared as was the impact of affinity purification of the polyclonal antibody to isolate the drug-specific fraction. The probes were evaluated for utility in analyzing 7-aminoflunitrazepam at sub ng/mL concentrations in urine, which is expected to be found several days after a single oral dose of 2 mg of flunitrazepam. Such analyses are required in monitoring for abuse of this drug, both in terms of 'club drug' use and in cases of drug-facilitated sexual assault. In these cases drug concentrations in blood and urine are much lower than in chronic abuse cases and are difficult to analyse by conventional methods. The method developed has a limit of detection of 0.02 ng/mL, with accuracy ranging from 1% to 27% and precision (% R.S.D.) ranging from 2% to 10% between the lower and upper limits of quantitation for the analysis of 7-aminoflunitrazepam in urine. The dynamic range of the method is from 0.02 ng/mL, which is limited by the instrument sensitivity, to 0.5 ng/mL, which is approaching the capacity of the probes. This would allow for quantitative analysis of samples at concentrations below that measurable by many other methods for general benzodiazepines analysis from urine, and a highly selective screen for samples at higher concentrations. The method has similar limits of detection to the most sensitive literature methods specifically designed for such analysis but with the advantage of significantly simplified sample preparation. This simplification makes the technique more amenable for use by both professionals and non-professionals.

Anaphylaxis during anesthesia: results of a 12-year survey at a French pediatric center.

BACKGROUND: Following adverse reactions to anesthesia, tests are carried out to determine the mechanism of the reaction and to identify the agent responsible. No specific data are available in France concerning such skin tests in children. METHODS: Between 1989 and 2001, we assessed hypersensitivity reactions to general anesthesia in 68 children. Thirty underwent more than one operation, for congenital malformations. Immunoglobulin (Ig)E-mediated anaphylaxis was diagnosed on skin tests combined with the clinical history. RESULTS: Grade I, II and III reactions were observed in 20, 27 and 21 children, respectively. IgE-mediated anaphylaxis was diagnosed in 51 children: 31 (60.8%) for neuromuscular blocking agents (NMBA), 14 (27%) for latex, seven (14%) for colloids, five (9%) for opioids and six (12%) for hypnotics. Vecuronium was the NMBA causing the largest number of reactions. Cross reactivity to NMBA available in France was observed in 23 of 30 children (76%), particularly for vecuronium and atracurium or pancuronium. The estimated frequency of IgE mediated anaphylactic reactions was one in 2100 operations. Based on our results, 25 children subsequently received a different anesthetic with no adverse reaction. CONCLUSIONS: As in adults, NMBA, then latex were responsible for most anaphylactic reactions during anesthesia. Our results confirm that skin tests with anesthetic agents are feasible and safe in children and improve the safety of subsequent anesthetic procedures.

Pentobarbital desensitization in a 3-month-old child.

Barbiturates, a class of medications commonly used as antiepileptics and sedatives, are known to cause adverse reaction, with the most commonly reported immune-mediated reactions being anticonvulsant hypersensitivity syndrome. Other types of allergic reactions such as immediate hypersensitivity reactions also can occur. We present a 3-month-old child with refractory generalized convulsive status epilepticus who required pentobarbital therapy in the context of phenobarbital sensitivity because of progressive generalized seizures unresponsive to other aggressive therapies. Skin tests to pentobarbital and phenobarbital were negative. In the intensive care unit setting, intravenous pentobarbital desensitization was performed without reaction. To our knowledge, this is the first reported protocol for pentobarbital desensitization.

Use of ANAR for the therapy of opium withdrawal syndrome.

We studied the efficiency of ANAR containing antibodies to morphine (dilutions C300 and C200) in the therapy of patients with the opium withdrawal syndrome. In patients with moderate to severe forms of the opium withdrawal syndrome therapeutic activity of ANAR was comparable to that of standard symptomatic drugs. ANAR possessed vegetostabilizing, sedative, and analgetic properties. Treatment with ANAR allowed us to reduce doses of psychotropic and analgetic preparations and delay the development of withdrawal symptoms by 18-24 h.

Incidence of histamine release after the administration of midazolam-ketamine in allergic patients.

OBJECTIVE: We examined the effects of midazolam-ketamine which was used during the induction of anesthesia against histamine release, skin reactions and hemodynamic changes in patients with a history of allergy. SUBJECTS: Forty allergic patients and 40 non-allergic patients undergoing oral surgery were examined. METHODS: Midazolam ketamine was used for the induction of anesthesia in 40 patients with a history of allergy (M-K group) and thiamylal was used for the induction of anesthesia in 40 patients without any history of allergy (BARB group). Venous blood samples were obtained before induction as a control and 0.5, 1, 3, 5 minutes after the administration of each drug in order to measure the plasma histamine level. In addition, any observed hemodynamic changes were simultaneously recorded. The plasma histamine level was measured using the HPLC (high performance liquid chromatography) post-label system. RESULTS: The incidence of histamine release, skin reactions and hemodynamic changes were 37.5%, 10.0% and 7.5%, in the M-K group, and 40.0%, 12.5% and 12.5%, in the BARB group, respectively. Although the mean basal plasma histamine level in the M-K group (0.46 +/- 0.23 ng/ml) who had a history of allergy was much higher than that in the BARB group (0.28 +/- 0.17 ng/ml) (p < 0.001), the incidence of histamine release and clinical symptoms were similar between the two groups. CONCLUSIONS: The induction of anesthesia with midazolam-ketamine was thus found to be a valuable method for allergic patients, because the incidence of histamine release, skin reactions and hemodynamic changes in allergic patients were similar to those in non-allergic patients induced by thiamylal and no significant changes were observed in the plasma histamine level after the administration of midazolam-ketamine in spite of the high level of basal plasma histamine.

A barbiturate screening assay for the Abbott AxSYM analyzer.

A fluorescence polarization immunoassay for barbiturates on the Abbott AxSYM analyzer is described. The assay displayed dilution linearity up to 1200 ng/mL; coefficients of variation varied from 5.96 to 8.61%; recovery varied from 94.9 to 105.3%; and sensitivity was less than 40 ng/mL. Good correlation between the standard six- and factory two-point calibration methods was observed. The Immunoassay demonstrated good cross-reactivity to several commonly prescribed barbiturates; low cross-reactivity with structurally similar compounds; low interference from endogenous substances, dyes, preservatives, and several commonly available adulterants; and good correlation with the TDx Barbiturate Urine assay.

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

OBJECTIVE: To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. DESIGN: Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). SETTING: Clinical Pharmacology Unit within a teaching hospital. MAIN OUTCOME MEASURES: Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. RESULTS: Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. CONCLUSIONS: These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.