Validation of the Critical Care Pain Observation Tool in Critically Ill Patients With Delirium: A Prospective Cohort Study.

OBJECTIVES: The 2013 clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the ICU suggest that pain be routinely assessed using a validated pain assessment tool. Currently available tools have only been evaluated in nondelirious critically ill patients, yet delirium can affect as many as 80% of ICU patients. The validated pain assessment tool adopted by our institution is the Critical Care Pain Observation Tool, and the objective of this study was to investigate the validity of this tool in patients with evidence of delirium. DESIGN: Prospective cohort study. SETTING: Two ICUs within a Canadian tertiary healthcare center. PATIENTS: Forty consecutive adult patients deemed delirious on the day of enrollment using the Confusion Assessment Method for ICU. MEASUREMENTS AND MAIN RESULTS: Serial Critical Care Pain Observation Tool assessments were conducted simultaneously by study personnel and objective nurses at baseline and after nonpainful and painful stimuli. Subjective opinions about pain and objective physical variables (including mean arterial pressure, heart rate, respiratory rate, and oxygen saturation) were collected at the same time points. Discriminant validity was described using paired t tests, whereas internal consistency was described using the Cronbach α statistic. Responsiveness of the Critical Care Pain Observation Tool was measured by effect size, and reliability was described as the agreement between raters. Comparisons between the Critical Care Pain Observation Tool and the subjective assessments and objective measurements were based on positive and negative percent agreement. Critical Care Pain Observation Tool demonstrated excellent discriminant validity as evidenced by a highly statistically and clinically significant change in mean Critical Care Pain Observation Tool scores between baseline and painful procedures (mean difference, 3.13 ± 1.56; p < 0.001; Cohen D, 2.0). Interrater agreement was also excellent (κ > 0.6), and scores between raters were highly correlated (r = 0.957). The Critical Care Pain Observation Tool possessed a high level of internal consistency (overall Cronbach α, 0.778). Percent agreement was found to be greater between the Critical Care Pain Observation Tool and the nurse's subjective opinion of the presence or absence of pain when compared with that between the Critical Care Pain Observation Tool and physiologic variables (80.5% vs 67.5%, respectively). CONCLUSIONS: The Critical Care Pain Observation Tool is a valid pain assessment tool in noncomatose, delirious adult ICU patients who are unable to reliably self-report the presence or absence of pain.

Inappropriate medication administration practices in Canadian adult ICUs: a multicenter, cross-sectional observational study.

BACKGROUND: Critically ill patients often receive multiple medications via continuous intravenous infusion. Coadministration of multiple medications through the same port of a venous access device often is necessary but requires an assessment of compatibility. OBJECTIVE: To describe the frequency of inappropriate coadministration of continuously infused medications via a Y-site and the use of intravenous catheters in patients in Canadian intensive care units (ICUs) in a multicenter, cross-sectional observational study. METHODS: Data pertaining to medication compatibility via Y-site infusion (medication combinations known to be incompatible or not known to be compatible), frequency of specific medications administered via continuous infusion, and catheter use (median number, location, and types of venous catheters) were collected from medical records of 434 patients in the ICUs of 13 teaching hospitals in Canada. RESULTS: Forty-six percent of patients were receiving 2 or more medication infusions simultaneously. Forty episodes of inappropriate coadministration of these infusions were identified in 37 patients. The prevalence of inappropriate coadministration of drugs via a Y-site port in all patients was 8.5% (95% CI 5.8-11.2). The prevalence of incompatible combinations via Y-site in patients with 2 or more medication infusions was 18.7%. Twenty-five of these 37 patients could have had their drug schedules rearranged into acceptable combinations, leaving 12 patients who would have required additional intravenous access to facilitate appropriate medication infusions. Median (range) number of central and peripheral venous access devices inserted per patient were 1 (0-4) and 1 (0-5), respectively. Seventeen of 95 patients with 2 or more central venous catheters could have had their medication infusions rearranged to render 1 catheter idle. CONCLUSIONS: Inappropriate Y-site combinations of medications continuously infused in Canadian ICUs are common. Management of medication infusions could, however, have been optimized in most of these situations.

Impaired gastrointestinal transit and its associated morbidity in the intensive care unit.

PURPOSE: To determine the proportion of critically ill adults developing impaired gastrointestinal transit (IGT) using a clinically pragmatic definition, its associated morbidity and risk factors. MATERIALS AND METHODS: Critically ill adult patients receiving enteral nutrition for ≥ 72 hours and mechanically ventilated for ≥ 48 hours were prospectively identified. IGT was defined as absence of a bowel movement for ≥ 3 days, treatment for constipation, and one of the following: (1) radiologic confirmed ileus, (2) feed intolerance, (3) abdominal distention, or (4) gastric decompression. RESULTS: One thousand patients were screened, and 248 were included for analysis. Fifty patients (20.1%; 95% confidence interval, 15.1-25.6%) developed IGT persisting for 6.5 ± 2.5 days. Patients with IGT had longer lengths of intensive care unit stay and were less likely to reach nutrition targets compared to patients without IGT or traditional definitions of constipation. Daily opioid use and pharmacological constipation prophylaxis were identified risk factors for IGT. CONCLUSION: Traditional definitions of constipation or ileus in intensive care unit patients are simplistic and lack clinical relevance. Pragmatically defined IGT is a common complication of critical illness and is associated with significant morbidity. Future interventional studies for IGT in critically ill adults should use a more clinically relevant definition and evaluate energy deficits and lengths of stay as clinically relevant outcomes.

The safety of ethanol infusions for the treatment of methanol or ethylene glycol intoxication: an observational study.

BACKGROUND: Methanol or ethylene glycol ingestion may result in significant morbidity or death without prompt treatment. Despite traditional and widespread use of intravenous ethanol as an antidote, its safety is not well described. An evaluation of the safety and ease of titrating ethanol infusions is necessary given the availability of an alternative antidote. OBJECTIVE: To evaluate the safety and ease of titrating ethanol infusions for the treatment of methanol or ethylene glycol ingestion. METHODS: We reviewed the hospital records of adults treated with ethanol at The Ottawa Hospital for methanol or ethylene glycol ingestion over a 9-year period. Using a standardized case report form, a single reviewer identified prespecified adverse events that developed after the start of ethanol therapy and classified dose adjustments during ethanol therapy as appropriate or inappropriate based on a priori criteria. RESULTS: Forty-nine cases of methanol or ethylene glycol ingestion treated with ethanol were included in the analysis, of which 45 underwent hemodialysis, 38 were admitted to the intensive care unit, and 4 died. At least one adverse event was identified in 45 (92%) cases, including 35 (71%) with agitation requiring chemical or physical restraints and 10 (20%) with a depressed level of consciousness treated with intubation. The median number of ethanol concentration measurements per treatment course was 6 (range 0-24), of which only 27% were within the target range of 22 to 30 mmol/L and 47% were below. When measured concentrations were outside the target, the adjustment in ethanol dosing (or lack thereof) was deemed inappropriate 59% of the time, including 69% of the time during hemodialysis. CONCLUSION: Based on actual practice in a large academic centre, adverse events occur frequently with intravenous ethanol infusions, and ethanol titration is inefficient. The safety profile and therapeutic drug monitoring considerations for ethanol should be considered when choosing an antidote for methanol or ethylene glycol ingestion.

Stability of venlafaxine immediate-release suspensions.

Venlafaxine is a novel antidepressant that works by inhibiting the reuptake of serotonin and norepinephrine. The objectives of this study were to reformulate a venlafaxine extended-release suspension into an immediate-release preparation and then determine the physical and chemical stability of the new venlafaxine formulation. Suspensions of venlafaxine (75mg/5mL) were prepared from extended-release microspheres that had been reduced to powder and then dispersed in either OraPlus/OraSweet (50:50) or simple syrup. Triplicate samples of the suspensions were collected from amber plastic bottles stored at either 5 degrees C or 23 degrees C on days 0, 7, 14, 21, and 28, and assayed. Physical stability was based on color and pH changes. A validated high performance liquid chromatography assay method was used to determine the chemical stability of the active ingredient. This study found that venlafaxine immediate-release suspensions, prepared in either OraPlus/OraSeet or simple syrup, are physically and chemically stable for 28 days when stored in amber plastic bottles at either 5 deg C or 23 deg C.

Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units.

OBJECTIVE: To quantify the physical and chemical stability data published for commonly used continuously infused medications in the intensive care unit and to evaluate the quality of the studies providing these data. DATA SOURCES AND STUDY SELECTION: We conducted a systematic electronic literature search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts as well as the references of electronic drug compatibility textbooks for all English and French language research publications evaluating the physical compatibility or chemical stability of the 820 possible two-drug combinations of 41 commonly used drugs in an adult intensive care unit. DATA EXTRACTION AND SYNTHESIS: A total of 93 studies comprised of 86 (92%) studies evaluating physical compatibility and 35 (38%) studies evaluating chemical compatibility of at least one drug combination of interest were included. Physical and/or chemical compatibility data exist for only 441 of the possible 820 two-drug combinations (54%), whereas chemical compatibility data exist for only 75 (9%) of the possible combinations. Of the 441 combinations for which compatibility data are available, 67 (15%) represent incompatible combinations and 39 (9%) had conflicting data in which both compatible and incompatible data were identified. CONCLUSIONS: Physical compatibility studies that provide the basis for y-site compatibility are lacking for commonly used medications in intensive care unit patients and may contribute to unsafe medication practices. Furthermore, the heterogeneity in the methodology of these studies likely contributes to the common finding of conflicting data for specific combinations of drugs. Future studies should apply similar methodologic and reporting principles to be able to reproduce and compare outcomes both clinically and in the laboratory.

Pharmacodynamic activity of telithromycin at simulated clinically achievable free-drug concentrations in serum and epithelial lining fluid against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae for which telithromycin MICs vary.

The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 microg/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [C(max)] in serum, 0.7 microg/ml; half-life [t(1/2)], 10 h; free-drug C(max) in ELF, 6.0 microg/ml; t(1/2), 10 h). Starting inocula were 10(6) CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log(10) CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were C(max) 0.9 +/- 0.08 microg/ml, area under the curve to MIC (AUC(0-24 h)) 6.4 +/- 1.5 microg . h/ml, and t(1/2) of 10.6 +/- 0.6 h. Telithromycin-free ELF concentrations achieved in the model were C(max) 6.6 +/- 0.8 microg/ml, AUC(0-24 h) 45.5 +/- 5.5 microg . h/ml, and t(1/2) of 10.5 +/- 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 microg/ml and 1 microg/ml, respectively. Free-telithromycin S and ELF concentrations simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C(max)/MIC > or = 1.8 and AUC(0-24 h)/MIC > or = 12.5 were bacteriostatic (0.1 to 0.2 log(10) killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h.

Ertapenem: review of a new carbapenem.

The carbapenems are beta-lactam-type antibiotics with an exceptionally broad spectrum of activity. Ertapenem is a new carbapenem developed to address the pharmacokinetic shortcomings (short half-life) of imipenem and meropenem. Ertapenem shares similar structural features with meropenem, including its stability to dehydropeptidase-1, allowing it to be administered without a dehydropeptidase-1 inhibitor. Ertapenem, like imipenem and meropenem, demonstrates broad-spectrum antimicrobial activity against many Gram-positive and -negative aerobes and anaerobes and is resistant to nearly all beta-lactamases, including extended-spectrum beta-lactamases and AmpCs. However, it differs from both imipenem and meropenem in demonstrating limited activity against Enterococcusspp., Pseudomonasaeruginosa and other nonfermentative Gram-negative bacteria commonly associated with nosocomial infections. The extensive protein binding of ertapenem extends the half-life and allows for once-daily dosing. Prospective, multicenter, randomized, double-blind, comparative clinical studies demonstrate similar clinical efficacy of ertapenem compared with other agents. Clinical trials of complicated intra-abdominal infection, acute pelvic infection, complicated skin and soft-structure infection, community-acquired pneumonia and complicated urinary tract infections demonstrated that ertapenem has equivalent efficacy and safety compared with ceftriaxone and piperacillin/tazobactam. Ertapenem is a promising new carbapenem with excellent efficacy and safety for the treatment of a variety of community-acquired infections. It also appears to be of great value as an outpatient parenteral antimicrobial therapy.

Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations.

BACKGROUND: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. MATERIALS AND METHODS: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 10(6) cfu/mL in Mueller-Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log(10) cfu/mL versus initial inoculum). RESULTS: Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. CONCLUSION: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.