The association of polypharmacy with functional decline in elderly patients undergoing cardiac surgery.

AIMS: Identifying preoperative risk factors in older patients becomes more important to reduce adverse functional outcome. This study investigated the association between preoperative medication use and functional decline in elderly cardiac surgery patients and compared polypharmacy as a preoperative screening tool to a clinical frailty assessment. METHODS: This sub-study of the Anaesthesia Geriatric Evaluation study included 518 patients aged ≥70 years undergoing elective cardiac surgery. The primary outcome was functional decline, defined as a worse health-related quality of life or disability 1 year after surgery. The association between polypharmacy (i.e. ≥5 prescriptions and <10 prescriptions) or excessive polypharmacy (i.e. ≥10 prescriptions) and functional decline was investigated using multivariable Poisson regression. Discrimination, calibration and reclassification indices were used to compare preoperative screening tools for patient selection. RESULTS: Functional decline was reported in 284 patients (55%) and preoperative polypharmacy and excessive polypharmacy showed higher risks (adjusted relative risk 1.57, 95% confidence interval [CI] 1.23-1.98 and 1.93, 95% CI 1.48-2.50, respectively). Besides cardiovascular medication, proton-pump inhibitors and central nervous system medication were significantly associated with functional decline. Discrimination between models with polypharmacy or frailty was similar (area under the curve 0.67, 95% CI 0.61-0.72). The net reclassification index improved when including polypharmacy to the basic model (17%, 95% CI 0.06-0.27). CONCLUSION: Polypharmacy is associated with functional decline in elderly cardiac surgery patients. A preoperative medication review is easily performed and could be used as screening tool to identify patients at risk for adverse outcome after cardiac surgery.

Oral drug dosing following bariatric surgery: General concepts and specific dosing advice.

Bariatric or weight-loss surgery is a popular option for weight reduction. Depending on the surgical procedure, gastric changes like decreased transit time and volume and increased pH, decreased absorption surface in the small intestine, decreased exposure to bile acids and enterohepatic circulation, and decreased gastrointestinal transit time may be expected. In the years after bariatric surgery, patients will also substantially lose weight. As a result of these changes, the absorption, distribution, metabolism and/or elimination of drugs may be altered. The purpose of this article is to report the general influence of bariatric surgery on oral drug absorption, and to provide guidance for dosing of commonly used drugs in this special population. Upon oral drug administration, the time to maximum concentration is often earlier and this concentration may be higher with less consistent effects on trough concentrations and exposure. Additionally, prescription of liquid formulations to bariatric patients is supported by some reports, even though the high sugar load of these suspensions may be of concern. Studies on extended-release medications result in an unaltered exposure for a substantial number of drugs. Also, studies evaluating the influence of timing after surgery show dynamic absorption profiles. Although for this group specific advice can be proposed for many drugs, we conclude that there is insufficient evidence for general advice for oral drug therapy after bariatric surgery, implying that a risk assessment on a case-by-case basis is required for each drug.

Population pharmacokinetic-pharmacodynamic model of propofol in adolescents undergoing scoliosis surgery with intraoperative wake-up test: a study using Bispectral index and composite auditory evoked potentials as pharmacodynamic endpoints.

BACKGROUND: In adolescents limited data are available on the pharmacokinetics (PK) and pharmacodynamics (PD) of propofol. In this study we derived a PK-PD model for propofol in adolescents undergoing idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia using both Bispectral Index (BIS) and composite A-line ARX index (cAAI) as endpoints. METHODS: Fourteen adolescents (9.8-20.1 years) were evaluated during standardized propofol-remifentanil anesthesia for idiopathic scoliosis surgery with an intraoperative wake-up test with reinduction of anesthesia. BIS and cAAI were continuously measured and blood samples collected. A propofol PKPD model was developed using NONMEM. RESULTS: The time courses of propofol concentrations, BIS and cAAI values during anesthesia, intra-operative wakeup and reduction of anesthesia were best described by a two-compartment PK model linked to an inhibitory sigmoidal Emax PD model. For the sigmoidal Emax model, the propofol concentration at half maximum effect (EC50) was 3.51 and 2.14 mg/L and Hill coefficient 1.43 and 6.85 for BIS and cAAI, respectively. The delay in PD effect in relation to plasma concentration was best described by a two compartment effect-site model with a keo of 0.102 min- 1, ke12 of 0.121 min- 1 and ke21 of 0.172 min- 1. CONCLUSIONS: A population PKPD model for propofol in adolescents was developed that successfully described the time course of propofol concentration, BIS and cAAI in individuals upon undergoing scoliosis surgery with intraoperative wake-up test and reinduction of anesthesia. Large differences were demonstrated between both monitors. This may imply that BIS and cAAI measure fundamentally different endpoints in the brain.

Bispectral Index Monitoring in Terminally Ill Patients: A Validation Study.

CONTEXT: If regular therapies cannot relieve symptoms sufficiently in the last days of life, continuous palliative sedation may serve to reduce consciousness. Sedation level can be measured with EEG monitoring with the bispectral index (BIS) monitor. OBJECTIVES: To determine the feasibility and validity of BIS monitoring in terminally ill patients. METHODS: In this prospective study, BIS registrations were performed in unconscious end-of-life patients admitted to a palliative care center. Validated scores were used to measure level of sedation (Ramsay score), pain (Numeric Rating Scale or Rotterdam Elderly Pain Observations Scale), delirium (Delirium Observation Screening score), and overall comfort (Numeric Rating Scale). Validity and sensitivity to change of BIS values were considered, and the effects of medication and the time till death on BIS values were evaluated in a linear mixed model analysis. RESULTS: Fifty-eight patients were included for analysis. BIS monitoring was acceptable to patients, relatives, and medical staff. BIS values were moderately correlated with Ramsay scores (0.46) but were highly variable for deeply sedated patients. BIS values changed significantly before and after a midazolam dose (P < 0.001). Midazolam treatment resulted on average in a statistically significant reduction of the BIS values (-4.5, 95% CI -7.0 to -2.0), whereas morphine and haloperidol did not. CONCLUSION: This is one of the first validation studies in which BIS monitoring in end-of-life patients is described. BIS monitoring is feasible in unconscious terminally ill patients. However, based on our results, the wide range of BIS values in deeply sedated and comfortable patients seems to hamper its use in daily clinical practice.

A bodyweight-dependent allometric exponent for scaling clearance across the human life-span.

PURPOSE: To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug. METHODS: Data from seven previously published propofol studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model. RESULTS: Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best. CONCLUSIONS: A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight.

The effects of mivacurium-induced neuromuscular block on Bispectral Index and Cerebral State Index in children under propofol anesthesia - a prospective randomized clinical trial.

BACKGROUND: In adults anesthetized with propofol, muscle relaxants may decrease the Bispectral Index (BIS). The aim of this prospective randomized trial was to detect the influence of a muscle relaxant bolus on the BIS and the Cerebral State Index (CSI) in children under propofol anesthesia. METHODS: Forty pediatric patients, age 6.6 +/- 3.3 years, weight 24 +/- 9 kg, scheduled for surgical procedures requiring general anesthesia were enrolled. Two minutes after i.v. injection of 0.3 mcg.kg(-1) of sufentanil, general anesthesia was induced by an initial bolus of 3 mg.kg(-1) of propofol, followed by a continuous infusion titrated to achieve a stable BIS value of 50 +/- 5. Patients received either mivacurium 0.25 mg.kg(-1) (Group Miva) or NaCl 0.9% 0.12 ml.kg(-1) (Group Control). Mean BIS and CSI values per minute were compared between (Miva vs. Control) and within groups (Baseline vs 5 min. after study drug administration). RESULTS: The observed changes in BIS and CSI values before and after administration of study drugs revealed no differences between the study groups. Mean baseline BIS and CSI values were lower than 5 min after study drug administration. There were no intergroup differences with respect to BIS and CSI values at any time point. CONCLUSIONS: These data suggest that in pediatric patients anesthetized with propofol, administration of mivacurium has no impact on BIS and CSI values.

Prediction of propofol clearance in children from an allometric model developed in rats, children and adults versus a 0.75 fixed-exponent allometric model.

For propofol clearance, allometric scaling has been applied successfully for extrapolations between species (rats and humans) and within the human bodyweight range (children and adults). In this analysis, the human bodyweight range is explored to determine for which range an allometric model with a fixed or estimated exponent can be used to predict propofol clearance, without correction for maturation. The predictive value of the allometric equation, clearance (CL) is equal to 0.071 x bodyweight in kg0.78, which was developed from rats, children and adults, and the predictive value of a fixed exponent allometric model derived from the basal metabolic rate, CL is equal to CL standardized to a 70 kg adult x (bodyweight in kg standardized to a 70 kg adult)0.75, were evaluated across five independent patient groups including (i) 25 (pre)term neonates with a postmenstrual age of 27-43 weeks; (ii) 22 postoperative infants aged 4-18 months; (iii) 12 toddlers aged 1-3 years; (iv) 14 adolescents aged 10-20 years; and (v) 26 critically ill adults sedated long term. The median percentage error of the predictions was calculated using the equation %error = (CL(allometric) - CL(i))/CL(i) x 100, where CL(allometric) is the predicted propofol clearance from the allometric equations for each individual and CL(i) is the individual-predicted (post hoc) propofol clearance value derived from published population pharmacokinetic models. In neonates, the allometric model developed from rats, children and adults, and the fixed-exponent allometric model, systematically overpredicted individual propofol clearance, with median percentage errors of 288% and 216%, respectively, whereas in infants, both models systematically underpredicted individual propofol clearance, with median percentage errors of -43% and -55%, respectively. In toddlers, adolescents and adults, both models performed reasonably well, with median percentage errors of -12% and -32%, respectively, in toddlers, 16% and -14%, respectively, in adolescents, and 12% and -18%, respectively, in adults. Both allometric models based on bodyweight alone may be of use to predict propofol clearance in individuals older than 2 years. Approaches that also incorporate maturation are required to predict clearance under the age of 2 years.

A comparison in adolescents of composite auditory evoked potential index and bispectral index during propofol-remifentanil anesthesia for scoliosis surgery with intraoperative wake-up test.

BACKGROUND: The electroencephalogram-derived Bispectral Index (BIS), and the composite A-line ARX index (cAAI), derived from the electroencephalogram and auditory evoked potentials, have been promoted as anesthesia depth monitors. Using an intraoperative wake-up test, we compared the performance of both indices in distinguishing different hypnotic states, as evaluated by the University of Michigan Sedation Scale, in children and adolescents during propofol-remifentanil anesthesia for scoliosis surgery. Postoperative explicit recall was also evaluated. METHODS: Twenty patients (aged 10-20 yr) were enrolled. Prediction probabilities were calculated for induction, wake-up test, and emergence. BIS and cAAI were compared at the start of the wake-up test, at purposeful movement to command, and after the patient was reanesthetized. During the wake-up test, patients were instructed to remember a color, and were then interviewed for explicit recall. RESULTS: Prediction probabilities of BIS and cAAI for induction were 0.82 and 0.63 (P < 0.001), for the wake-up test, 0.78 and 0.79 (P < 0.001), and 0.74 and 0.78 for emergence (P < 0.001). During the wake-up test, a significant increase in mean BIS and cAAI (P < 0.05) was demonstrated at purposeful movement, followed by a significant decline after reintroduction of anesthesia. CONCLUSIONS: During induction, BIS performed better than cAAI. Although cAAI was statistically a better discriminator for the level of consciousness during the wake-up test and emergence, these differences do not appear to be clinically meaningful. Both indices increased during the wake-up test, indicating a higher level of consciousness. No explicit recall was demonstrated.

Awareness in children: another two cases.

Intraoperative awareness is an anesthesia complication and occurs when a patient becomes conscious during a procedure performed under general anesthesia and subsequently has recall of these events. Awareness is well described phenomenon in adults, with an incidence of 0.1-0.2 % for low-risk surgical procedures. Recent studies have shown that awareness in children is more common than in adults. However, causes and the long-term psychological impact of awareness in children are unknown. We report on two cases of intraoperative awareness in children in an attempt to throw further light on this complex problem.

Comparison of bispectral index and composite auditory evoked potential index for monitoring depth of hypnosis in children.

BACKGROUND: In pediatric patients, the Bispectral Index (BIS), derived from the electroencephalogram, and the composite A-Line autoregressive index (cAAI), derived from auditory evoked potentials and the electroencephalogram, have been used as measurements of depth of hypnosis during anesthesia. The performance and reliability of BIS and cAAI in distinguishing different hypnotic states in children, as evaluated with the University of Michigan Sedation Scale, were compared. METHODS: Thirty-nine children (aged 2-16 yr) scheduled to undergo elective inguinal hernia surgery were studied. For all patients, standardized anesthesia was used. Prediction probabilities of BIS and cAAI versus the University of Michigan Sedation Scale and sensitivity/specificity were calculated. RESULTS: Prediction probabilities for BIS and cAAI during induction were 0.84 for both and during emergence were 0.75 and 0.74, respectively. At loss of consciousness, the median BIS remained unaltered (94 to 90; not significant), whereas cAAI values decreased (60 to 43; P < 0.001). During emergence, median BIS and cAAI increased from 51 to 74 (P < 0.003) and from 46 to 58 (P < 0.001), respectively. With respect to indicate consciousness or unconsciousness, 100% sensitivity was reached at cutoff values of 17 for BIS and 12 for cAAI. One hundred percent specificity was associated with a BIS of 71 and a cAAI of 60. To ascertain consciousness, BIS values greater than 78 and cAAI values above 52 were required. CONCLUSIONS: BIS and cAAI were comparable indicators of depth of hypnosis in children. Both indices, however, showed considerable overlap for different clinical conditions.

Human immunodeficiency virus infection in children hospitalised with tuberculosis.

The impact of HIV infection on clinical presentation and outcome of tuberculosis (TB) was studied in children hospitalised at the Brooklyn Hospital for Chest Diseases (BCH), Cape Town over the 2-year period January 1998 to December 1999. Clinical data were extracted from a prospectively compiled patient register. Of 261 children with TB, 114 (median age 24 mths) were not HIV-infected and 36 (median age 23 mths) were HIV-infected. The HIV status of 111 children (median age 37 mths) was not determined. Pulmonary TB with or without extrapulmonary TB occurred in 97 (85%) children who were not HIV-infected, 35 (97%) HIV-infected children and 87 (78%) of those not tested (p = 0.025). A tuberculin reaction > or = 15 mm was elicited in ten (31%) of 32 HIV-infected children, 76 (72%) of 106 non-HIV-infected and 62 (71%) of those not tested (p < 0.001). Mycobacterium tuberculosis was cultured from 116 (49%) of 238 children and drug sensitivity was evaluated in 79. Nine isolates (11%) were resistant to isoniazid (INH) and 11 (14%) to INH and rifampicin (RMP). Two HIV-infected children treated previously in BCH for drug-sensitive TB were re-admitted with INH and RMP resistance. Two (2%) non-HIV-infected children, six (17%) HIV-infected children and one (1%) child with undetermined HIV status died (p < 0.001).