Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction.

STUDY OBJECTIVE: Several methods are available to predict unbound (free) phenytoin concentrations in patients with hypoalbuminemia; however, predictive methods have not been evaluated in patients with concurrent hypoalbuminemia and kidney dysfunction or in patients with mild to moderate (estimated glomerular filtration rate [eGFR] 30-90 ml/min/1.73 m2 ) kidney dysfunction alone. Thus the objective was to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or kidney dysfunction. DESIGN: Retrospective chart review. SETTING: Large academic medical center. PATIENTS: A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. MEASUREMENTS AND MAIN RESULTS: Free phenytoin concentrations were estimated in patients without kidney dysfunction using the Winter-Tozer, Anderson, Kane, and Cheng equations. For the analysis in patients with eGFR lower than 90 ml/min/1.73 m2 , free phenytoin concentrations were estimated using the Shiner-Tozer derivation with adjusted affinity coefficients (C = 0.15, 0.20, 0.25, and 0.30). For both analyses, accuracy of predictive methods was evaluated by P20, the proportion of estimations within 20% of the measured free phenytoin concentration. In 158 patients with normal kidney function/normal albumin concentrations, 73 with normal kidney function/hypoalbuminemia, or 47 with mild kidney dysfunction/normal albumin concentrations, the Anderson method had the highest accuracy (86%, 82%, and 92%, respectively) and highest precision compared with the other methods. In 47 patients with normal albumin concentrations and mild kidney dysfunction or 13 with moderate kidney dysfunction, the free fraction was unchanged, and total phenytoin concentrations accurately reflected free concentrations. In 17 patients with hypoalbuminemia and mild or 17 with moderate kidney dysfunction, the Winter-Tozer (67% and 50%, respectively) and the Anderson (56% and 67%, respectively) methods had the highest accuracy compared with other methods with significantly lower accuracy compared with patients with normal kidney function. In the 14 patients with severe kidney dysfunction and hypoalbuminemia, none of the coefficients had a P20 accuracy greater than 45%. CONCLUSION: In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein-binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.

Do-not-attempt-resuscitation orders and prognostic models for intraparenchymal hemorrhage.

OBJECTIVES: Statistical models predicting outcome after intraparenchymal hemorrhage include patients irrespective of do-not-attempt-resuscitation orders. We built a model to explore how the inclusion of patients with do-not-attempt-resuscitation orders affects intraparenchymal hemorrhage prognostic models. DESIGN: Retrospective, observational cohort study from May 2001 until September 2003. SETTING: University-affiliated tertiary referral hospital in Seattle, WA. PATIENTS: Four hundred twenty-four consecutive patients with spontaneous intraparenchymal hemorrhage. MEASUREMENTS AND MAIN RESULTS: We retrospectively abstracted information from medical records of intraparenchymal hemorrhage patients admitted to a single hospital. Using multivariate logistic regression of presenting clinical characteristics, but not do-not-attempt-resuscitation status, we generated a prognostic score for favorable outcome (defined as moderate disability or better at discharge). We compared observed probability of favorable outcome with that predicted, stratified by do-not-attempt-resuscitation status. We then generated a modified prognostic score using only non-do-not-attempt-resuscitation patients. Records of 424 patients were reviewed: 44% had favorable outcome, 43% had a do-not-attempt-resuscitation order, and 38% died in hospital. The observed and predicted probability of favorable outcome agreed well with all patients taken together. The observed probability of favorable outcome was significantly higher than predicted in non-do-not-attempt-resuscitation patients and significantly lower in do-not-attempt-resuscitation patients. Results were similar when applying a previously published and validated prognostic score. Our modified prognostic score was no longer pessimistic in non-do-not-attempt-resuscitation patients but remained overly optimistic in do-not-attempt-resuscitation patients. CONCLUSIONS: Although our prognostic model was well-calibrated when assessing all intraparenchymal hemorrhage patients, predictions were significantly pessimistic in patients without and optimistic in those with do-not-attempt-resuscitation orders. Such pessimism may drive decisions not to attempt resuscitation in patients in whom a favorable outcome may have been possible, thereby creating a self-fulfilling prophecy. To be most useful in clinical decision making, intraparenchymal hemorrhage prognostic models should be calibrated to large intraparenchymal hemorrhage cohorts in whom do-not-attempt-resuscitation orders were not used.

Prior antiplatelet therapy, platelet infusion therapy, and outcome after intracerebral hemorrhage.

BACKGROUND: Recent studies examining the effect of prior antiplatelet therapy (APT) on outcome in patients with spontaneous intracerebral hemorrhage (ICH) have shown conflicting results. The effect of platelet infusion therapy (PIT) on outcome in patients with ICH taking APT is unknown. METHODS: We reviewed records of patients with ICH admitted to a single hospital, excluding those with international normalized ratio greater than or equal to 1.5. Baseline characteristics were compared by APT status in all patients and by PIT status in the subgroup of patients on APT. We used multivariate analyses to generate propensity and prognostic scores for exposures (APT and PIT) and outcomes (favorable outcome and hospital death), respectively. We examined the associations between exposures and outcomes and adjusted these for propensity and/or prognostic scores. We then validated our findings with a sensitivity analysis. RESULTS: Of 368 patients identified, 121 (31.3%) were taking APT, mostly aspirin. Patients on APT were older and more likely to have vascular comorbidities than those not. The APT group also had a higher initial Glasgow Coma Scale score at presentation. In analyses adjusted for both propensity and prognostic scores, APT was associated with a higher likelihood of hospital death (odds ratio [OR] 2.4; 95% confidence interval [CI] 1.1-5.6); PIT did not prevent hospital death (OR 1.2; 95% CI 0.3-5.5) or increase favorable outcome (OR 1.4; 95% CI 0.4-5.4). CONCLUSIONS: In patients with ICH, APT is associated with an increased risk of hospital death. In the subgroup of patients on APT, PIT did not prevent death or improve outcome.