Dale S. Bikin

The clinical significance of variations in ethanol toxicokinetics.

IntroductionMany variables affect the interpretation of an isolated ethanol level in an acutely intoxicated patient. This review demonstrates the significant variability in metabolism and elimination of ethanol, how it can differ between individuals, and the clinical importance of these variables.DiscussionIsolated ethanol values in a clinical scenario are only a snapshot of a dynamic process. The individual pharmacokinetic differences of people make it extremely difficult to estimate ethanol elimination rates or calculate previous ethanol concentrations at the time of an accident because of medical-legal reasons. Not only are the techniques used in measuring ethanol concentrations in bodily fluids (blood, serum, breath, and urine) not equivalent, but also the units used to report ethanol concentrations are often misinterpreted. Acute and chronic tolerance and social adaptive changes make interpreting this isolated ethanol level extremely difficult. The purpose of this review is to enable the clinician to appropriately interpret ethanol concentrations.ConclusionThe clinical evaluation of a patient’s inebriation is always more reliable than an isolated ethanol level for determining disposition. Only an estimation of a current serum ethanol level can be made if the blood draw was performed hours earlier. This review is clinically important because it shows the clinically significant variability in metabolism and elimination of ethanol and how it can differ between individuals. It will also describe different ways to measure ethanol concentrations and how to compare them. Finally, the interpretation of isolated ethanol levels will be discussed.

Ethylene Glycol Elimination Kinetics and Outcomes in Patients Managed Without Hemodialysis

STUDY OBJECTIVE Ethylene glycol remains an important toxic cause of metabolic acidosis and acute renal failure. Traditionally, inhibition of alcohol dehydrogenase along with hemodialysis has been used for treatment. Because of reported long elimination half-life of ethylene glycol during alcohol dehydrogenase inhibition, hemodialysis has been used in patients who are otherwise doing well to clear ethylene glycol. We study ethylene glycol elimination kinetics in patients treated with fomepizole, but without hemodialysis. METHODS This was a retrospective, multicenter cohort study of patients older than 15 years who were treated at one of 3 medical centers during an 8-year period. Inclusion criteria were peak serum ethylene glycol concentration greater than 20 mg/dL, lack of renal failure on admission, treatment with fomepizole but without hemodialysis, and availability of serial serum ethylene glycol concentrations, allowing calculation of elimination half-life. The primary outcome variable was ethylene glycol elimination half-life; mortality and onset of renal failure were secondary outcome variables. RESULTS During the study period, 85 patients were treated for ethylene glycol toxicity, of whom 40 met inclusion criteria. The mean serum ethylene glycol elimination half-life was 14.2 hours (SD=3.7 hours; 95% confidence interval 13.1 to 15.3 hours). One patient presented with metabolic acidosis on admission and developed mild transient renal insufficiency but did not require hemodialysis. No patient died. CONCLUSION The mean elimination half-life of ethylene glycol in this population was shorter than previously reported without hemodialysis, and this select group of patients did well without enhanced elimination by hemodialysis.

The lack of transplacental movement of the cyanide antidote thiosulfate in gravid ewes

UNLABELLED A previous study reported that the co-infusion of IV sodium thiosulfate (STS) with sodium nitroprusside (SNP) to near-term gravid ewes prevented both maternal and fetal cyanide toxicity. We questioned whether maternally administered STS crossed the ovine placenta to enhance fetal transulfuration of cyanide, or whether the fetus was dependent on maternal detoxification of cyanide after diffusion of cyanide into the maternal circulation. Ten anesthetized, near-term gravid ewes underwent hysterotomies with delivery of fetal heads for venous catheterization. Five control ewes received IV isotonic sodium chloride solution, whereas five experimental ewes received IV STS (50 mg/kg over 15 min). Serial plasma thiosulfate concentrations in ewes and fetuses were measured over 135 min. Areas under the time-plasma thiosulfate concentration curves were calculated for experimental and control ewes at 2758+/-197 and 508+/-74 min x mg(-1) x L(-1), respectively (P < 0.008). Mean areas under the curve for experimental and control fetuses were 236+/-34 and 265+/-23 min x mg(-1) x L(-1), respectively (P > 0.5). Maternally administered STS may prevent fetal cyanide poisoning from SNP administration without relying on STS crossing the placenta into the fetal circulation. Fetal cyanide may cross down a concentration gradient from fetal to maternal circulation, to be transulfurated to thiocyanate in maternal tissues. IMPLICATIONS We evaluated the mechanism of action of sodium thiosulfide (STS) in sodium nitroprusside-induced cyanide toxicity in the ewe. Fetal cyanide poisoning is alleviated by maternal administration of STS, although this cyanide antidote apparently does not cross the placenta.

Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients

Background: Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial. Objective: The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations. Methods: A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia. Results: A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level. Conclusions: There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized.

Trigger alerts associated with laboratory abnormalities on identifying potentially preventable adverse drug events in the intensive care unit and general ward

Background Medication safety strategies involving trigger alerts have demonstrated potential in identifying drug-related hazardous conditions (DRHCs) and preventing adverse drug events in hospitalized patients. However, trigger alert effectiveness between intensive care unit (ICU) and general ward patients remains unknown. The objective was to investigate trigger alert performance in accurately identifying DRHCs associated with laboratory abnormalities in ICU and non-ICU settings. Methods This retrospective, observational study was conducted at a university hospital over a 1-year period involving 20 unique trigger alerts aimed at identifying possible drug-induced laboratory abnormalities. The primary outcome was to determine the positive predictive value (PPV) in distinguishing drug-induced abnormal laboratory values using trigger alerts in critically ill and general ward patients. Aberrant lab values attributed to medications without resulting in an actual adverse event ensuing were categorized as a DRHC. Results A total of 634 patients involving 870 trigger alerts were included. The distribution of trigger alerts generated occurred more commonly in general ward patients (59.8%) than those in the ICU (40.2%). The overall PPV in detecting a DRHC in all hospitalized patients was 0.29, while the PPV in non-ICU patients (0.31) was significantly higher than the critically ill (0.25) (p = 0.03). However, the rate of DRHCs was significantly higher in the ICU than the general ward (7.49 versus 0.87 events per 1000 patient days, respectively, p < 0.0001). Although most DRHCs were considered mild or moderate in severity, more serious and life-threatening DRHCs occurred in the ICU compared with the general ward (39.8% versus 12.4%, respectively, p < 0.001). Conclusions Overall, most trigger alerts performed poorly in detecting DRHCs irrespective of patient care setting. Continuous process improvement practices should be applied to trigger alert performance to improve clinician time efficiency and minimize alert fatigue.

Comparison of acute kidney injury risk associated with vancomycin and concomitant piperacillin/tazobactam or cefepime in the intensive care unit

Purpose: The objective of this study was to evaluate AKI incidence with concomitant vancomycin and piperacillin/tazobactam (PTZ) compared to vancomycin and cefepime (FEP) in critically ill patients. Materials and methods: A retrospective, cohort study was conducted in adult critically ill patients from January 1, 2014 to December 31, 2017. The primary aim was to compare the incidence of AKI during concomitant therapy or until hospital discharge. Secondary analyses included AKI severity, time to AKI as well as recovery, and clinical outcomes. Results: Overall, 333 patients were evaluated. The AKI rate in the vancomycin/PTZ group and vancomycin/FEP group were similar (19.5% vs. 17.3%, respectively, p = .612). Renal replacement therapy (RRT) was initiated in 10.0% and 3.8% administered vancomycin/PTZ and vancomycin/FEP groups, respectively (p = .04). Multivariate regression found vancomycin/PTZ was not associated with an increased risk of developing AKI although the presence of shock was identified as an independent risk factor (odds ratio, 3.22; 95% CI, 1.66–6.26). No significant differences in hospital or ICU length of stay or in‐hospital mortality were observed between study groups. Conclusions: Concomitant PTZ and vancomycin in ICU patients was not associated with an increased risk of developing AKI compared to FEP and vancomycin combinations. More patients administered vancomycin/PTZ received RRT.