A computerized scoring system to improve assessment of heparin-induced thrombocytopenia risk.

Essentials Current risk scores for heparin-induced thrombocytopenia (HIT) are not computer-friendly. We compared a new computerized risk score with the 4Ts score in a large healthcare system. The computerized risk score agrees with the 4Ts score 85% of the time. The new score could potentially improve HIT diagnosis via incorporation into decision support. SUMMARY: Background (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The 4Ts score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation. Objectives Our main objective was to develop an HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified as being at risk for HIT. Methods We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system with that of a clinically calculated 4Ts score. We took a 4Ts score of ≥ 4 as the gold standard to determine whether HIT diagnostic testing should be performed. Results The best cutoff point of the HIT-CR score was a score of 3, which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% confidence interval 0.57-0.81). Ninety per cent of patients with 4Ts score of ≥ 4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT. Conclusion The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT.

Clinical effectiveness of a Bayesian algorithm for the diagnosis and management of heparin-induced thrombocytopenia.

Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated 'four Ts' (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93-1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95-99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48-0.98), specificity 0.99 (95% CI, 0.97-1.00), PPV 0.90 (95% CI, 0.56-0.99) and NPV 0.99 (95% CI, 0.96-1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients.

The effectiveness of implementing the weight-based heparin nomogram as a practice guideline.

OBJECTIVE: To determine the effectiveness of the nomogram in a community hospital that implemented it as a practice guideline. DESIGN: A nonexperimental, retrospective time series. SETTING: A 600-bed community teaching hospital and regional referral center in Phoenix, Ariz. PATIENTS: The study population included 591 consecutive patients with venous thromboembolism, treated over a 5-year study period. METHODS: During this period, the weight-based heparin nomogram was adapted into a preprinted order sheet and distributed to the hospital wards. The main outcome variables were the time to achieve a therapeutic activated partial thromboplastin time and the rate of bleeding complications. RESULTS: Voluntary implementation of the nomogram steadily increased, reaching 94%. Comparison of the periods before and after 50% implementation demonstrated an increase in initial heparin dose (1185 vs 1420 U/h, P < .001), a decrease in time to achieve therapeutic activated partial thromboplastin time (19.6 vs 11.8 hours), a decrease in the variance of this parameter (25 vs 4 hours, P < .001), and no change in bleeding rates. The proportion of patients achieving a therapeutic activated partial thromboplastin time within 24 hours decreased from 97% to 86% when the results from our previous randomized controlled trial (efficacy) are compared with the present results (effectiveness). CONCLUSIONS: The weight-based heparin nomogram was well accepted by clinicians at our institution and led to more aggressive heparin dosing and improvements in intermediate outcomes, without increasing bleeding. Mitigation of benefit is likely to occur when practice guidelines are moved from the realm of efficacy research into clinical practice. Therefore, the effectiveness of such measures requires monitoring.

Apparent heparin resistance from elevated factor VIII during pregnancy.

BACKGROUND: Heparin resistance is the need for more than 35,000 units of heparin per 24 hours to achieve therapeutic activated partial thromboplastin time (APTT) values. Elevated factor VIII can cause apparent heparin resistance by suppressing the APTT result without inhibiting the antithrombotic effect of heparin. CASE: A 41-year-old gravida 2 para 0 presented at 25 weeks of a twin gestation with a deep venous thrombosis that required unusually high doses of heparin, resulting in hematuria. Apparent heparin resistance caused by elevated factor VIII was diagnosed, and the heparin dose was appropriately decreased with anti-Xa heparin monitoring. The deep venous thrombosis and hematuria resolved. CONCLUSION: Factor VIII rises significantly during pregnancy, and can cause apparent heparin resistance. When this occurs, anti-Xa heparin levels are superior to APTT for monitoring heparin therapy.

Effect of magnesium hydroxide on iron absorption following simulated mild iron overdose in human subjects.

OBJECTIVE: To determine the effect of oral magnesium hydroxide [Mg(OH)2] on iron absorption after simulated iron overdose in human subjects. METHODS: A randomized, controlled crossover study was conducted in healthy adult male human volunteers taking no medications. Subjects received an average of 5.0 mg/kg elemental iron orally followed 1 hour later by either oral administration of 4.5 g of Mg(OH)2 per g ingested elemental iron or no treatment. Serial serum specimens were obtained over the 12 hours following iron ingestion and stored at -60 degrees C until standard serum iron assay was performed. After a 2-week washout period, the subjects were enrolled in the alternative trial arm. Individual baseline diurnal variation in serum iron levels was determined over a 12-hour period on the day prior to each trial. Area under time-concentration curves (AUCs) were calculated, and the AUC due to experimental iron ingestion (deltaAUC) was determined by subtracting the baseline diurnal AUC from the experimental AUC for each subject. RESULTS: Thirteen healthy adult male subjects were enrolled. Mean +/- SEM for deltaAUC due to experimental iron ingestion followed by treatment with Mg(OH)2, 78 +/- 23 micromol(hr)/L, was significantly less than that followed by no treatment, 144 +/- 33 micromol(hr)/L (p = 0.03 by signed rank test). CONCLUSIONS: Magnesium hydroxide, administered 1 hour post-iron ingestion at an oral dose of 4.5 g per g elemental iron ingested, significantly reduced iron absorption during a 12-hour period following simulated mild iron overdose in healthy adult human volunteers.

Toxic effects of drugs used in the ICU. Anticoagulants and thrombolytics. Risks and benefits.

Anticoagulation is being used increasingly in the critical care areas. Thrombolytic therapy is now commonly used in emergency departments and coronary care units for treatment of AMI. Heparin therapy for unstable angina and for a 48 to 72 hour period following thrombolytic therapy for AMI is becoming commonplace. Beginning warfarin therapy concomitantly with heparin to decrease the total duration of heparin and the duration of hospital stay for DVT therapy is encouraged. The use of low-dose warfarin to prevent DVT in hip surgery, improve catheter patency, and prevent catheter-related subclavian thrombosis is increasing. Along with the increased use of anticoagulation must come a greater appreciation of the complications associated with the agents used, and of how to prevent or treat the hemorrhagic or thrombotic morbidity that may arise. Acute hemorrhage with thrombolytic agents must be recognized and the immediate implementation of conservative and aggressive measures begun. Heparin-induced thrombocytopenia with thrombosis is an often-unrecognized problem that may occur in 1% to 2% of heparin recipients and result in limb amputations. A delayed onset (6-10 days) requires frequent platelet counts for early diagnosis and treatment. The resurgence of warfarin use for prevention of cardiovascular and cerebrovascular disorders demands observation for skin necrosis from protein C and S inhibition. Early recognition of symptoms and syndromes associated with organ system hemorrhage in patients receiving chronic anticoagulation is imperative. The use of antagonists, such as protamine sulfate for heparin, vitamin K1 for warfarin, and antifibrinolytic drugs for thrombolytic agents, may be necessary in treating hemorrhagic events. However, their use may worsen the thromboembolic event initially treated.

New method to predict patients' intravenous heparin dose requirements.

OBJECTIVE: To predict intravenous heparin dose requirements of patients treated for thromboembolic disorders. DESIGN: A retrospective cohort study in which we used simple linear regression to predict patients' effective maintenance dose (EMD) of heparin (units/kg/hour needed to achieve and maintain APTT therapeutic range) from patients' "heparin responsiveness" (the APTT increase after the initial 6 hours of heparin treatment per units/kg/hour received). SETTING/PATIENTS: The model was derived from 46 patients treated at one hospital (Hospital A) and then tested in 42 patients treated at another hospital (Hospital B). MEASUREMENTS AND MAIN RESULTS: Among Hospital A patients, there was a strong linear correlation (r = -.880; p < .001) between EMD (mean 16.02 units/kg/hour; 95% CI 14.9, 17.15) and "heparin responsiveness" (HR): EMD = 25.651 - [95.118 x HR]. This model accurately predicted Hospital B patients' EMD: 97% (37/38) fell within the model's 95% prediction interval; the mean absolute difference between predicted and actual EMD was 1.73 units/kg/hour (95% CI 1.39, 2.08); and only 16% of patients had EMD's more than 3 units/kg/hour different from that predicted by the regression model. The model's accuracy was comparable to that of our gold standard, the weight-based heparin dosing nomogram. CONCLUSION: The infusion dose of intravenous heparin effective for an individual patient can be predicted accurately from the patient's body weight and APTT response to the initial 6 hours of treatment. Especially in hospitals where validated heparin dosing nomograms are not used, clinicians may find this simple technique useful in achieving timely therapeutic anticoagulation.

Prevention of fetal and maternal cyanide toxicity from nitroprusside with coinfusion of sodium thiosulfate in gravid ewes.

Coadministration of sodium thiosulfate with sodium nitroprusside (SNP) to children and adults prevents increases in cyanide concentrations during anesthesia or long-term SNP infusions. We wondered whether maternally administered sodium thiosulfate would prevent increases in fetal red cell cyanide concentrations in gravid ewes receiving SNP infusions. Under anesthesia, the fetal head was delivered through a lateral hysterotomy for catheterization of the jugular vein; the fetus was left in utero. Six control ewes near term received SNP at 25 micrograms.kg-1.min-1 for 4 h. Norepinephrine was used to maintain maternal mean arterial pressure at 80% baseline values. Six experimental ewes received the same treatment except that sodium thiosulfate was infused with SNP (1 g sodium thiosulfate per 100 mg SNP). Serial red cell cyanide concentrations in ewes and fetuses were followed. One control fetal death resulted from abruptio placenta, and this ewe and fetus were excluded from analysis. An additional control ewe and fetus died from apparent cyanide poisoning late during the course of the experiment. While control ewes and fetuses suffered progressive increases in red cell cyanide concentrations into the toxic range, experimental ewes and fetuses never developed toxic red cell cyanide levels (ewes P < .003, fetuses P < .004). These data, if applicable to humans, suggest that coadministration of sodium thiosulfate with SNP to pregnant women at doses currently in use for nonpregnant patients will prevent fetal, as well as maternal, cyanide toxicity.

Effect of the cyanide antidote hydroxocobalamin on commonly ordered serum chemistry studies.

STUDY HYPOTHESIS: Concentrated aqueous solutions of hydroxocobalamin (OHCob) are given intravenously for the treatment of cyanide poisoning. Because OHCob solutions are intensely red and have peak light absorptions at 352 nm and 525 nm, we investigated whether the presence of OHCob in serum would interfere with various automated, colorimetric chemistry measurements. DESIGN: Selected serum chemistry colorimetric measurements were compared in seven patients, using their own serum as control, with serum containing OHCob at the following concentrations: 100 mg/L, 500 mg/L, and 1,000 mg/L. These concentrations are in the range achieved with therapeutic doses of OHCob when given for cyanide poisoning. MEASUREMENTS AND MAIN RESULTS: Statistically significant alterations in serum values for aspartate aminotransferase, total bilirubin, creatinine, magnesium, and iron were seen in the presence of OHCob. CONCLUSION: The presence of OHCob in serum interferes with several chemistry methodologies, and such interference should be anticipated when this antidote is used.

Nonfamilial diffuse palmoplantar keratoderma associated with bronchial carcinoma.

A 61-year-old black woman had epidermoid carcinoma of the lung and the recent onset of diffuse hyperkeratosis of the palms and soles. These findings suggested an association between internal malignancy and palmoplantar hyperkeratosis. This report discusses the palmoplantar keratodermas, including those associated with malignancy.

The weight-based heparin dosing nomogram compared with a "standard care" nomogram. A randomized controlled trial.

OBJECTIVE: To determine whether an intravenous heparin dosing nomogram based on body weight achieves therapeutic anticoagulation more rapidly than a "standard care" nomogram. DESIGN: Randomized controlled trial. SETTING: Two community teaching hospitals in Phoenix, Arizona, and Rochester, New York. PARTICIPANTS: One hundred fifteen patients requiring intravenous heparin treatment for venous or arterial thromboembolism or for unstable angina. INTERVENTION: Patients were randomized to the weight-based nomogram (starting dose, 80 units/kg body weight bolus, 18 units/kg per hour infusion) or the standard care nomogram (starting dose, 5000-unit bolus, 1000 units per hour infusion). Activated partial thromboplastin time (APTT) values were monitored every 6 hours, and heparin dose adjustments were determined by the nomograms. MEASUREMENTS: Activated partial thromboplastin times were measured using a widely generalizable laboratory method. The primary outcomes were the time to exceed the therapeutic threshold (APTT > 1.5 times the control) and the time to achieve therapeutic range (APTT, 1.5 to 2.3 times the control). Bleeding complications and recurrent thromboembolism were also compared. RESULTS: Kaplan-Meier curves for the primary outcomes favored the weight-based nomogram (P < 0.001 for both). In the weight-based heparin group, 60 of 62 patients (97%) exceeded the therapeutic threshold within 24 hours, compared with 37 of 48 (77%) in the standard care group (P < 0.002). Only one major bleeding complication occurred (in a standard care patient). Recurrent thromboembolism was more frequent in the standard care group; relative risk, 5.0 (95% CI, 1.1 to 21.9). CONCLUSIONS: The weight-based heparin nomogram is widely generalizable and has proved to be effective, safe, and superior to one based on standard practice.

A computer alert system to prevent injury from adverse drug events: development and evaluation in a community teaching hospital.

CONTEXT: Adverse drug events (ADEs) are the most common type of iatrogenic injury occurring in hospitalized patients. Errors leading to ADEs are often due to restricted availability of information at the time of physician order writing. OBJECTIVES: To develop, implement, and evaluate a computer alert system designed to correct errors that might lead to ADEs and to detect ADEs before maximum injury occurs. DESIGN: Prospective case series. SETTING: A 650-bed community teaching hospital in Phoenix, Ariz. PATIENTS: Consecutive sample of 9306 nonobstetrical adult patients admitted during the last 6 months of 1997. INTERVENTIONS: Thirty-seven drug-specific ADEs were targeted. Our hospital information system was programmed to generate alerts in clinical situations with increased risk for ADE-related injury. A clinical system was developed to ensure physician notification of alerts. MAIN OUTCOME MEASURES: A true-positive alert was defined as one in which the physician wrote orders consistent with the alert recommendation after alert notification. RESULTS: During the 6-month study period, the alert system fired 1116 times and 596 were true-positive alerts (positive predictive value of 53%). The alerts identified opportunities to prevent patient injury secondary to ADEs at a rate of 64 per 1000 admissions. A total of 265 (44%) of the 596 true-positive alerts were unrecognized by the physician prior to alert notification. CONCLUSIONS: Clinicians can use hospital information systems to detect opportunities to prevent patient injury secondary to a broad range of ADEs.