The rational clinical examination. Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy.

CONTEXT: Clinicians frequently withhold antibiotics that contain penicillin based on patients' self-reported clinical history of an adverse reaction to penicillin and the clinicians' own misunderstandings about the characteristics of a true penicillin allergy. OBJECTIVES: To determine the likelihood of true penicillin allergy with consideration of clinical history and to evaluate the diagnostic value added by appropriate skin testing. DATA SOURCES: MEDLINE was searched for relevant English-language articles dated 1966 to October 2000. Bibliographies were searched to identify additional articles. STUDY SELECTION: We included original studies describing the precision of skin testing in diagnosis of penicillin allergy. We excluded studies that did not use both minor and major determinants, provide an explicit definition of penicillin allergy, or list the specific criteria necessary for a positive skin test result. Fourteen studies met the inclusion criteria. DATA EXTRACTION: Three authors independently reviewed and abstracted data from all articles and reached consensus about any discrepancies. DATA SYNTHESIS: Patients' self-reported history has low accuracy for diagnosis of true penicillin allergy. By evaluating studies comparing clinical history to the skin test for penicillin allergy among patients with and without a positive history for penicillin allergy, positive and negative likelihood ratios were calculated. History of penicillin allergy had a positive likelihood ratio of 1.9 (95% confidence interval [CI], 1.5-2.5), while absence of history of penicillin allergy had a negative likelihood ratio of 0.5 (95% CI, 0.4-0.6). CONCLUSIONS: Only 10% to 20% of patients reporting a history of penicillin allergy are truly allergic when assessed by skin testing. Taking a detailed history of a patient's reaction to penicillin may allow clinicians to exclude true penicillin allergy, allowing these patients to receive penicillin. Patients with a concerning history of type I penicillin allergy who have a compelling need for a drug containing penicillin should undergo skin testing. Virtually all patients with a negative skin test result can take penicillin without serious sequelae.

Monitoring drug therapy in the intensive care unit.

Drugs are among the most commonly administered therapeutic interventions received. In the intensive care unit (ICU), patients routinely receive more therapies than on general medical or surgical wards, and practitioners caring for these patients are presented with the challenge of monitoring each of these therapies for efficacy and toxicity. The goal of this article is to describe a conceptual approach that practitioners can use to monitor for drug efficacy and predictable and unpredictable adverse drug effects. Although therapeutic drug monitoring (TDM) assumes a relatively small role in the overall monitoring scheme, TDM is discussed because it serves an important function for a select group of agents.

Nutrition support in the critically ill patient.

Despite an absence of well-controlled studies demonstrating a clear mortality benefit, providing nutrition support in the critically ill patient has become routine in most ICU settings. Unless clearly contraindicated, patients should be fed enterally, using conventional isotonic feedings employing gastric or postpyloric access. When to begin nutrition support varies, depending on baseline nutritional status, anticipated time until oral feedings are resumed, and the degree of stress. Energy and protein requirements should be assessed routinely with minimum goals of avoiding overfeeding and minimizing any net negative nitrogen balance. All patients receiving feedings require close surveillance to identify predictable complications and to tailor therapy to achieve nutritional goals. Adjunctive therapies should be employed as needed to help achieve nutritional goals, eg, insulin infusions to control serum glucose and prokinetic agents to improve gastric emptying. When feasible and safe, parenterally fed patients should be transitioned to enteral or oral feedings when appropriate.

A double-blind placebo controlled trial of oral midazolam as premedication before flexible sigmoidoscopy.

OBJECTIVE: We aimed to determine the efficacy of oral midazolam as premedication to improve tolerance of flexible sigmoidoscopy. METHODS: Ninety-nine patients were randomized to receive 7.5 mg of oral midazolam solution mixed with apple juice or placebo (apple juice), 20 min before sigmoidoscopy. Patients' anxiety and pain experienced before sedation, before the procedure, and during the procedure were assessed using a 10-cm visual analog scale (VAS) by both patients and physicians (0 = no pain, anxiety, 10 = severe pain, anxiety). Extent of sedation, amnesia, overall tolerance, adequacy of sedation, and willingness to repeat the procedure were assessed, and changes in vital signs and oximetries were recorded. RESULTS: Fifty-one patients received midazolam and 48 patients received placebo. Patients reported less pain and anxiety (VAS 2.56, 1.64) compared with placebo (VAS 4.62, 4.16) during the procedure (p < 0.005, p < 0.0005). Physicians observed less pain and anxiety (VAS 2.19, 1.52) with midazolam than placebo (VAS 5.00, 3.97) during the procedure (p < 0.0001, p < 0.0001). A significantly greater number of patients judged tolerance of the procedure to be "excellent" using midazolam (p < 0.005) compared with placebo. A majority of patients in both groups was willing to repeat the procedure if recommended. Two patients in the midazolam group had transient asymptomatic hypotension during sigmoidoscopy, but no patients were observed to have desaturation by oximetry. CONCLUSIONS: Oral midazolam significantly reduces anxiety and pain during flexible sigmoidoscopy as assessed by both patients and physicians. Oral midazolam is a safe and effective premedication before flexible sigmoidoscopy in patients who require or prefer sedation.

Antibiotic classification: implications for drug selection.

This article presents a useful antibiotic classification model for the busy clinician who must select agents for patients in the critical care setting. The model organizes antibiotics based on their mechanism of action, ie, cell-wall inhibitors, nucleic acid inhibitors, and protein-synthesis inhibitors; clinicians are encouraged to further segregate agents within the broader categories by generation. An overview of the antimicrobial spectrum for each class is presented, and important differences within individual classes are highlighted. The most common indications for each antibiotic class are reviewed, and key pharmacokinetic characteristics that help distinguish one drug from another are outlined.

Predicting the patient at low risk for lymph node metastasis with localized prostate cancer: an analysis of four statistical models.

PURPOSE: Statistical models using preoperative Prostate-Specific Antigen, Gleason primary grade or score of the biopsy specimen, and clinical stage have been developed to predict those patients with clinically localized prostate cancer at low risk for lymph node metastasis. It has been recommended that these patients do not require pelvic lymph node dissections. Four such models were evaluated to assess their accuracy in identifying this subgroup of patients. METHODS AND MATERIALS: We reviewed the records of 214 patients with clinically localized prostate cancer who underwent pelvic lymph node dissections. Data from these patients were entered into the four models. RESULTS: Lymph node metastasis was detected in 14% of patients. The results showed the following for each of the proposed models respectively: 78, 50, 76, and 42% of the patients were identified as low risk and, hence, would be spared pelvic lymph node dissections. The false negative rates are 13 (7.8%), 5 (4.6%), 14 (8.6%), and 1 (1.1%). Sensitivities are 56.7, 83.3, 53.3, and 96.7%. CONCLUSIONS: While the pelvic lymph node dissection is the most accurate method of detecting occult nodal metastasis, statistical models can identify a cohort of low risk patients that may be spared lymphadenectomy.

Recent advances: parenteral nutrition support.

Even though there is an abundance of research related to the clinical and physiologic effects of parenteral nutrition and specific nutritional substrates, few new products have been released for clinical use. This review illustrates some of the directions being taken in the future development of parenteral nutrition products and some new perspectives related to the current effects (or lack of effects) of TPN. When considering the individual effects of specific nutrient substrates (arginine, glutamine, LCTs, MCTs, SCFAs) as reviewed here, it becomes apparent that the infusion of parenteral nutrition has the potential to produce a variety of metabolic responses that could be both beneficial and harmful. These effects depend on the type and quantity of substance infused as well as the disease and clinical condition of the patient. This also is true for those substances (GH, IGF-1) being evaluated to direct the effects of TPN infusions in a manner that improves protein accretion and supports the immunologic response of the body. At best, these investigations are producing a great amount of new and more specific information about the metabolic response to illness and the effects of TPN and individual substrate on that response.

Theophylline disposition following parenteral feeding of malnourished patients.

OBJECTIVE: To investigate the effect of parenteral nutrition on theophylline disposition in malnourished patients. DESIGN: Before-after trial. SETTING: Tertiary care center. PATIENTS: Ten patients with historic, anthropometric, and laboratory evidence of malnutrition. INTERVENTIONS: Patients received two 5-mg/kg intravenous infusions of theophylline separated by at least 48 hours of glucose-based parenteral nutrition providing the entire estimated nutritional requirements. MAIN OUTCOME MEASURES: Following each theophylline administration, serum theophylline samples were collected over a 24-hour period for delineation of maximum plasma concentrations, volume of distribution, elimination rate constant, clearance, and area under the curve. RESULTS: Peak plasma theophylline concentrations were significantly lower prior to feeding (5.3 mumol/L, 95 percent confidence interval [CI] 0.78-10.0 mumol/L, p = 0.028). Volume of distribution decreased after parenteral feeding (0.08 L/kg, 95 percent CI 0.006-0.15 L/kg, p = 0.037). The elimination rate of theophylline increased after parenteral feeding reflected by an increase in the elimination rate constant (0.06 h-1, 95 percent CI 0.01-0.10 h-1, p = 0.023). CONCLUSIONS: This study suggests that parenteral nutrition using a glucose-based solution acutely influences theophylline disposition in malnourished patients.

Enteral feeding in the hypoalbuminemic patient.

Previous studies have correlated intolerance of isotonic, intact protein enteral solutions with hypoalbuminemia. The purpose of this retrospective study was to determine whether the level of serum albumin (SA) influenced tolerance of such an enteral nutrient solution (ENS). All patients who received Entrition during 1987 for a minimum of 48 hr were studied for the first 10 days of enteral feeding. Documentation included SA, medications, stool frequency, gastric residuals (GR), and daily caloric intake. ENS intolerance was defined as greater than 3 stools/day for greater than 48 hr or GR greater than twice the hourly infusion rate for greater than 48 hr. Patients were categorized into two groups: those with SA greater than or equal to 2.5 g/dl (group I) and those with SA less than 2.5 g/dl (group II). Of 88 patients studied, 48 (86%) in group I and 28 (88%) in group II tolerated the ENS. Eight (14%) in group I and 4 (12%) in group II experienced ENS intolerance. There was no statistically significant difference in the frequency of ENS intolerance between these two groups (p less than 0.05). Also, 97% of all those with a SA less than 2.5 g/dl were fed 80% or more of their estimated caloric requirements. We concluded that ENS tolerance was not affected by the SA level and patients with hypoalbuminemia (SA less than 2.5 g/dl) could be fed enterally.

Branched-chain amino acid support of stressed patients.

Branched-chain amino acid-enriched formulas have been evaluated in a number of clinical trials. The efficacy of these solutions in the management of stressed patients is controversial. This review discusses the proposed benefits of the branched-chain amino acid-fortified solutions and summarizes prospective clinical trials regarding their use in stressed patients. A cost comparison is also included.

Theophylline and diaphragmatic contractility. Investigation of a dose-response relationship.

Our study evaluated whether a dose-response relationship exists for theophylline and diaphragmatic contractility within the usual therapeutic range for theophylline. The study, involving 16 patients with mild to moderate chronic obstructive pulmonary disease, was done in a randomized, placebo-controlled, double-blind, crossover fashion. We found no statistically significant effect of theophylline on diaphragmatic contractility at mean theophylline concentrations of 5.13, 12.07, and 18.6 micrograms/ml.

Should dihydroergotamine-heparin be used for prevention of postoperative thromboembolism?

The combination of heparin 5000 U and dihydroergotamine 0.5 mg (HDHE) was marketed in the U.S. in 1985 for prophylaxis of postoperative deep venous thrombosis (DVT). This article evaluates the efficacy, safety, and cost of HDHE for abdominal, pelvic, thoracic, and total hip surgical prophylaxis. Although several controlled trials comparing HDHE to minidose heparin (MDH) indicate superior efficacy of HDHE for nonorthopedic surgical procedures, others do not. Differences in study design and insufficient sample sizes may account for the dichotomy. In the U.S. Multicenter Trial, MDH was surprisingly ineffective for preventing radiofibrinogen uptake test-proven DVT. The apparent superiority of HDHE over MDH is therefore questionable. Ergot-related side effects have been minimized in all studies due to careful patient selection. In actual use, the potential for such side effects appears to be increased. Because twice-daily HDHE is no more effective, costs 4-11 times more, and may pose a greater risk than MDH, the authors do not recommend its use for general surgical prophylaxis. HDHE may prove to be useful in patients undergoing total hip replacement.

Effect of sucralfate on phenytoin bioavailability.

The mechanism of action of the antiulcer agent, sucralfate, involves drug binding to proteins, pepsin, and bile salts. The potential for sucralfate to bind to, and inhibit the oral absorption of, concurrently-administered drugs has been studied for very few agents. Phenytoin bioavailability was studied following a single dose of phenytoin 500 mg po in nine normal subjects during a control period and when given with sucralfate. Area under the serum concentration-time curve was compared at 48 hours (AUC48) and 120 hours (AUC120) using observed and extrapolated data. The phenytoin AUC48 was reduced from 173.6 +/- 22.6 mg . h/L to 157.1 +/- 19.6 mg . h/L (p less than 0.02), and the phenytoin AUC120 was reduced from 200.5 +/- 31.9 mg . h/L to 185.0 +/- 26.8 mg . h/L (p less than 0.05), when sucralfate was administered. Because AUC comparisons for drugs with nonlinear elimination kinetics may reflect changes in rate, as well as extent, of absorption, these small changes in AUC may not reflect a change in the fraction of dose absorbed. However, our results suggest that sucralfate does affect phenytoin absorption. Further studies may be useful in determining the precise nature and clinical importance of this interaction.

Influence of mitotane on the hypoprothrombinemic effect of warfarin.

Mitotane (o,p'-DDD) is closely related to the organochlorine insecticides and shares their effects on drug metabolism. We have reported the first documented interaction of mitotane and warfarin in a human being. Because the potential for significant toxicity is great when mitotane and warfarin are used concomitantly, caution is recommended when titrating warfarin therapy in patients receiving mitotane. Other drugs susceptible to the influence of enzyme inducers should also be given with caution to patients receiving mitotane.

The effectiveness of a slide-tape program on literature evaluation.

The effectiveness of a slide-tape program on literature evaluation skills was assessed. The slide-tape program was viewed by nine medical students (group 1) on an individual basis. Nine additional medical students (group 2) attended a lecture which addressed the same topic. Computerized questionnaire responses were obtained before and after viewing the program and the conventional lecture. No significant differences were observed between groups 1 and 2 in pre- and post-test responses (p greater than 0.05); however, significant improvement in score was observed in both groups after viewing the program and the lecture (p less than 0.05). The slide-tape program was felt to be comparable to the conventional lecture in introducing the concepts of literature evaluation.

Evaluating the medical literature, Part III: Results and discussion.

This series has addressed the basic segments of a research publication and discussed critical considerations that a reader should make as he progresses through the segments. The questions listed in Figure 3 may be helpful to guide the reader through the evaluation process.

Evaluating the medical literature. Part II: Statistical analysis.

We have attempted to provide sufficient information to enable the reader to verify that the investigator has used an appropriate statistical test for the evaluation of his study data. We have not discussed the actual calculation of the tests presented. With the wide availability of computers and programmable calculators, it is safe to assume that the investigator has performed the necessary mathematics accurately. Instead of assessing the accuracy of these calculations, the reader should verify that the correct statistical test was chosen in the first place. The astute reader may be surprised at how frequently an incorrect test is used. Merely achieving statistical significance does not characterize the author's data as clinically important. Neither does it, in and of itself, prove one agent superior to another nor prove a cause-and-effect relationship between two variables. When appropriately interpreted, however, statistical analysis can be a very useful and powerful tool in helping to arrive at the "truth."

Evaluating the medical literature. Part I: Abstract, introduction, methods.

In this installment on critical evaluation of medical literature, we have discussed the Abstract, Introduction, and Methods sections. A great deal of information is placed in the methodology section of any paper. To critically evaluate a research publication, one must evaluate the methodology, for evaluation of the results of an investigation is meaningless if the methodology is unsound.

Benzathine penicillin G in the treatment of neurosyphilis.

The definition, pathogenesis, incidence, diagnosis, and treatment of neurosyphilis are discussed. Controlled trials of benzathine penicillin in the treatment of neurosyphilis are reviewed, as are recent case reports of benzathine penicillin failures. Although few well-controlled studies exist to document conclusively the efficacy of benzathine penicillin in the treatment of neurosyphilis, its use is recommended in selected situations.