Michael L. Macknin

Zinc Gluconate Lozenges for Treating the Common Cold: A Randomized, Double-Blind, Placebo-Controlled Study

The common cold is one of the most frequently occurring human illnesses in the world. More than 200 viruses can cause common colds in adults, including rhinoviruses (the most frequent cause), coronaviruses, adenoviruses, respiratory syncytial virus, and parainfluenza viruses. In the United States each year, adults develop an average of two to four colds and children develop an average of six to eight colds [1, 2]. The morbidity resulting from this disease and the subsequent financial loss in terms of working hours are substantial [3]. Many previously described treatments have not provided consistent or well-documented relief of symptoms. Even a treatment that is only partially effective in relieving cold symptoms could markedly reduce physical malaise and economic losses in a large population. The medical literature describes many possible mechanisms by which zinc may treat the common cold, and seven controlled trials have studied the use of zinc for this purpose. All seven were double-blind, placebo-controlled studies, but each used different formulations and dosages of zinc. Three of these studies showed that zinc had a beneficial effect [4-6] and four did not [7-10]. In the studies that examined virus shedding [5, 7], zinc treatment had no effect on this shedding. We designed a study similar to that of Godfrey and colleagues [6] and used the symptom score developed by these researchers. We emphasized starting treatment within 24 hours after the onset of symptoms, because Godfrey and colleagues found that early treatment was most effective. We used zinc gluconate lozenges, which appeared to be well tolerated and had the best bioavailability profile in previous studies. Other studies [4-7, 9] used lozenges containing 23 mg of zinc. To improve palatability, lozenges in our study contained 13.3 mg of zinc. This provided a local concentration of zinc ions of about 4.4 mmol/L, an amount greater than that necessary to suppress rhinovirus (0.1 mmol/L) [11, 12]. The placebo lozenge contained 5% calcium lactate so that it had a medicinal taste similar to that of the zinc gluconate lozenge. Ours was a pragmatic study designed to determine the efficacy of zinc gluconate lozenges in reducing clinical symptom scores under conditions that reflected usual medical care for the common cold [13, 14]. We did not seek to define the mechanism of any zinc effect. Although virus cultures or serologic tests might have been desirable, we decided not to do these tests because they are almost never done in the course of standard care. Methods Study Design We determined that a 50% reduction in the duration of symptoms (in days) would represent a significant clinical effect. A previous study of zinc gluconate given during the first day of cold symptoms suggested that the duration of illness was reduced from approximately 8 days to 4 days after treatment began [6]. Our previous research on patients with colds who were seen at the Cleveland Clinic suggested that the mean duration (SD) of cold symptoms was approximately 7 6 days [15, 16]. We chose a sample size of 100 patients so that we could detect a difference in the mean number of days of symptoms from 8 days in the placebo group to 4 days in the zinc group with a standard deviation of 6 days, a two-sided P value of 0.05, and an approximate power of 90%. Patients were recruited from among the Cleveland Clinic staff through announcements in internal Clinic publications and by word of mouth. One hundred volunteers were enrolled between 3 October and 4 November 1994. All patients who completed the study as specified by the protocol were enrolled in a raffle for one of two prizes: dinner for two or a trip for two to the Bahamas. The Institutional Review Board at the Cleveland Clinic Foundation approved the study, and participants gave informed consent at the time of enrollment. Participants were informed of the placebo-controlled, double-blind nature of the study. Patients who volunteered for the study were enrolled only if they had had cold symptoms for 24 hours or less. Patients must have had at least two of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, or an oral temperature greater than 37.7 C. Patients were excluded if they were pregnant, had a known immune deficiency, or had had symptoms of the common cold for more than 24 hours. The zinc gluconate-glycine and placebo lozenges were supplied by the Quigley Corporation of Doylestown, Pennsylvania. The zinc lozenges consisted of a boiled hard-candy base prepared with approximately equal proportions of sucrose and corn syrup, zinc gluconate trihydrate (AKZO Chemie, Amersfoort, the Netherlands), a molar proportion of glycine (aminoacetic acid), and lemon and lime flavoring oils. The mixture was formed into lozenges that weighed 4.4 g and contained 13.3 mg of zinc. Placebo lozenges, also weighing 4.4 g, were prepared from the same flavored hard-candy base and contained 5.0% calcium lactate pentahydrate. Placebo and active lozenges were identical in weight, appearance, flavoring content, and texture. The zinc lozenges, however, were more astringent than the placebo lozenges. A statistical consultant prepared a computer-generated randomization code and the packages of medication. The packages were identical in appearance except for the randomization numbers. The study medication was distributed by the study nurse, who was masked to treatment assignments. Patients were given 120 lozenges and were asked to dissolve 1 lozenge in their mouths every 2 hours while awake for as long as they had cold symptoms. The study nurse administered the first lozenge to assess initial tolerability. Participants were asked to take no other cold preparations during the study period. Acetaminophen samples and oral digital thermometers were given to the patients at the time of enrollment. All patients were called on the second day of medication use to make sure that they were not developing a more serious illness and to assess the adequacy of the masking through responses to a questionnaire. By assessing the adequacy of the placebo on the second day of treatment rather than only at the end of treatment, we hoped to decrease the likelihood that a rapid cure would help patients in the zinc group correctly determine that they were receiving the active medication. This questionnaire was also administered at the end of treatment with the addition of questions about the occurrence of specific, previously described side effects of zinc therapy. Patients returned to the Clinic for the final visit within 1 day of noting that their cold symptoms had resolved. At this visit, they returned unused lozenges so that adherence to the protocol could be checked through lozenge counts, and the study nurse confirmed that cold symptoms had resolved. Patients were asked to complete a daily log documenting the severity of symptoms and the medications taken throughout the duration of their cold for as long as 18 days. Every day, patients graded each symptom as 0 for none, 1 for mild, 2 for moderate, or 3 for severe. Total symptom scores were calculated by summing the scores of the 10 symptoms for each day. Cold resolution was defined as resolution of all symptoms (a total symptom score of 0) or resolution of all but one mild symptom (a total symptom score of 1). Statistical Analysis The time to cold resolution was calculated as the number of days from study entry. Resolution rates were estimated using the Kaplan-Meier method, and resolution profiles were compared between groups using the log-rank test [17, 18]. We estimated median resolution times using the method suggested by Lee [19]. The effect of treatment on individual symptoms was examined by comparing the number of days with each symptom using the Wilcoxon rank-sum test. For analysis of treatment effect, we combined hoarseness, sore throat, and scratchy throat into a category called throat symptoms and nasal drainage and congestion into a category called nasal symptoms. Plots of individual patient symptoms give the percentage of the baseline total severity score (sum of symptom scores for all patients) by assignment group and study day. When appropriate, we used the Fisher exact test and the chi-square test to analyze associations between the side effects and assigned groups. Patient adherence was examined by comparing the total lozenge counts between the two groups using the Wilcoxon rank-sum test. These analyses were done using an intention-to-treat framework, regardless of patient adherence [20-22]. Before the randomization code was broken, patients who received antibiotic therapy or whose condition was diagnosed by a physician as an illness other than the common cold were considered nonadherent. Patients who wrote their diaries from memory were also considered nonadherent. Patients were considered adherent if they took an average of four or more lozenges per day for the first 4 days of the study (16 lozenges) and if they took no antibiotic agents. Results One hundred patients were enrolled in the study; 50 were assigned to the zinc group, and 50 were assigned to the placebo group. All patients were Cleveland Clinic employees older than 18 years of age. One patient in the zinc group withdrew from the study on the first day because she could not tolerate the lozenges; she did not complete the symptom diary. All other patients, as directly observed by the study nurse, indicated that they had good tolerance of the first lozenge. Demographic characteristics of the groups are given in Table 1. Table 1. Demographic Characteristics of 99 Volunteers Receiving Zinc or Placebo Lozenges for Treatment of the Common Cold The mean (SD) and median symptom scores at baseline (the first measurement) were 8.6 3.3 and 8 for the entire sample, 9.3 3.6 and 8 for the placebo group, and 7.9 2.8 and 8 for the zinc group. In practice, an increase in score

Pediatric Wandering Spleen Case Report and Review of Literature

Wandering spleen is a rare diagnosis, especially in the pediatric population. We reviewed the English literature from 1900 through April 1991 for all cases of wandering spleen in patients from birth through age 10. There are 50 case reports prior to the one presented here. The goals of this article are to summarize the histories, findings, and treatment of the 51 patients, describe diagnostic and treatment modalities, and increase the clinicians suspicion for wandering spleen. This condition is probably underdiagnosed and potentially treatable by splenopexy if suspected and diagnosed early in the course of disease.

Tympanic Membrane Temperatures Compared to Rectal and Oral Temperatures

contrast enhancement was normal. A magnetic resonance study was normal and did not demonstrate cavernous sinus thrombosis. Lumbar puncture revealed an opening pressure of 250 mm of water with 3830 white blood cells/ mm3, 67 red blood cells/mm3 with a differential of 85% polymorphonuclear leukocytes, 8% monocytes and 7% lymphocytes. The protein was 300 mg/dl and the glucose was less than 10 mg/dl; gram positive diplococci were noted on gram stain. The peripheral white blood cell

Effect of Inhaling Heated Vapor on Symptoms of the Common Cold

A double-blind, randomized study tested the efficacy of steam (technically, heated, humidified air) inhalation in the treatment of common cold symptoms. Two 20-minute treatments spaced 60 to 90 minutes apart were given at the time of enrollment. The active device (Rhinotherm, Netzer-Sereni, Beer Yaacov, Israel) delivered 40 L/min of saturated air at 40 degrees C to 42 degrees C, while the identical-appearing placebo delivered 2 L/min of ambient air at 20 degrees C to 24 degrees C. There were 34 patients in the placebo group and 32 in the active group. Significant improvements in the placebo-treated group were obtained on subjective symptom scores for nasal congestion, nasal drainage, and sneezing on isolated days during the treatment period (40%, vs 25% on day 3, 71% vs 60% on day 6, and 100% vs 67% on day 7). Improvement in nasal resistance as measured by rhinomanography was better in the placebo group than in the active group on day 7 (11% vs -6%). Our study demonstrated no beneficial effects of steam inhalation on common cold symptoms.

A novel approach to improve influenza vaccination rates among health care professionals: a prospective randomized controlled trial.

BACKGROUND Although influenza is the leading infections cause of death in the United States, only 40% of health care workers (HCW) comply with Centers for Disease Control and Prevention recommendation for routine influenza vaccination. METHODS This study investigated a novel approach for improving influenza vaccination rates among HCW. Eight hundred employees we selected, 200 each from the following 4 categories: professional staff, resident physicians, registered nurses, and licensed practical nurses. Subjects were randomly assigned to receive (1) no intervention, (2) a letter explaining the importance of influenza vaccine for HCW, (3) a ticket activated with influenza vaccine administration for a raffle of a free Caribbean vacation for 2, or (4) both the educational letter and the raffle ticket. We compared the proportion of employees receiving vaccination and participating in the raffle across groups. RESULTS The influenza vaccination rate for all study subjects was 41%. The number of subjects receiving vaccine did not differ by occupation (P = .87) or intervention group (P = .66). CONCLUSIONS This study provides no evidence to support the use of mailed educational letters or a single large raffle prize incentive as a means to boost hospital employee influenza vaccination rates.

Risk/Benefit Ratio in Enuresis Therapy

Address correspondence to: Michael L. Macknin, M.D., Department of Pediatrics, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195 Enuresis is a common probH lem affecting 15% to 20% of five-year-olds. By adolescence, the frequency declines to only 1% to 2%.1-3 The natural history of the disease is that most patients have a spontaneous resolution of their symptoms with or without therapy. Unfortunately, enuresis can carry a significant emotional stigma that concerns large numbers of affected patients and their parents.’ It is because of the emotional factors and inconve-

The Ohio Bicycle Injury Study

To understand bicycle injuries and determine how to prevent them, we designed prospectively a descriptive study of bicycle-crash-related admissions in July 1993 to 10 major Ohio hospitals that admit child trauma patients. All patients studied were under the age of 16. In the 52 cases (38 male, 73%), impact with another vehicle accounted for 23 (44%) crashes. Of these crashes, only three (13%) were caused by definite motor vehicle operator error, and all 20 (87%) of the remaining motor vehicle-bicycle collisions were caused by bicyclist error, including 10 (43%) caused by bicyclists failing to yield properly at an intersection. Head injuries were the primary cause of morbidity in 29 (56%) cases. No child was wearing a bicycle helmet at the time of the crash. Efforts to reduce childhood morbidity from bicycle-related crashes should focus on helmet education and safe riding skills.

Ribose versus dextrose supplementation, association with rowing performance: a double-blind study.

Objective:It has been hypothesized that ribose supplementation rapidly replenishes adenosine triphosphate stores and thereby improves exercise performance. We compared the effects of ribose versus dextrose on rowing performance. Design:Double-blind randomized trial. Setting:Rowing team training area of large midwestern university. Participants:Thirty-one women collegiate rowers. Interventions:We studied the effects of ribose versus dextrose supplementation (10 g each in 8 oz water) for 8 weeks before and after practice and 2000-m time trials. Outcome Measurements and Results:In the time trials, the dextrose group showed significantly more improvement at 8 weeks than the ribose group (median, 15.2 vs. 5.2 s; P = 0.031). Conclusions:We doubt ribose impaired, and hypothesize dextrose enhanced, rowing performance. Further research is needed to define what role, if any, dextrose and ribose play as athletic supplements.

No Technological Innovation Is a Panacea: A Case Series in Quality Improvement for Primary Care Mental Health Services:

Evaluations of quality improvement efforts targeted at mental health services in primary care pediatrics are rare. We evaluated a short-targeted educational session, a Web-based system, the Child Health and Development Interactive System, and a local area mental health services resource guide. Most physicians believed the information in the educational session was at least somewhat likely to change their practice. However, only 9.2% of the families invited to complete the Web-based system did so. Physicians found access to the Web-based system time consuming and, because the billing code for the screening activity was carved out of most of Ohios privately-insured contract, physicians received no reimbursement for the screenings. Physicians were unenthusiastic about the local resource guide because the resources were not rated for quality. This quality improvement effort demonstrates that there are not easy solutions to practice change and highlights the need for implementation support when introducing new technology.

Plant-Based, No-Added-Fat or American Heart Association Diets: Impact on Cardiovascular Risk in Obese Children with Hypercholesterolemia and Their Parents

Objective To perform a randomized trial to determine if there is cardiovascular disease (CVD) risk reduction from a plant-based no added fat diet (PB) and the American Heart Association Diet (AHA) in children. Study design Four-week (4/20/2013-5/18/2013) prospective randomized trial in a large Midwestern hospital system’s predominantly middle class outpatient pediatric practices. Thirty children (9–18 years old) parent pairs with a last recorded child BMI >95th percentile and child cholesterol >169 mg/dL were randomized to PB or AHA with weekly 2-hour classes of nutrition education. Results Children on PB had nine and children on AHA had four statistically significant (P<0.05) beneficial changes from baseline (mean decreases): BMI Z-scorePB (−0.14), systolic blood pressurePB (−6.43 mm Hg), total cholesterolPB (−22.5 mg/dL), low density lipoproteinPB (−13.14 mg/dL), hsCRPPB (−2.09 mg/L), insulinPB (−5.42uU/ml), myeloperoxidasePB/AHA (−75.34/69.23 pmol/L), mid-arm circumferencePB/AHA (−2.02/−1.55 cm), weightPB/AHA (−3.05/ −1.14kg) and waist circumferenceAHA (−2.96 cm). Adults on PB and AHA had seven and two respectively statistically significant (P<0.05) beneficial changes. The significant change favoring AHA was a 1% difference in children’s waist circumference. Difficulty shopping for food for the PB was the only statistically significant acceptability barrier. Conclusions PB and the AHA in both children and adults demonstrated potentially beneficial changes from baseline in risk factors for CVD. Future larger, long-term randomized trials with easily accessible PB foods will further define the role of the PB in preventing CVD.