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Calicitonin Precusors and IL-8 as a Screen Panel for Bacterial Sepsis
Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129-35.
Identification of sensitive and specific markers for serious bacterial infection (SBI) in children has commanded significant attention in recent literature. These researchers present a prospective cohort study of 56 children aged 5 months to 17 years (median 6.7 years) with fever (axillary temperature ≥37.5°C or oral temperature ≥38°C) and neutropenia (absolute neutrophil count ≤500/mm3) admitted to Children’s National Medical Center during a 15-month period. Researchers hypothesized that a highly sensitive assay for calcitonin precursors (CTpr) would detect levels of CTpr early in the course of illness, and that these levels in conjunction with measured levels of the cytokines interleukin (IL)-6 and IL-8 would provide a sensitive and specific set of markers for diagnosing bacterial sepsis in the study population. Markers were measured at admission, at 24 hours and at 48 hours. CTpr at 24 hours (adjusted odds ratio [95% confidence interval], 1.8 [1.2–2.8], p=.001) and IL8 (at 48 hours 1.08 [1.2–2.8], p=.02) were found to have association with bacterial sepsis. The authors conclude that based on the data generated, using cutoff values of 500 pg/mL for CTpr at 24 hours and 20 pg/mL for IL-8 at 48 hours would provide a sensitivity of 94% and specificity of 90%. Reliable biochemical markers that are highly associated with SBI and/or sepsis will likely improve the care of pediatric patients by guiding more specific therapy and potentially limiting exposure to unnecessary antibiotic . The results of this study cannot be generalized to all pediatric patients with fever and risk for SBI, due to the unique attributes of the study population. However, the study does provide information for future research into the development of markers and/or scoring systems to aid in the early diagnosis of SBI/sepsis in the general pediatric population.
Which Tests are Helpful and Cost-Effective in the Evaluation of Pediatric Syncope?
Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr. 2005;146:355-8.
Evaluation of syncope in children is not uncommon. This evaluation can often include multiple expensive tests, and evidence defining the most efficacious and cost-effective course of evaluation is lacking. Researchers from the Children’s Heart Center at St. Vincent Hospital in Indianapolis and the Division of Cardiology at Children’s Hospital Medical Center in Cincinnati present a retrospective review of 169 patients aged 4.5 to 18.7 years (mean, 13.1 ± 3.6) presenting to a tertiary care center for evaluation of transient loss of consciousness associated with loss of postural tone to describe the cost and utility of testing used to make a diagnosis. Costs were based on hospital costs for 1999 and did not include professional fees, the cost of clinic evaluations, or hospital admissions. There are significant limitations in the study design, and these are adequately discussed by the authors. A diagnosis was established in 128 patients (76%), and neurocardiogenic syncope was the most common diagnosis occurring in 116 patients (68%). Other diagnoses included seizure disorder (3 patients), pseudoseizure (2), anxiety disorder (2), psychogenic syncope (2) and 1 patient each with breathholding spells, long QT syndrome, and exertonal ventricular tachycardia. Tilt-testing had the highest diagnostic yield, although the researchers aptly point out that in the literature the specificity of tilt-testing ranges from 48 to 100% and that this test is rarely required to diagnose neurocardiogenic syncope, the most frequent diagnosis in this review. Loop memory cardiac monitoring had the lowest cost per diagnostic result. Electrocardiography had the lowest diagnostic yield and highest cost per test. Echocardiogram, chest radiograph, cardiac catheterization, electrophysiology studies, and evaluation of serum and body fluids were not diagnostic in this series. This respective review highlights the need for a consistent, evidence-based approach to this common presenting problem while emphasizing the importance of judicious testing guided by a thorough history and physical exam.
An Increase in Severe Community Acquired MRSA Infections in Texas
Gonzales BE, Martinez-Aguilar G, Hulten KG, et al. Severe staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642-8.
Gonzales et al. describe data prospectively gathered since August 1, 2001, showing an increase in the number of severely ill patients with community acquired (CA) Staphylococcus aureus infections. Fourteen patients with a mean age of 12.9 years (range: 10–15 years) were admitted to the PICU with sepsis. Twelve patients had CA methicillin-resistant S. aureus (CAMRSA). Thirteen patients (93%) had bone and joint infections. Thirteen patients had pulmonary involvement. Acute prerenal failure and peripheral vascular thrombosis were present in 50% and 29% of patients, respectively. Thirteen patients were bacteremic. All CAMRSA isolates were resistant to erythromycin, without inducible resistance to clindamycin. The review is interesting in light of the other literature reviewed by the authors suggesting a trend toward more severe infections caused by CAMRSA.
TheoPhylline vs. Terubutaline in Critically III Asthmatics
Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6:142-7.
Status asthmaticus is a common diagnosis on the pediatric inpatient unit and in the pediatric intensive care unit (PICU). Inhaled beta-2 agonists, systemic corticosteroids, and supplemental oxygen are accepted as the standard of care for children with status asthmaticus who require admission. For critically ill children who are poorly responsive to the aforementioned triad of therapy, both theophylline and terbutaline are considered possible adjunctive therapies. Wheeler et al. suggest that the many studies failing to demonstrate added benefit of theophylline in non–critically ill patients has decreased the use of theophylline in the critical care setting, but point out that recent studies involving critically ill populations with status asthmaticus treated with theophylline have suggested benefit with comparison to placebo. Therefore, these researchers present a randomized, prospective, controlled, double-blind trial comparing the efficacy of theophylline alone, terbutaline alone, and theophylline and terbutaline together in critically ill pediatric patients receiving continuous nebulized albuterol and intravenous steroids. Forty patients with impending respiratory failure between the ages of 3 and 15 years were randomized to 1 of 3 groups: theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Thirty-six patients completed the study; 3 patients from group 1 were withdrawn due to parental request secondary to agitation (2 patients) and being inadvertently placed on a terbutaline infusion (1 patient). One patient from group 3 was withdrawn by the treating physician due to lack of improvement. All study participants, with the exception of the study pharmacist, were blinded to group assignment. Adjunctive therapies, including magnesium, ipatropium bromide and ketamine, were utilized at the discretion of the treating physician and were not controlled for. The primary outcome variable was change in a clinical scoring tool. Secondary outcomes variables included time to a specific clinical score, length of stay in the PICU, progression to mechanical ventilation, and incidence of adverse events. In addition, a cost analysis was performed isolating the 3 groups based on fiscal year 2003 cost estimates for theophylline and terbutaline. Results demonstrated no difference in the primary or secondary clinical outcome measures, with the exception of a higher incidence of nausea in group 3. The hospital costs were significantly lower in group 1 compared with groups 2 and 3 ($280 vs. $3,908 vs. $4,045, respectively, p<.0001). Significant limitations to the study include the lack of control of adjunctive therapies, a small sample size that confounds the ability to conclude no clinical difference between groups, and a baseline Pediatric Risk of Mortality (PRISM) Score in group 3 compared with groups 1 and 2. Despite these limitations the researchers suggest that the addition of intravenous theophylline to continuous nebulized albuterol and corticosteroids in the management of critically ill children with status asthmaticus is as safe and effective as adding intravenous terbutaline while being more cost-effective. Subsequent larger, well-controlled studies are required to support this conclusion.
Can Computerized Physician Ordering Create Errors?
Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293:1197-203.
Adverse drug events are a frequent etiology of inpatient morbidity and prescribing errors are the most frequent source. Computerized physician order entry (CPOE) is touted as a potential remedy for some types of adverse drug events. Few studies have investigated the potential for novel medication errors generated by a change to CPOE from conventional ordering. Koppel et al. present a quantitative and qualitative study of medication errors caused or exacerbated by a CPOE system. Interviews, surveys, and focus groups were the primary means of data collection. Housestaff who typically enter more than 9 orders per month were the primary study population, but data collection also included pharmacists, nursing staff , information technology managers, and attending physicians. The study was conducted in a tertiary-care teaching hospital between 2002 and 2004 utilizing a CPOE system in place since 1997. The CPOE system utilized is described as “monochromatic” and having “pre-Windows interfaces.” While not integrated with all hospital functions, the system was integrated with pharmacy and nursing medication lists. Researchers grouped errors into two broad categories: (1) information errors (fragmentation and systems integration failure) and (2) human-machine interface flaws (machine rules that do not correspond to work organization or usual behaviors). In total, 22 types of errors were recorded.
An example of an “information error” is assumed and incorrect dose information based on viewing doses intended only to describe pharmacy stocking practice―i.e. assuming that because the pharmacy stocks a 10mg dose of a medication, 10mg is an appropriate “minimally effective” dose. A “human-machine interface error” example is selecting an incorrect patient for ordering due to properties of the CPOE screen, such as the patient name not appearing on all screens. There are several important limitations to this study, but perhaps most important is the inability to generalize this data to other settings with potentially different physician users and software. Also important is a lack of description regarding physician user training and/or correlation of errors with amount of training or frequency of use, considering that the study population was defined as housestaff who may only use the system for 9 orders each . Despite these limitations, the study represents a requisite component to the growing trend toward the complete electronic record―namely, the use of objective investigations to study the safety and effectiveness of CPOE and the electronic record to promote the most optimal implementation and evolution of this new clinical tool.
Single-Dose Azithromycin for Acute Otitis Media
Arguedas A, Emparanza P, Schwartz RH, et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J. 2005;24: 153-61.
Acute otitis media is a common comorbid condition in pediatric inpatients. Patients at risk of having AOM with drug-resistant Streptococcus pneumoniae can be treated with high-dose amoxicillin as a first-line therapy according to recent American Academy of Pediatrics (AAP) recommendations. Despite this recommendation, there is evidence of reduced in vitro activity of amoxicillin against β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, as well as a lack of data from controlled and blinded studies demonstrating efficacy, adverse events and compliance for high-dose regimens. Azithromycin has in vitro activity against the 4 pathogens of clinical significance in AOM, and studies have shown that a single-dose regimen of azithromycin by the oral route is pharmacokinetically feasible, safe, and comparable in success rate to 3- and 5-day azithromycin regimens. With these considerations in mind, Arguedas et al. designed this study to compare single-dose (30 mg/kg) azithromycin with high-dose (90 mg/kg/day) amoxicillin in uncomplicated AOM.
In this double-blind, double-dummy, multinational, clinical trial, children between the ages of 6 and 30 months with uncomplicated AOM were randomized to treatment with single-dose azithromycin or high-dose amoxicillin (90 mg/kg/day, in 2 div doses) for 10 days. The primary outcome measure was clinical efficacy assessed at the end of treatment on the basis of a modified intent-to-treat (MITT) population. Secondary outcomes were analyses of safety and compliance. Three hundred thirteen patients were enrolled, of whom 83% were <2 years old, with 158 patients randomized to receive azithromycin and 154 to receive amoxicillin. Tympanocentesis was performed at baseline, and clinical responses were assessed at days 12–14 (end of therapy) and 25–28 (end of study). A middle-ear pathogen was detected in 212 patients (68%). H. Influenzae was the most common pathogen isolated (96 cases), followed by S. pneumoniae (92), M. catarrhalis (23), and S. pyogenes (23). At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithro(80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well designed, randomized, controlled trial. (Jadad Score = 4/5) all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively
(p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well-designed, randomized, controlled trial. (Jadad Score = 4/5)
Calicitonin Precusors and IL-8 as a Screen Panel for Bacterial Sepsis
Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129-35.
Identification of sensitive and specific markers for serious bacterial infection (SBI) in children has commanded significant attention in recent literature. These researchers present a prospective cohort study of 56 children aged 5 months to 17 years (median 6.7 years) with fever (axillary temperature ≥37.5°C or oral temperature ≥38°C) and neutropenia (absolute neutrophil count ≤500/mm3) admitted to Children’s National Medical Center during a 15-month period. Researchers hypothesized that a highly sensitive assay for calcitonin precursors (CTpr) would detect levels of CTpr early in the course of illness, and that these levels in conjunction with measured levels of the cytokines interleukin (IL)-6 and IL-8 would provide a sensitive and specific set of markers for diagnosing bacterial sepsis in the study population. Markers were measured at admission, at 24 hours and at 48 hours. CTpr at 24 hours (adjusted odds ratio [95% confidence interval], 1.8 [1.2–2.8], p=.001) and IL8 (at 48 hours 1.08 [1.2–2.8], p=.02) were found to have association with bacterial sepsis. The authors conclude that based on the data generated, using cutoff values of 500 pg/mL for CTpr at 24 hours and 20 pg/mL for IL-8 at 48 hours would provide a sensitivity of 94% and specificity of 90%. Reliable biochemical markers that are highly associated with SBI and/or sepsis will likely improve the care of pediatric patients by guiding more specific therapy and potentially limiting exposure to unnecessary antibiotic . The results of this study cannot be generalized to all pediatric patients with fever and risk for SBI, due to the unique attributes of the study population. However, the study does provide information for future research into the development of markers and/or scoring systems to aid in the early diagnosis of SBI/sepsis in the general pediatric population.
Which Tests are Helpful and Cost-Effective in the Evaluation of Pediatric Syncope?
Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr. 2005;146:355-8.
Evaluation of syncope in children is not uncommon. This evaluation can often include multiple expensive tests, and evidence defining the most efficacious and cost-effective course of evaluation is lacking. Researchers from the Children’s Heart Center at St. Vincent Hospital in Indianapolis and the Division of Cardiology at Children’s Hospital Medical Center in Cincinnati present a retrospective review of 169 patients aged 4.5 to 18.7 years (mean, 13.1 ± 3.6) presenting to a tertiary care center for evaluation of transient loss of consciousness associated with loss of postural tone to describe the cost and utility of testing used to make a diagnosis. Costs were based on hospital costs for 1999 and did not include professional fees, the cost of clinic evaluations, or hospital admissions. There are significant limitations in the study design, and these are adequately discussed by the authors. A diagnosis was established in 128 patients (76%), and neurocardiogenic syncope was the most common diagnosis occurring in 116 patients (68%). Other diagnoses included seizure disorder (3 patients), pseudoseizure (2), anxiety disorder (2), psychogenic syncope (2) and 1 patient each with breathholding spells, long QT syndrome, and exertonal ventricular tachycardia. Tilt-testing had the highest diagnostic yield, although the researchers aptly point out that in the literature the specificity of tilt-testing ranges from 48 to 100% and that this test is rarely required to diagnose neurocardiogenic syncope, the most frequent diagnosis in this review. Loop memory cardiac monitoring had the lowest cost per diagnostic result. Electrocardiography had the lowest diagnostic yield and highest cost per test. Echocardiogram, chest radiograph, cardiac catheterization, electrophysiology studies, and evaluation of serum and body fluids were not diagnostic in this series. This respective review highlights the need for a consistent, evidence-based approach to this common presenting problem while emphasizing the importance of judicious testing guided by a thorough history and physical exam.
An Increase in Severe Community Acquired MRSA Infections in Texas
Gonzales BE, Martinez-Aguilar G, Hulten KG, et al. Severe staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642-8.
Gonzales et al. describe data prospectively gathered since August 1, 2001, showing an increase in the number of severely ill patients with community acquired (CA) Staphylococcus aureus infections. Fourteen patients with a mean age of 12.9 years (range: 10–15 years) were admitted to the PICU with sepsis. Twelve patients had CA methicillin-resistant S. aureus (CAMRSA). Thirteen patients (93%) had bone and joint infections. Thirteen patients had pulmonary involvement. Acute prerenal failure and peripheral vascular thrombosis were present in 50% and 29% of patients, respectively. Thirteen patients were bacteremic. All CAMRSA isolates were resistant to erythromycin, without inducible resistance to clindamycin. The review is interesting in light of the other literature reviewed by the authors suggesting a trend toward more severe infections caused by CAMRSA.
TheoPhylline vs. Terubutaline in Critically III Asthmatics
Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6:142-7.
Status asthmaticus is a common diagnosis on the pediatric inpatient unit and in the pediatric intensive care unit (PICU). Inhaled beta-2 agonists, systemic corticosteroids, and supplemental oxygen are accepted as the standard of care for children with status asthmaticus who require admission. For critically ill children who are poorly responsive to the aforementioned triad of therapy, both theophylline and terbutaline are considered possible adjunctive therapies. Wheeler et al. suggest that the many studies failing to demonstrate added benefit of theophylline in non–critically ill patients has decreased the use of theophylline in the critical care setting, but point out that recent studies involving critically ill populations with status asthmaticus treated with theophylline have suggested benefit with comparison to placebo. Therefore, these researchers present a randomized, prospective, controlled, double-blind trial comparing the efficacy of theophylline alone, terbutaline alone, and theophylline and terbutaline together in critically ill pediatric patients receiving continuous nebulized albuterol and intravenous steroids. Forty patients with impending respiratory failure between the ages of 3 and 15 years were randomized to 1 of 3 groups: theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Thirty-six patients completed the study; 3 patients from group 1 were withdrawn due to parental request secondary to agitation (2 patients) and being inadvertently placed on a terbutaline infusion (1 patient). One patient from group 3 was withdrawn by the treating physician due to lack of improvement. All study participants, with the exception of the study pharmacist, were blinded to group assignment. Adjunctive therapies, including magnesium, ipatropium bromide and ketamine, were utilized at the discretion of the treating physician and were not controlled for. The primary outcome variable was change in a clinical scoring tool. Secondary outcomes variables included time to a specific clinical score, length of stay in the PICU, progression to mechanical ventilation, and incidence of adverse events. In addition, a cost analysis was performed isolating the 3 groups based on fiscal year 2003 cost estimates for theophylline and terbutaline. Results demonstrated no difference in the primary or secondary clinical outcome measures, with the exception of a higher incidence of nausea in group 3. The hospital costs were significantly lower in group 1 compared with groups 2 and 3 ($280 vs. $3,908 vs. $4,045, respectively, p<.0001). Significant limitations to the study include the lack of control of adjunctive therapies, a small sample size that confounds the ability to conclude no clinical difference between groups, and a baseline Pediatric Risk of Mortality (PRISM) Score in group 3 compared with groups 1 and 2. Despite these limitations the researchers suggest that the addition of intravenous theophylline to continuous nebulized albuterol and corticosteroids in the management of critically ill children with status asthmaticus is as safe and effective as adding intravenous terbutaline while being more cost-effective. Subsequent larger, well-controlled studies are required to support this conclusion.
Can Computerized Physician Ordering Create Errors?
Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293:1197-203.
Adverse drug events are a frequent etiology of inpatient morbidity and prescribing errors are the most frequent source. Computerized physician order entry (CPOE) is touted as a potential remedy for some types of adverse drug events. Few studies have investigated the potential for novel medication errors generated by a change to CPOE from conventional ordering. Koppel et al. present a quantitative and qualitative study of medication errors caused or exacerbated by a CPOE system. Interviews, surveys, and focus groups were the primary means of data collection. Housestaff who typically enter more than 9 orders per month were the primary study population, but data collection also included pharmacists, nursing staff , information technology managers, and attending physicians. The study was conducted in a tertiary-care teaching hospital between 2002 and 2004 utilizing a CPOE system in place since 1997. The CPOE system utilized is described as “monochromatic” and having “pre-Windows interfaces.” While not integrated with all hospital functions, the system was integrated with pharmacy and nursing medication lists. Researchers grouped errors into two broad categories: (1) information errors (fragmentation and systems integration failure) and (2) human-machine interface flaws (machine rules that do not correspond to work organization or usual behaviors). In total, 22 types of errors were recorded.
An example of an “information error” is assumed and incorrect dose information based on viewing doses intended only to describe pharmacy stocking practice―i.e. assuming that because the pharmacy stocks a 10mg dose of a medication, 10mg is an appropriate “minimally effective” dose. A “human-machine interface error” example is selecting an incorrect patient for ordering due to properties of the CPOE screen, such as the patient name not appearing on all screens. There are several important limitations to this study, but perhaps most important is the inability to generalize this data to other settings with potentially different physician users and software. Also important is a lack of description regarding physician user training and/or correlation of errors with amount of training or frequency of use, considering that the study population was defined as housestaff who may only use the system for 9 orders each . Despite these limitations, the study represents a requisite component to the growing trend toward the complete electronic record―namely, the use of objective investigations to study the safety and effectiveness of CPOE and the electronic record to promote the most optimal implementation and evolution of this new clinical tool.
Single-Dose Azithromycin for Acute Otitis Media
Arguedas A, Emparanza P, Schwartz RH, et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J. 2005;24: 153-61.
Acute otitis media is a common comorbid condition in pediatric inpatients. Patients at risk of having AOM with drug-resistant Streptococcus pneumoniae can be treated with high-dose amoxicillin as a first-line therapy according to recent American Academy of Pediatrics (AAP) recommendations. Despite this recommendation, there is evidence of reduced in vitro activity of amoxicillin against β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, as well as a lack of data from controlled and blinded studies demonstrating efficacy, adverse events and compliance for high-dose regimens. Azithromycin has in vitro activity against the 4 pathogens of clinical significance in AOM, and studies have shown that a single-dose regimen of azithromycin by the oral route is pharmacokinetically feasible, safe, and comparable in success rate to 3- and 5-day azithromycin regimens. With these considerations in mind, Arguedas et al. designed this study to compare single-dose (30 mg/kg) azithromycin with high-dose (90 mg/kg/day) amoxicillin in uncomplicated AOM.
In this double-blind, double-dummy, multinational, clinical trial, children between the ages of 6 and 30 months with uncomplicated AOM were randomized to treatment with single-dose azithromycin or high-dose amoxicillin (90 mg/kg/day, in 2 div doses) for 10 days. The primary outcome measure was clinical efficacy assessed at the end of treatment on the basis of a modified intent-to-treat (MITT) population. Secondary outcomes were analyses of safety and compliance. Three hundred thirteen patients were enrolled, of whom 83% were <2 years old, with 158 patients randomized to receive azithromycin and 154 to receive amoxicillin. Tympanocentesis was performed at baseline, and clinical responses were assessed at days 12–14 (end of therapy) and 25–28 (end of study). A middle-ear pathogen was detected in 212 patients (68%). H. Influenzae was the most common pathogen isolated (96 cases), followed by S. pneumoniae (92), M. catarrhalis (23), and S. pyogenes (23). At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithro(80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well designed, randomized, controlled trial. (Jadad Score = 4/5) all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively
(p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well-designed, randomized, controlled trial. (Jadad Score = 4/5)
Calicitonin Precusors and IL-8 as a Screen Panel for Bacterial Sepsis
Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129-35.
Identification of sensitive and specific markers for serious bacterial infection (SBI) in children has commanded significant attention in recent literature. These researchers present a prospective cohort study of 56 children aged 5 months to 17 years (median 6.7 years) with fever (axillary temperature ≥37.5°C or oral temperature ≥38°C) and neutropenia (absolute neutrophil count ≤500/mm3) admitted to Children’s National Medical Center during a 15-month period. Researchers hypothesized that a highly sensitive assay for calcitonin precursors (CTpr) would detect levels of CTpr early in the course of illness, and that these levels in conjunction with measured levels of the cytokines interleukin (IL)-6 and IL-8 would provide a sensitive and specific set of markers for diagnosing bacterial sepsis in the study population. Markers were measured at admission, at 24 hours and at 48 hours. CTpr at 24 hours (adjusted odds ratio [95% confidence interval], 1.8 [1.2–2.8], p=.001) and IL8 (at 48 hours 1.08 [1.2–2.8], p=.02) were found to have association with bacterial sepsis. The authors conclude that based on the data generated, using cutoff values of 500 pg/mL for CTpr at 24 hours and 20 pg/mL for IL-8 at 48 hours would provide a sensitivity of 94% and specificity of 90%. Reliable biochemical markers that are highly associated with SBI and/or sepsis will likely improve the care of pediatric patients by guiding more specific therapy and potentially limiting exposure to unnecessary antibiotic . The results of this study cannot be generalized to all pediatric patients with fever and risk for SBI, due to the unique attributes of the study population. However, the study does provide information for future research into the development of markers and/or scoring systems to aid in the early diagnosis of SBI/sepsis in the general pediatric population.
Which Tests are Helpful and Cost-Effective in the Evaluation of Pediatric Syncope?
Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr. 2005;146:355-8.
Evaluation of syncope in children is not uncommon. This evaluation can often include multiple expensive tests, and evidence defining the most efficacious and cost-effective course of evaluation is lacking. Researchers from the Children’s Heart Center at St. Vincent Hospital in Indianapolis and the Division of Cardiology at Children’s Hospital Medical Center in Cincinnati present a retrospective review of 169 patients aged 4.5 to 18.7 years (mean, 13.1 ± 3.6) presenting to a tertiary care center for evaluation of transient loss of consciousness associated with loss of postural tone to describe the cost and utility of testing used to make a diagnosis. Costs were based on hospital costs for 1999 and did not include professional fees, the cost of clinic evaluations, or hospital admissions. There are significant limitations in the study design, and these are adequately discussed by the authors. A diagnosis was established in 128 patients (76%), and neurocardiogenic syncope was the most common diagnosis occurring in 116 patients (68%). Other diagnoses included seizure disorder (3 patients), pseudoseizure (2), anxiety disorder (2), psychogenic syncope (2) and 1 patient each with breathholding spells, long QT syndrome, and exertonal ventricular tachycardia. Tilt-testing had the highest diagnostic yield, although the researchers aptly point out that in the literature the specificity of tilt-testing ranges from 48 to 100% and that this test is rarely required to diagnose neurocardiogenic syncope, the most frequent diagnosis in this review. Loop memory cardiac monitoring had the lowest cost per diagnostic result. Electrocardiography had the lowest diagnostic yield and highest cost per test. Echocardiogram, chest radiograph, cardiac catheterization, electrophysiology studies, and evaluation of serum and body fluids were not diagnostic in this series. This respective review highlights the need for a consistent, evidence-based approach to this common presenting problem while emphasizing the importance of judicious testing guided by a thorough history and physical exam.
An Increase in Severe Community Acquired MRSA Infections in Texas
Gonzales BE, Martinez-Aguilar G, Hulten KG, et al. Severe staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics. 2005;115:642-8.
Gonzales et al. describe data prospectively gathered since August 1, 2001, showing an increase in the number of severely ill patients with community acquired (CA) Staphylococcus aureus infections. Fourteen patients with a mean age of 12.9 years (range: 10–15 years) were admitted to the PICU with sepsis. Twelve patients had CA methicillin-resistant S. aureus (CAMRSA). Thirteen patients (93%) had bone and joint infections. Thirteen patients had pulmonary involvement. Acute prerenal failure and peripheral vascular thrombosis were present in 50% and 29% of patients, respectively. Thirteen patients were bacteremic. All CAMRSA isolates were resistant to erythromycin, without inducible resistance to clindamycin. The review is interesting in light of the other literature reviewed by the authors suggesting a trend toward more severe infections caused by CAMRSA.
TheoPhylline vs. Terubutaline in Critically III Asthmatics
Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: A prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6:142-7.
Status asthmaticus is a common diagnosis on the pediatric inpatient unit and in the pediatric intensive care unit (PICU). Inhaled beta-2 agonists, systemic corticosteroids, and supplemental oxygen are accepted as the standard of care for children with status asthmaticus who require admission. For critically ill children who are poorly responsive to the aforementioned triad of therapy, both theophylline and terbutaline are considered possible adjunctive therapies. Wheeler et al. suggest that the many studies failing to demonstrate added benefit of theophylline in non–critically ill patients has decreased the use of theophylline in the critical care setting, but point out that recent studies involving critically ill populations with status asthmaticus treated with theophylline have suggested benefit with comparison to placebo. Therefore, these researchers present a randomized, prospective, controlled, double-blind trial comparing the efficacy of theophylline alone, terbutaline alone, and theophylline and terbutaline together in critically ill pediatric patients receiving continuous nebulized albuterol and intravenous steroids. Forty patients with impending respiratory failure between the ages of 3 and 15 years were randomized to 1 of 3 groups: theophylline plus placebo (group 1), terbutaline plus placebo (group 2), or theophylline and terbutaline together (group 3). Thirty-six patients completed the study; 3 patients from group 1 were withdrawn due to parental request secondary to agitation (2 patients) and being inadvertently placed on a terbutaline infusion (1 patient). One patient from group 3 was withdrawn by the treating physician due to lack of improvement. All study participants, with the exception of the study pharmacist, were blinded to group assignment. Adjunctive therapies, including magnesium, ipatropium bromide and ketamine, were utilized at the discretion of the treating physician and were not controlled for. The primary outcome variable was change in a clinical scoring tool. Secondary outcomes variables included time to a specific clinical score, length of stay in the PICU, progression to mechanical ventilation, and incidence of adverse events. In addition, a cost analysis was performed isolating the 3 groups based on fiscal year 2003 cost estimates for theophylline and terbutaline. Results demonstrated no difference in the primary or secondary clinical outcome measures, with the exception of a higher incidence of nausea in group 3. The hospital costs were significantly lower in group 1 compared with groups 2 and 3 ($280 vs. $3,908 vs. $4,045, respectively, p<.0001). Significant limitations to the study include the lack of control of adjunctive therapies, a small sample size that confounds the ability to conclude no clinical difference between groups, and a baseline Pediatric Risk of Mortality (PRISM) Score in group 3 compared with groups 1 and 2. Despite these limitations the researchers suggest that the addition of intravenous theophylline to continuous nebulized albuterol and corticosteroids in the management of critically ill children with status asthmaticus is as safe and effective as adding intravenous terbutaline while being more cost-effective. Subsequent larger, well-controlled studies are required to support this conclusion.
Can Computerized Physician Ordering Create Errors?
Koppel R, Metlay JP, Cohen A, et al. Role of computerized physician order entry systems in facilitating medication errors. JAMA. 2005;293:1197-203.
Adverse drug events are a frequent etiology of inpatient morbidity and prescribing errors are the most frequent source. Computerized physician order entry (CPOE) is touted as a potential remedy for some types of adverse drug events. Few studies have investigated the potential for novel medication errors generated by a change to CPOE from conventional ordering. Koppel et al. present a quantitative and qualitative study of medication errors caused or exacerbated by a CPOE system. Interviews, surveys, and focus groups were the primary means of data collection. Housestaff who typically enter more than 9 orders per month were the primary study population, but data collection also included pharmacists, nursing staff , information technology managers, and attending physicians. The study was conducted in a tertiary-care teaching hospital between 2002 and 2004 utilizing a CPOE system in place since 1997. The CPOE system utilized is described as “monochromatic” and having “pre-Windows interfaces.” While not integrated with all hospital functions, the system was integrated with pharmacy and nursing medication lists. Researchers grouped errors into two broad categories: (1) information errors (fragmentation and systems integration failure) and (2) human-machine interface flaws (machine rules that do not correspond to work organization or usual behaviors). In total, 22 types of errors were recorded.
An example of an “information error” is assumed and incorrect dose information based on viewing doses intended only to describe pharmacy stocking practice―i.e. assuming that because the pharmacy stocks a 10mg dose of a medication, 10mg is an appropriate “minimally effective” dose. A “human-machine interface error” example is selecting an incorrect patient for ordering due to properties of the CPOE screen, such as the patient name not appearing on all screens. There are several important limitations to this study, but perhaps most important is the inability to generalize this data to other settings with potentially different physician users and software. Also important is a lack of description regarding physician user training and/or correlation of errors with amount of training or frequency of use, considering that the study population was defined as housestaff who may only use the system for 9 orders each . Despite these limitations, the study represents a requisite component to the growing trend toward the complete electronic record―namely, the use of objective investigations to study the safety and effectiveness of CPOE and the electronic record to promote the most optimal implementation and evolution of this new clinical tool.
Single-Dose Azithromycin for Acute Otitis Media
Arguedas A, Emparanza P, Schwartz RH, et al. A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media. Pediatr Infect Dis J. 2005;24: 153-61.
Acute otitis media is a common comorbid condition in pediatric inpatients. Patients at risk of having AOM with drug-resistant Streptococcus pneumoniae can be treated with high-dose amoxicillin as a first-line therapy according to recent American Academy of Pediatrics (AAP) recommendations. Despite this recommendation, there is evidence of reduced in vitro activity of amoxicillin against β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis, as well as a lack of data from controlled and blinded studies demonstrating efficacy, adverse events and compliance for high-dose regimens. Azithromycin has in vitro activity against the 4 pathogens of clinical significance in AOM, and studies have shown that a single-dose regimen of azithromycin by the oral route is pharmacokinetically feasible, safe, and comparable in success rate to 3- and 5-day azithromycin regimens. With these considerations in mind, Arguedas et al. designed this study to compare single-dose (30 mg/kg) azithromycin with high-dose (90 mg/kg/day) amoxicillin in uncomplicated AOM.
In this double-blind, double-dummy, multinational, clinical trial, children between the ages of 6 and 30 months with uncomplicated AOM were randomized to treatment with single-dose azithromycin or high-dose amoxicillin (90 mg/kg/day, in 2 div doses) for 10 days. The primary outcome measure was clinical efficacy assessed at the end of treatment on the basis of a modified intent-to-treat (MITT) population. Secondary outcomes were analyses of safety and compliance. Three hundred thirteen patients were enrolled, of whom 83% were <2 years old, with 158 patients randomized to receive azithromycin and 154 to receive amoxicillin. Tympanocentesis was performed at baseline, and clinical responses were assessed at days 12–14 (end of therapy) and 25–28 (end of study). A middle-ear pathogen was detected in 212 patients (68%). H. Influenzae was the most common pathogen isolated (96 cases), followed by S. pneumoniae (92), M. catarrhalis (23), and S. pyogenes (23). At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithro(80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well designed, randomized, controlled trial. (Jadad Score = 4/5) all patients (84% and 84%, respectively) and for children <2 years of age (82% and 82%, respectively). At the end of the study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of adverse events for azithromycin and amoxicillin were 20% and 29%, respectively
(p=.064). Diarrhea was more common in the amoxicillin group (17.5%) as compared to the azithromycin group (8.2%) (p=.017). Compliance, defined as completion of >80% of the study medications, was higher in the azithromycin group (100%) then in the amoxicillin group (90%) (p=.001). For practitioners ordering medications, compliance and efficacy are uppermost considerations. Single-dose azithromycin ensured 100% compliance, decreased adverse reactions, and equal efficacy, compared to high-dose amoxicillin in this well-designed, randomized, controlled trial. (Jadad Score = 4/5)