Effect of Metformin Added to Insulin on Glycemic Control Among Obese Adolescents with Type 1 Diabetes

Studies currently show that 24% of children and adolescents with Type 1 Diabetes are overweight and 15% are obese. The need for high doses of insulin may further promote weight gain. Additionally, insulin resistance has been associated with increased risk for cardiovascular risk factors. Metformin lowers glucose and was associated with low insulin doses without having an effect on A1C.

A trial was conducted using patients aged 12 to 19 diagnosed with Type 1 Diabetes for at least one year who had an insulin pump or administered at least 3 injections of insulin each day. The patients had an A1C between 7.5% and 9.9% and were in the 85th percentile for BMI. The patients were given 500 mg of metformin that was titrated over 4 weeks to reach 2000mg daily. The rest of the patients were given a placebo.

The baseline A1C was 8.8% in each both groups. At 13 weeks, the mean change in the metformin group was -0.2% and 0.1% in the placebo group. However at 26 weeks, the mean change in the metformin group was 0% and 0.3% in the placebo group. There was no significant difference for glycemic control. However, the patients in the metformin group used less insulin throughout the 26 weeks than the patients on the placebo and more patients in the metformin group maintained or lost weight.

In conclusion, metformin did not improve glycemic control in children or adolescents with Type 1 Diabetes. A few outcomes were favored but not significantly. Additionally, taking metformin increases the risk of GI adverse effects. Therefore, it is not indicated to prescribe metformin to this patient population.

This is interesting because many people do not fully understand the difference between Type 1 and Type 2 Diabetes and the medications to treat each. It is important to know what medications are indicated for each to educate children and parents. Thoughts on another oral medication that may be better suited for this patient population?

JAMA. 2015;314(21):2241-2250. 

Use of Cranberry Products for UTI Prevention in Pediatric Patients

A common infection in the pediatric population is a Urinary Tract Infection (UTI). A UTI can occur due to obstruction of urine flow or urinary stasis. The pathogen that causes most UTIs is called Escherichia coli in adults. In children, however, the most common cause of UTIs is Pseudomonas. Low-dose antibiotics were given for prophylaxis in the past to children who showed obstructive disease or recurrent UTIs. Now, it is realized that this leads to antibiotic resistance and other interventions need to be explored.

Healthcare professionals initially believed that cranberry would be an effective prevention of UTIs because it would cause the urinary tract system to be more acidic, but it is not known for sure that the urine pH changes. Now, cranberry is thought to stop the attachment of bacteria to the uroepithelial cells and also that it inhibits the formation of biofilm bacteria. Cranberry use has been studied in the prevention of recurrent UTIs in women, so now researchers are studying the possible benefits in children.

Eight clinical trials were reviewed and their results showed that cranberry is a safe and effective option that could prevent recurrent UTIs in pediatric  patients. This is especially true for otherwise healthy patients. A dose of 2-5 mL/kg/day proved to have the most benefit in the pediatric population. Should clinicians promote the use of cranberry supplements  for the prophylaxis of UTIs  to parents with children or should they only address that if the child develops a UTI first?

Durham SH, Stamm PL, Eiland LS. Cranberry Products for the Prophylaxis of Urinary Tract Infections in Pediatric Patients. Ann Pharmacother. 2015: 49(12); 1349-1356. http://aop.sagepub.com/content/49/12/1349.full.pdf

Asenapine for the Acute Treatment of Pediatric Manic or Mixed Episode of Bipolar I Disorder

Asenapine, brand name Saphris, is a sublingual tablet that is FDA labeled for the treatment of bipolar disorder and schizophrenia. Like most antipsychotics, the exact mechanism of action is unknown, just that it acts on dopamine receptors in the brain. Findling and colleagues preformed a double-blind placebo controlled study in which they studied the use of asenapine for the treatment of manic or mixed episode bipolar disorders in children aged 10 to 17 years old. The doses included placebo 2.5 mg, 5 mg, and 10 mg twice daily and they were distributed to the patients in a 1:1:1:1 ratio. 403 patients were included in the study, so about 101 patients received each dose. The results were measured based on the Young-mania rating scale (YMRS). The YMRS is a rating scale based on the patient’s subjective view of his or her manic symptoms in the last 48 hours. The YMRS was assessed after 21 days of the assigned medication strength.

The average YMRS rating is 12 and the results showed that after the 21 days the average difference in YMRS for those with the placebo controlled versus the asenapine doses were -3.2 for the 2.5 mg, -5.3 for the 5.0 mg, and -6.2 for the 10 mg. In contrast to the average improvement in the YMRS, there was significantly more adverse effects experienced by those taking the asenapine doses. These adverse effects include somnolence, sedation, increased appetite, weight gain, and increased fasting blood glucose levels. The researchers also looked at the presence of ADHD and if the symptoms were changed, which they were not.

The researchers concluded that asenapine is superior to the placebo with the improvement of YMRS scores and was very well tolerated, even with the increase in side effects.

This is really interesting, and relevant to our learning in top drugs currently. This is not one of the antipsychotics we are learning about specifically, but its really interesting to see actual data for the use of an antipsychotic, especially on kids. I wonder if there have been studies done that look to see if antipsychotics affect the brain development of these children as they grow.

J AM ACAD CHILD ADOLESC PSYCHIATRY. 2015;45(12):1032-1041.

http://www.jaacap.com/article/S0890-8567(15)00614-0/abstract

Lorazepam vs. Diazepam for Pediatric Status Epilepticus

In pediatric patients indicated for status epilepticus, benzodiazepines are considered first line therapy. Lorazepam is not FDA approved for this indication, but studies show it may be more effective and safe.

A double-blind, randomized clinical trial was conducted from March 1, 2008 to March 14, 2012 using 273 patients aged 3 months to younger than 18 years. Patients included in the trial had generalized tonic-clonic status epilepticus, which is defined as, 3 or more convulsions within the preceding hours and currently experiencing a convulsion, 2 of more convulsions in succession with no recovery of consciousness and currently experiencing a convulsion, or a current single convulsion with a duration of least 5 minutes.

140 were given 0.2 mg/kg diazepam IV and 133 were given 0.1 mg/kg lorazepam IV. In the diazepam group, 72.1% of patients had cessation of the status epilepticus and in the lorazepam group, 72.9% of patients had cessation of the status of epilepticus. Sedation was seen in 50% of patients taking diazepam and 66.9% of patients taking lorazepam.

It was determined that between the 2 medications, there were no significant differences in primary efficacy and safety outcomes. This does not support the theory that lorazepam is the superior treatment. This is interesting because the study showed that the medications have fairly equal efficacy, but lorazepam has an increase risk of producing sedation. Pharmacists should be aware of this when recommending medications for pediatric patients.

JAMA. 2014;311(16):1652-1660.

Is Trimethoprim-Sulfamethoxazole a Valid Alternative in the Management of Infections in Children in the Era of Community-Acquired Methicillin-Resistant Staphylococcus aureus? A Comprehensive Systematic Review

One of the growing problems in he practice of pharmacy is the increasing emergence of strains of bacteria immune to the antibiotics that are currently on the market. Through over-prescribing, non-adherence, and other contributing factors, the need for new antibiotics is as high as it was when penicillin was first discovered. But as we all know, a drug doesn’t hit the market immediately. It can be over 10 years to before a drug is approved so what are we supposed to do in that time? Let the bacteria beat our current antibiotics? Or is there something more we can do to combat antibiotic resistance.

 

Rosanova et. al reviewed the literature to determine if trimethoprim-sulfamethoxazole had been proven to effectively treat Methicillin-Resistant Staphylococcus aureus (MRSA) in children. According to the first consult page on MRSA on clinicalkey, the outpatient treatment of MRSA includes drugs like clindamycin and linezolid for both pediatrics and adults. It also mentions trimethoprim-sulfamethoxazole as a treatment but only in adults. The review done by Rosanova et al found just 4 primary articles that studied trimethoprim-sulfamethoxazole in a randomized controlled study in children and the results were inconclusive.

 

While the findings of this article may not be significant, the fact that it was even written is. This article proves that while we work to discover newer and more effective antibiotics, we must also reevaluate the ones we currently use and find other possible uses for them.

 

Rosanova, M. T., Pompa, L. C., Perez, G., Sberna, N., Serrano-Aguilar, P., & Lede, R. (2016). Is Trimethoprim-Sulfamethoxazole a Valid Alternative in the Management of Infections in Children in the Era of Community-Acquired Methicillin-Resistant Staphylococcus aureus? A Comprehensive Systematic Review. Journal of Pharmacy Technology, 32(2), 81-87. Retrieved February 22, 2016.

 

Does Faster Time to Epinephrine Improve Outcomes in Pediatric Pulseless Arrest with Nonshockable Rhythm?

A study completed from 2000 to 2014 by Andersen and colleagues used 15,959 pediatric patients in-hospital cardiac arrests. 1,558 children (9.8%) received epinephrine in at least one dose for nonshockable rhythms during cardiopulmonary resuscitation (CPR). 50% of these children received the medication during the same or next minute after the pulse was lost. 15% received the medication after 5 minutes.

740 patients were excluded because they did not receive epinephrine, 363 patients were excluded for having rapid return of spontaneous circulation (ROSC) within 2 minutes. For a variety of reasons, this study was different from a randomized clinical trial, which would be nearly impossible to initiate in a pediatric hospital for this condition.

This study reinforced that overall, pediatric patients with in-hospital cardiac arrests and nonshockable rhythms have poor overall prognosis. Fewer than 33% of patients survive to discharge and many have poor neurocognitive outcomes. The results of the study proved that epinephrine should be given within the first 5 minutes after CPR, as currently recommended. Since many patients reached ROSC within the first 2 minutes without receiving the medication, it cannot be determined that outcomes are better within 2 minutes.

JAMA. 2015;314(8):776-777. 

This article is interesting and shows the importance of providing efficient and correct care. Patients rely on health care providers to think and work quickly. Since it is impossible to do a randomized clinical trial in this setting, research is difficult. I think that despite the lack of research, clinicians should diagnose and administer the medication as quickly as possible. I believe that this would improve patient outcomes by increasing survival and decreasing poor neurocognitive outcomes. How can a pharmacist help the interprofessional team to improve pediatric patient outcomes? Are the guidelines different for adult patients?

Improving Pediatric Outcomes in Oncology through Genomics

Within the past decade, target therapies have been prescribed using genomic data to more precisely diagnose cancer and predict future outcomes. The pediatric field is lacking by not targeting mutated oncogenic drivers and rare ALK translocated malignancies. Pediatric cancer does not have as many mutations, and many studies on focused on the disease state. New evidence shows that post therapy relapse samples accumulate more mutations and may lead to chemotherapy resistance.

A study with 102 children and young adults (up to age 22) involved exam sequencing of paired blood mononuclear cell and tumor DNAs along with tumor RNA sequencing. 69% had solid tumors. The study was designed to identify germ-line mutations that could cause an effect, tumor-specific alterations that would alter the histopathologic diagnosis, change risk status or both, and medically targetable somatic mutations.

Potentially actionable findings were found in 46% of cases and action was taken in 23 of those 42 patients (54%). A change of therapy was initiated for 14 patients (15%), a gremlin mutation was found to be clinically relevant in 9 patients, and 9 of the 14 patients had clinical benefit from the intervention.

This data is very relevant and suggests a promising field of research. With genomic sequencing, therapies were personalized in order to better target the cancer. As pharmacists, we should consider this and acknowledge that patients may require different treatment even with the same disease state. The research and sequencing in adults can and should be applied to children to better care for their cancer.

JAMA. 2015;314(9):881-883. 

Interventions by Health Care Professionals in Reducing Tobacco Smoke Exposure in Children : A Review and Meta-analysis

A recent review was conducted to determine the effectiveness of interventions delivered by health care professionals who provide routine child health care in reducing tobacco smoke exposure in children. A meta-analysis conducted on 57 trials was performed. The primary outcome was reduction in child tobacco smoke exposure with a secondary outcome of parental smoking cessation. 16 studies met the selection criteria. The only trials that demonstrated a significant overall intervention effect were trials that affected maternal postpartum smoking relapse prevention.

Although this meta-analysis did not provide much in the way of finding interventions that could be effective in reducing child tobacco smoke exposure, it did find one intervention that could affect child TSA. This could be a first step towards finding other interventions that are effective. Much like the other intervention types, this intervention gets to the heart of the problem; parents smoking around their offspring. Even though tobacco use in adults over 18 have decreased since 2004, the percentage of adult smokers are still high. I believe interventions like this will prove useful in the future.

Daly JB., Mackenzie LJ., Freund M., et al Interventions by Health Care Professionals Who Provide Routine Child Health Care to Reduce Tobacco Smoke Exposure in Children. J Am Pharm Assoc Ped 2016; 170

Melatonin Supplementation for Children With Atopic Dermatitis and Sleep Disturbance

Difficulty sleeping is commonplace for children with atopic dermatitis, a condition similar to eczema that causes itchy inflammation of the skin. It has been found that children suffering from AD have decreased levels of nighttime melatonin. Because melatonin has both sleep-inducing and anti-inflammatory properties, the researchers in this study hypothesized that melatonin may be an effective treatment for pediatric patients suffering from AD.

The researchers used a randomized, double blind, placebo-controlled study involving patients aged 1-18 who had AD affecting at least 5% of their total body surface area. patients received either 3mg daily of melatonin or placebo for four weeks. The primary outcome of AD severity was measured using the SCORAD index, and the secondary outcome of sleep impact was measured using actigraphy and polysomnography, as well as urinalysis of sulfatoxymelatonin, the byproduct of melatonin metabolism.

After treatment, the SCORAD mean score dropped by 9.1, and the sleep-onset time dropped by 21.4 minutes on average. Importantly, no adverse effects were reported during the trial.

This study is interesting for patients looking for an OTC solution to both atopic dermatitis as well as sleep issues. The fact that no adverse events occured helps to support the conclusion that melatonin is not only an effective and cheaper solution to two issues as once, but it is also a safe solution in the pediatric population. This knowledge will be useful for us to know in the future, as over 3 million cases of AD are diagnosed annually(Source: Mayo Clinic)

http://archpedi.jamanetwork.com/article.aspx?articleid=2470860

Weight Gain in Children

In the longitudinal study, researchers were determined to track and identify possible causes of adolescent weight gain in hopes of finding an area of effective intervention. The study included 652 children aged 4, 6 and 8 with follow-ups every two years as well as regular community health checkpoints. The body mass index and body fat phenotypes were measured for each of the children at the beginning and throughout the study. Of the beginning 652, nine percent were overweight and just .2 percent were obese. Additionally, genetic risks for obesity were measured using a genetic risk score for 32 single-nucleotide polymorphisms. The results of the study indicated that children with a higher genetic risk for obesity gained weight and fat mass much faster than those without. The study was looking more specifically at the appetite traits of individuals with and without the genetic risk for obesity in order to eventually use this as a means of treating and preventing obesity, especially in the younger populations. The study revealed that those children with a higher genetic risk for obesity had higher levels of obesogenic appetite traits meaning that their decision making and portion control were poor in comparison to a healthy individual.

Identifying this specific problem with weight gain in the adolescent population is significant in making a future change in the developments and obesity patterns of children. Knowing what area to target for intervention can help lead to a more successful treatment plan. The results of the study ultimately lead to the idea that education is a large part of the treatment plan. Teaching families including parents and the children at risk, how to eat healthy can avoid the significant weight gain associated with the genetic risk that may be unavoidable. As my future role in the field of medicine, I can make an impact with direct patient care and counseling to aide in the education process of treating and changing the appetite traits of children with a genetic risk for obesity.

JAMA Pediatrics. 2016;170(2)