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. 

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.

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. 

Improving Outpatient Antibiotic Prescribing

Over 250 millions antibiotic medications are prescribed each year and a large percentage of these prescriptions are unnecessary. Unneeded and extended antibiotic use can lead to adverse drug effects and antibacterial-resistant infections. There are regulatory agencies that require acute care hospitals to have stewardship programs to improve antibiotic use. Unfortunately, the majority of antibiotic use occurs in the outpatient setting where there are no steward programs.

A study over 18 months was completed to compare the effect of behavioral interventions that occurred after an antibiotic was prescribed for a respiratory tract infection. The interventions were suggested alternatives to antibiotic use, accountable justification for antibiotic treatment, and peer comparison by other providers. Inappropriate prescribing decreased from 22% to 6% with suggested alternatives, from 23% to 5% with accountable justification, and from 20% to 4% with peer comparison. The control group also had a decrease from 24% to 13%.

This study justifies further investigation to create interventions to decrease inappropriate antibiotic use. This includes specifying tactics toward each outpatient clinics and certain common antibiotics. A suggestion is to require clinicians to justify every prescription for antibiotics with indication documentation and comparison with peers.

This is very interesting. If all prescribers were required to justify their prescriptions, I believe that there would be less antibiotic use. Additionally, the prescribers could provide the pharmacists with test results if applicable, proving that an antibiotic is needed. This would greatly reduce antibiotic resistance and the related complications. Can you think of any cons to this solution?

JAMA. doi: 10.1001/jama.2016.0430. (accessed 11 Feb 2016). 

Treatment for Migraines in Pediatric Patients

Migraines often bring pediatric patients into the emergency department and can continue on for 2 to 3 days. One study conducted a systematic review to determine what treatments are best to use in pediatric patients. The therapies included antiemetics, fluids, opioids, NSAIDS, acetaminophen, 5HT receptor agonists, DA receptor antagonists, and anesthetics.

Fluids were determined to be more beneficial for those prone to emesis symptoms due to dehydration. Ibuprofen and acetaminophen to a lesser degree may be effective in preventing migraine worsening to avoid the need for other aggressive therapies. DA receptor antagonists are effective in treating migraines; prochlorperazine patients had a lower chance of returning to the emergency department than patients on metoclopramide. Propofol reduced patients’ pain greatly and shortened their emergency department stay.

Magnesium improved pain by a decrease of 3 or more points on a 10 point pain scale. Opioids are not part of the American Academy of Neurology practice for pediatric patients. Triptans are effective in the treatment of adult migraines in adolescents and there are a variety of formulations.

In conclusion, ibuprofen, prochlorperazine, and triptans are the most effective and safe medications to use in pediatric patients for the treatment of acute migraines. This is important because many pediatric patients come into the emergency department with migraines. If the escalation of migraines can be prevented with the use of these medications, the amount of time the patient spends in the emergency department will greatly be reduced. Pharmacists play a key role in making recommendations for these pediatrics therapies. How does the treatment for pediatric migraines differ than that for adult migraines?

Headache. doi: 10.1111/head.12746 (published 21 January 2016). 


Pediatric Weight-based Dosing in Outpatient Pharmacies

A retrospective outpatient prescription record review was conducted for 6 months to determine the percentage of outpatient pediatric prescriptions with errors. Johns Hopkins Outpatient Pharmacy fills about 450 prescriptions daily with 30% for pediatric patients. Weight-based checking includes having 2 pharmacists complete a dosing calculation and cite an appropriate reference. The final verification pharmacist then double checks the calculation before dispensing to the patient. Any discrepancies are sent to the problem queue for further investigation.

For the 6 month study, 5,010 pediatric prescriptions were filled, 1,448 were sent to the problem queue and 156 required a pharmacist intervention. 50% of those prescriptions (78) were changed. The majority of prescribing errors included dose too high, incomplete or illegible prescription, inappropriate dosing interval, and dose too low.

There were several limitations to the study because pharmacists could call the physician directly and change the prescription without documenting it in the problem queue. Additionally, the majority of prescribers were from a teaching hospital where errors may have been higher.

Although the numbers seem small, I think that any reduction in error is significant. Since pediatric patients require very specific doses, it is so critical to check and double check the prescribed dosing. I wonder how many less errors are given to the patients due to weight-based dosing. This study showed that many errors were caught by pharmacists but did not compare it to other outpatient pharmacies. What other factors should the pharmacist consider when filling pediatric prescriptions?

J Am Pharm Assoc. 2016;56(1):54-57. 

Potential Risks to Mother and Fetus with Use of Psychotropic Medications

Chisolm and Payne conducted a literature review to summarize the known and unknown risks of using psychotropic drugs during pregnancy. 15% of pregnant women have a psychiatric illness and 10% to 13% of fetuses are exposed to a psychotropic medication. Studies showed that many women relapsed if their medications were discontinued during pregnancy. It was found that most classes of psychotropic drugs are relatively safe to the fetus during pregnancy. A risk-benefit analysis should be conducted to determine if the risks associated with the drug or untreated psychiatric disorder are worse.

CYP1A2 enzymes are down-regulated in pregnant women so medications such as olanzapine and clozapine require a lower dose. Additionally, these medications have an increased risk for maternal weight gain, increased infant birth weight, and gestational diabetes, so ultrasound monitoring of fetal size may be beneficial in late pregnancy. High potency first generation antipsychotics are recommended over low potency first generation antipsychotics to minimize maternal anticholinergic, hypotensive, and antihistamine effects. Second generation antipsychotics are no safer than first generation antipsychotics and may have an increased risk of high infant birth weight and hypoglycemia.

There is still an inadequate amount of literature on the safety of antipsychotic use in pregnant women. Focus should be emphasized on drug management during pregnancy, including before and after delivery. The psychotropic medications should not be suddenly discontinued, and a comprehensive treatment plan should be developed for women to ensure quality and safe care to the mother and developing fetus.

BMJ. doi: http://dx.doi.org/10.1136/bmj.h5918 (published 20 Jan. 2016).

There is still not enough evidence to completely decide which antipsychotics are safe during pregnancy. What other medications could potentially be safe during pregnancy but are often discontinued due to a lack of research? And why?