Late Surfactant Administration in Very Preterm Neonates With Prolonged Respiratory Distress and Pulmonary Outcome at 1 Year of Age

Because the lungs are one of the last organs to develop, their function is a major concern in infants born prematurely. Premature neonates may require mechanical ventilation if their lungs have not fully developed and they are not able to breathe sufficiently on their own. Mechanical ventilation (along with other factors) in infants can lead to an increased risk of developing bronchopulmonary dysplasia, which leads to chronic lung disease and abnormal neurodevelopment. Surfactant is a substance produced in the lungs that decreases surface tension in the lungs and stabilizes alveoli, ultimately preventing the lung from collapsing when exhaling. Surfactant can also be produced exogenously and can be used to treat premature infants.

This randomized, controlled, double-blind study examined the effects of late surfactant administration in 118 infants who were born before 33 weeks’ gestation and still required mechanical or high-frequency oscillatory ventilation at 14 days old. The primary end point was the time to first successful extubation; secondary outcomes were respiratory outcomes at 36 weeks postmenstrual age and at one year. Infants either received the treatment of surfactant or air. The results showed that the two groups were not significantly different in time to first successful extubation or respiratory outcomes at 36 weeks’ postmenstrual age. Bronchopulmonary dysplasia severity was also similar in both groups. There was a significant difference between the treatment and control in the number of hospitalizations required for respiratory issues at one year of age. The study concluded that surfactant was a safe therapy and that it did allow for better pulmonary outcomes at one year of age.

This study is just one example of the usefulness of synthesis of exogenous versions of endogenous substances to treat certain diseases. Although the study did not show overly successful outcomes, it was very logical to try to replace the substance that was missing in these infants, and this strategy could likely be used to find treatments for other diseases. Also, I really like seeing studies done in infants because they are an extremely vulnerable population and must be treated in different ways than adults or even children. I think it is very important to continue to do research on therapies specifically for infants.

 

JAMA Pediatr. doi: 10.1001/jamapediatrics.2015.4617 (published February 29, 2016).

A Randomized Safety and Efficacy Study of Somavaratan (VRS-317), a Long-Acting rhGH, in Pediatric Growth Hormone Deficiency

Interested by today’s topic of discussion in A&P, I decided to look for an article on the use of growth hormones on pediatric growth hormone deficiency. I found a study by Moore, et al. looked to explore the safety and efficacy of somavaratan in treating pediatric growth hormone deficiency. The study took 68 prepubescent children and randomly assigned them to doses of somavaratan. They were monitored for six months, which included a 30-day dose-finding phase. Somavaratan was found to help reduce the amount of injections of growth hormones the patients needed, up to only one injection per month.

As a pharmacist I think that this study was pretty helpful. Growth hormones can be very important for certain pediatric patients, but daily injections may be something a patient is not willing or able to adhere too. If the addition of somavaratan is continued to be researched and becomes an approved usage, it could do a lot to help patients who suffer from pediatric growth hormone stay adherent and could potentially reduce long term costs for the disorder. What did you think of the study? What do you think of using children in research to begin with?

Link to the article

Moore, Wayne V., Huong Jil Nguyen, Gad B. Kletter, Bradley S. Miller, Douglas Rogers, David Ng, Jerome A. Moore, Eric Humphriss, Jeffrey L. Cleland, and George M. Bright. “A Randomized Safety and Efficacy Study of Somavaratan (VRS-317), a Long-Acting RhGH, in Pediatric Growth Hormone Deficiency.” The Journal of Clinical Endocrinology & Metabolism 101.3 (2016): 1091-097. Web.

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. 

Buprenorphine versus Methadone Treatment for Neonatal Abstinence Syndrome

Neonatal abstinence syndrome (NAS) is the heartbreaking condition in infants that results from maternal use of opioids during pregnancy. This condition is characterized by infants’ experiences of withdrawal symptoms. Illegal opioid pain relievers or heroin were used by more than 1% of pregnant women in 2011, but illicit drug use is not the only source of opioid use during pregnancy. Surprisingly, opioids were dispensed to over 14% of pregnant women between 2005 and 2011. Approximately 5.8 cases of NAS per 1000 live births occurred by 2012. As the opioid crisis continues and grows in our nation, it is becoming more important to study treatment options available for infants with NAS. The standard treatment is oral methadone and morphine. This study investigates the potential use of buprenorphine in treating NAS.

This retrospective cohort analysis performed in six hospitals in Southwest Ohio between 2012 and 2014 sought to compare the duration of opioid therapy and length of inpatient hospital stay in infants treated for NAS with the standard oral methadone treatment regimen versus sublingual buprenorphine-weaning protocol. At the six sites a total of 163 infants were treated with the standard 8-step methadone protocol, and at one site a total of 38 infants were treated with sublingual buprenorphine based on a 5-step protocol from another study. Buprenorphine dosing was weight-based and initiated at 4.4 μg/kg every 8 hours at a maximum daily dose of 39 μg/kg. Infants who had chronic intrauterine exposure to methadone were excluded from the buprenorphine treatment group and were treated with oral methadone.

The results of the study showed that patients who received buprenorphine had an average duration of treatment of 9.4 days and an average length of stay of 16.3 days while patients who received methadone had an average duration of treatment of 14 days and an average length of stay of 20.7 days. The were no adverse effects or increases in adjunct therapy with phenobarbital in the buprenorphine group compared to the methadone group. Additionally, buprenorphine may be safer than methadone because it has a ceiling effect on respiratory depression.

This study concluded that buprenorphine could be superior to methadone in the treatment of NAS in infants whose mothers did not use methadone. I found this article extremely interesting because I do not often think of the need to treat opioid dependence in infants, and it seems like much more research could be done on this topic. One of the authors of the study was a pharmacist, and I think that this area of practice has a lot of potential for pharmacist involvement. Pharmacists could play in important role in selecting treatment for NAS as well as determining drug dosing because it could be very different for this population and involves constantly changing doses in order to wean infants off of opioids.

 

J Pediatr. 2016; 170: 39-44.

Parent-Reported Errors and Adverse Events in Hospitalized Children

Parents play a large role in monitoring the condition of their children. They are consistently observing and playing an active part in their children’s hospital care. They are able to notice things that health providers might not see. Having different personnel and systems make the efforts to provide the best care to the children complicated. Medical errors unnoticed can lead to preventable adverse side effects. Parents can be a vital resource in identifying errors that can be prevented in the future.

In 2013, a study was conducted to evaluate parent reports of safety incidents their children experienced. These reports that met stated definitions were labeled medical errors or potential adverse events. Parents of randomly selected inpatient children were given surveys to report any safety incidents throughout their stay at the hospital. Reviewers would categorize the safety incidents as either harmful or non-harmful. Finally, they reviewed clinical/demographic data and analyzed medical records obtained from the hospital.

The results showed 37 safety concerns had been reported from 34 of the 383 parents surveyed. 62% of the safety incidents were found to be physician review medical errors. 43% of the medical errors reported by parents did not show up on the medical record review. 30.4% of the medical errors were defined as harmful. They also found that the length of stay was correlated with parental reporting a medical error. This makes sense because the risk increases with greater exposure.

One of the issues that was brought up in this study was excluding non-English speaking families. They should be included in further studies and I think their input will be valuable in further identifying medical errors and potential adverse events. Researchers can utilize language interpreters to translate their surveys to the families.

Khan A, Furtak SL, Melvin P, et al. Parent-Reported Errors and Adverse Events in Hospitalized Children. JAMA Pediatr. doi:10.1001/jamapediatrics.2015.4608 (published 29 February 2016).

 

Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses

The goal of this study was to determine if early administration of azithromycin in preschool children suffering from recurrent lower respiratory tract infections would effective at preventing the progression of the infection.

The study was a randomized, double-blind, placebo controlled parallel study taking place across 9 centers in the US. There were 607 patients, ranging in age from 12-71 months old, with past history of recurrent respiratory infections. Patients either received 12mg/kg daily of azithromycin or a placebo at the onset of infection sympthoms, with the clinical endpoint being the number of infections not progressing to a severe level.

The study concluded that the azithromycin treatment significantly reduced the risk of progression of the infection, with a hazard ratio of 0.64, and a risk difference of developing the first infection between the azithromycin group and the placebo group of 0.03. The patients treated with azithromycin infrequently experienced any adverse side effects from the treatment.

This study is interesting to me because it seems that many respiratory infections can be prevented early on if treated with azithromycin, reducing the suffering of the child and saving the patient and the healthcare system money, which is desirable for all parties. It is also useful to know for a fact that this particular antibiotic is successful in treating these types of infections so that an appropriate drug therapy can be chosen from the start instead of having to try multiple different antibiotics.

Link to Article

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.

Efficacy and safety of gelatine tannate for the treatment of acute gastroenteritis in children

Acute gastroenteritis causes increased mortality and morbidity in children. Currently, treatment for this illness focuses on treating and preventing dehydration, reducing severity and duration of diarrhea, and promoting weight gain following rehydration. Gelatine tannate has anti-inflammatory and astringent characteristics which gives it protective properties. It also inhibits growth of certain bacteria in the gut. In Europe recently, it has been advertised to treat gastroenteritis. However, currently there is only little evidence to demonstrate the efficacy of gelatine tannate to treat gastroenteritis in children or adults. The objective of this trial is determine the safety and efficacy of gelatine tannate for treating acute gastroenteritis in children.

This is a randomized, placebo-controlled, blind trial. A total of 158 children younger than 5 years old were recruited for the study. Children older than 3 years old will receive 500 mg per day, and children under 3 years old will receive 350 mg per day for 5 days. If not given the drug, they were given a matching placebo. The main outcome measured was duration of diarrhea. All participants were followed up for the 5 days of the intervention, as well as an additional 48 hours. This study has not been conducted yet. I am interested to see if this study finds gelatine tannate to be a potential treatment for this condition.

Michałek D, Kołodziej M, Konarska Z, Szajewska H. Efficacy and safety of gelatine tannate for the treatment of acute gastroenteritis in children: protocol of a randomised controlled trial. BMJ Open. 2016;6(2):e010530. doi:10.1136/bmjopen-2015-010530.

U.S. Poison Control Center Calls for Infants 0-6 Months Old

This article concerned a retrospective study on poison control center calls about infants aged 0 to 6 months.  The study used data from the National Poison Data System that combines all the electronic records of all the United States Poison Control Centers.  The study was conducted to explore the reason behind the majority of poison center calls made for infants in the first six months of their lives.  Infants at that stage of development have very little mobility, reducing the possibility of poisoning by exploration, a common cause for poisoning of infants and toddlers older than six months of age.  This rationale would indicate that poisoning caused by a mistake of a caregiver is more common in younger infants than it is in infants and toddlers older than six months of age.  Many programs for young parents that address the issue of poisoning focus on the need to keep dangerous substances out of reach of children, but the instances of caregiver mistakes in poisoning events of infants 0-6 months old would not be prevented by keeping medicines inaccessible to the infants.  Also, most of these programs do not begin poison education before children reach six months of age anyways.  The results of the study presented a couple key takeaways.  One of the results was that 97.5% of poisoning events for this age group originated in people’s homes, whereas only 85.2% of the phone calls made about these events originated in people’s homes, with others originating from health care facilities, meaning some caregivers travelled to a health care facility before contacting a Poison Control Center.  Additionally, the percentage of calls made for unintentional poisonings by the caregiver for this early infant age range was a large proportion of the total poisonings for this age range, of which there were numerous recorded over the 10-year (2004-2013) period of the study.

I believe that early education of parents about the resource of Poison Control Centers and about how to properly use medications in infants would prevent many of the poisoning events that occur in the age group of infants 0-6 months old.  The study also concluded that increased education concerning PCC’s and proper infant medical care to parents before they leave the nursery at the hospital would eradicate many of the poisoning occurrences in this age group.  What do you think the best approach to reducing poisoning of infants aged 0-6 months in the United States is?

Kang AM, Brooks DE. US Poison Control Center Calls for Infants 6 Months of Age and Younger. Pediatrics. 2016;137:1-7.

Link to Article

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?