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Article Analysis
CCHS 315
Comparative Evaluation of Six Extended-Interval Gentamicin Dosing in Full Term Neonates.
Authors: F.Fullas, M. Padomer, C. Theiman and A. Van Gorp.
Mary Haverty-Robinson
Ferris State University
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Summary
This article compared the use traditional multiple dosing per day of gentamicin to extendedinterval dosing of gentamicin in pediatric patients with confirmed or suspected cases of sepsis.
The researchers conducted a retrospective study of neonates who received gentamicin between
January 2006 and December 2008. Data collected included pharmacokinetic values, gestational
age, sex and weight (F.Fullas, M., C. Padomek, Theiman & A. Van Gorp 2011).
Dosages for gentamicin have been traditionally based on standard industry guidelines. These
guidelines called for multiple doses per day. The pharmacy staff noted that many of the neonates
had supratherapeutic peak levels. In order to lower the peak gentamicin levels the pharmacists
hypothesized that using extended dosing intervals of gentamicin would result in more peak and
trough levels in the desired range. The pharmacists began dosing the neonates differently based
on age and weight. The neonates were broken into the following groups; gestational age (GA) 29
weeks or younger received 4.5mg/kg every 48 hours. 30-34 weeks of GA received either 3.5,4 or
4.5 mg/kg every 36 hours and neonates 35 weeks GA or older received gentamicin 3.5 or 4 mg
/kg every 24 hours. Trough and peak levels were drawn 30 minutes before and after
administration of the drug, respectively (Fullas et.al, 2011, p.53).
Neonates of GA30-34 weeks dosed with gentamicin 3.5mg/kg/36 hours faired the best with the
largest percentage of peaks in the desired range. Neonates 35 weeks or older GA did the best
with a dose of 3.5mg/kg/24hours. For those neonates 29 weeks old or less GA receiving
gentamicin 4.5mg/kg/28hours resulted in 60% within the target range. Therefore adjusting
gentamicin dosing based on weight and age can yield better results than following industry
standards (Fullas et.al, p.52).
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Name of statistic: Peak
Was this statistic covered in class? No
Number of times used in the article: Six times.
Why do you think this statistic was used? The researchers wanted to see the highest
gentamicin level in the blood serum. The basis of the study was to compare different ways
to dose the drug and whether it fell within acceptable ranges. Peak levels of gentamicin
should fall within an acceptable range according to standardized dosing protocols. Peak
levels are tested by drawing a blood sample from the neonate 30 minutes after the drug is
administered as it distributes rapidly and reaches its peak in therapeutic range (Langlass,
Mickle, 1999, p.440-443).
What did this statistic show or prove? To correctly dose gentamicin in neonate, the
common clinical peak levels are in the range of 5-10g/ml. This study showed several
different results for the various groups of neonates. For neonates 30-34 weeks GA 3.5
mg/kg gentamicin has the largest percentages of peaks in the target range. The group of
GA 35 weeks or older neonates showed the greatest percentage of peak ranges when dosed
at 3.5 mg/kg/24hours. For the GA of 29 weeks or less the percentage of peaks at a dosing of
4.5mg/kg/48 was 60 percent.
Was there an associated P value? Yes
If yes, what was the P value and what did the P value show? There were several P
values associated with the different GA groups when reviewing the Peak levels. The P
values ranged from <0.01 to <0.0001. This means that there was strong evidence against the
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null hypothesis which is that extended gentamicin dosing does not result in target range
concentrations.
Name of Statistic: Trough
Was this statistic covered in class? No
How many times was it used? Six times.
Why do you think this statistic was used? If trough levels (obtained just prior to
infusion of the next dose) are too high or low, the dosing interval should be prolonged or
shortened, respectively, while maintaining the same total daily dose. This was the basis that
the experiment was built on. To correctly dose gentamicin in neonate, the common clinical
trough levels are in the range of 0.5-2 g/ml. By maintaining troughs within the acceptable
ranges, the neonate is getting an adequate dose of the drug and therefore hastens
healing/cure.
What did this statistic show or prove? There were several trough results because there
were several groups in the study. The percent of trough levels in the acceptable range were:
Neonates 29 weeks GA and younger had the lowest percentage (60%) in the target range.
GA neonates 30-34 weeks had a percentage of 96.7% in the target range and the neonates
35 weeks and older had a 92% rate in the target range. This proved that the extended
dosing regimen was effective when interpreting trough target ranges.
Was there an associated P value? No
If yes, what did the P value show? NA
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Name of Statistic: Mean
Was this statistic covered in class? Yes
How many times was it used in the article? Five times.
Why do you think this statistic was used? It is a measure of central tendency and can
give more weight to certain data. The mean was used to show the demographic and
pharmacokinetic values in the groups of neonates. This statistic was used to get an average
for each GA neonate group to compare the differences in dosing regimens. The mean
statistics were used to describe, gestational age (GA), weight in kgs, elimination rate
constant, half-life and volume of distribution.
What did this statistic show or prove? It showed that each group had statistically
significant differences in the areas of age, weight and half-life of the drug. The differences
in constant elimination rate and volume of distribution were not hugely different.
Was there an associated P value? No
If yes, what did the P value show? NA
Name of Statistic: Standard Deviation
Was this statistic covered in class? Yes
How many times was it used in the article? The standard deviation was used multiple
times when comparing the demographic and pharmacokinetic variables for the three age
groups.
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Why do you think this statistic was used? This statistic was used to show an accurate
picture of the data set for the peak and trough. A narrow standard deviation shows that
most of the results are gathered narrowly around the mean. It was used to assess the
degree of dispersion of the values around its mean.
What did this statistic show or prove? Measurements had high precision and
were narrowly centered around the mean. The Peak concentrations for the groups had
standard deviations ranging from + 1.4 to + 1.9. Trough concentrations were also tightly
centered around the mean with a range of + of .01 to .48. These results showed that all the
groups were similar. All of these results were within 2 standard deviations of the mean and
therefore the precision of the testing was excellent.
Was there an associated P value? No
If yes, what did the P value show? NA
Name of Statistic: One Way ANOVA
Was this statistic covered in class? Yes
How many times was it used in the article? Once
Why do you think this statistic was used? Because the researchers were comparing 3
or more groups that were receiving one treatment. A One-Way Analysis of Variance is a
way to test the equality of three or more means at one time by using variances. The
researchers used this to determine if there were any other demographic differences among
the three groups of 30-34 week old neonates.
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What did this statistic show or prove? There was a significant F value although it was
not reported. The results showed there was a difference in the groups but we don’t know if
it was just one or two groups that were different or even if all three that were different.
Was there an associated P value? Yes,p= 0.01 for the 30-34 week old group only.
If yes, what did the P value show? The relatively small P value of 0.01 in the 30-34
week group that received 3.5mg/kg/36/hr dosing showed that we can be fairly confident
that this particular dosing regimen is statistically different from the other 30-34 week
groups although the P values from the other groups were not shown.
Name of Statistic: Tukey’s Pairwise Comparison
Was this statistic covered in class? Yes
How many times was it used in the article? Once
Why do you think this statistic was used? It was used to compare the mean peak and
trough in the GA group of 35 weeks and older and to disprove that one of the results from
the one way ANOVA that was significant wasn’t a chance result. Multiple comparison
procedures are commonly used in an analysis of variance after obtaining a
significant omnibus test result, like the ANOVA F-test. The significant ANOVA result
suggests rejecting the global null hypothesis H0 that the means are the same across the
groups being compared. Multiple comparison procedures are then used to determine which
means differ. In this instance the test was used to show between which groups the
significance occurs.
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What did this statistic show or prove? For half- life and elimination rate, the GA
group of 29weeks< differed the most from the other 2 groups. There was no significant
difference between GA 30-34 weeks and 35 >.
Was there an associated P value? Yes- GA group 29 weeks or less (group 1) vs. GA
group 30-34 weeks (group 2) p=<0.01. Group 1 vs. GA group 35 weeks or> (group 3),
p=<0.01. Group 2 vs. group3 p=, 0.01
If yes, what did the P value show?
This result showed that group 1 differed from groups 2 and 3, and that Group 2 differed
from group 3. Overall it showed there was a significant difference in demographics and
pharmacokinetics (half-life and elimination rate).
Name of Statistic: Two Tailed Student’s T Test
Was this statistic covered in class? Yes
How many times was it used in the article? Once
Why do you think this statistic was used? This statistical tool was used to compare
mean peak and mean trough level for the 2 groups in the 35 weeks or older group. The
groups were normally distributed so the 2 tailed test was appropriate for testing for the
possibility of the relationship in both directions.
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What did this statistic show or prove? It showed that in the GA group of 35 weeks and
older, the higher dose of gentamicin (4mg/kg/36hr) had the highest levels of mean peak and
trough concentrations.
Was there an associated P value? Yes P = <0.0001
If yes, what did the P value show? The P value of <0.0001 shows that one can be
confident the probability is highly likely of getting the same result if the test was done again
on another group.
Name of Statistic: Chi Square
Was this statistic covered in class? Yes
How many times was it used in the article? Once
Why do you think this statistic was used? It was used because it is a non-parametric
test for data that is not normally distributed. This test is looking at expected not achieved
outcomes.
What did this statistic show or prove? It showed there was a systematic difference in
the 3 groups of neonates in the 30-34 week GA range.
Was there an associated P value? Yes P = <0.0001
If yes, what did the P value show? The P value of <0.001 shows that this was a very
reliable result. Note that the subjects in this study were not randomly assigned and this
may have affected the outcomes.
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Name of Statistic: Two Tailed Fischer’s Exact
Was this statistic covered in class? Yes
How many times was it used in the article? Once
Why do you think this statistic was used? It was used to as a post hoc to the Chi square
test. This non parametric test was used for the 2 groups of 35 week and older neonates as a
way of looking at the directionality of the results. The sample size was small for the 2
groups, n=163 and n=69.
What did this statistic show or prove? That of the 2 groups of 35 weeks and older
neonates, those receiving the lower dose of gentamicin(3.5mg/kg/24hr) were in the target
range for mean Peak concentration 87.7% of the time. Comparatively those in the 35 week
or older group receiving the 4/mg/kg/24hr were only in the target Peak range 53% of the
time.
Was there an associated P value? Yes P=0.476
If yes, what did the P value show? The P-value of 0.476 barely reached significance.
Note that the two groups varied greatly in size and that the subjects were not randomly
assigned. This P value tells us that had the groups been larger and or randomly assigned
we might get different results.
Name of Statistic. Frequency Count
Was this statistic covered in class? Yes
How many times was it used? Once
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Why do you think it was used? It is a descriptive statistic and was used to describe
the size of the group.
What did this show or prove? It showed that in GA group 29weeks < there were 5
neonates. In the 30-34 week GA groups there were 67 neonates and finally in the 35 week
GA group there were 232 neonates.
Was there an associated P value? No
If yes, what did this P value show? NA
Name of the statistic: Percentages
Was this statistic covered in class? No
How many times was it used in the article? Many
Why do you think this statistic was used? It was used to describe the results of the
data. It is a descriptive statistic that helps to visualize how much of a whole is being
represented
What did this statistic show or prove? It showed what percent of the group fell into a
certain range or category. It was used frequently throughout the study when discussing
results and of both inferential and descriptive data.
Was there an associated P value? No
If yes, what did the P value show? NA
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References
Fullas F., Padomek,C., Theiman,C., VanGorp,A.(2011). Comparative evaluation of six
extended-interval gentamicin dosing regimens in premature and full term neonates. American
Journal of Health-Systems Pharmacists, (68) 52-56. DOI 10.2146/ajhp100114.
Langlass, T., Mickle,T.,(1999). Standard gentamicin dosage regimen in neonates.
American Journal of Health Systems-Pharmacists, 1999, (56) 440-443.