Abstract
This open label clinical trial was conducted in the Neonatal Intensive Care Unit (NICU), Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, during the period of March, 2012 to November, 2012. It was aimed to observe the peak (the efficacy) and trough concentration (toxicity level) of gentamicin in once daily dose (ODD) versus twice daily dose (TDD) as a primary outcome, and also to observe the renal and hearing status as secondary outcome in the neonates, treated with gentamicin. Peak level of gentamicin is the maximum concentration within 30 minutes to one hour after injection and expected concentration is to be 5 to 10 microgram /ml and trough level is the concentration of gentamicin that is measured before giving the next doe it must be <2 microgram/ml. Two groups were matched with the gestational age, post natal age and birth weight. Fifty neonates were enrolled in the study. After matching, lottery method was used to select the patient, lottery was conducted by duty doctor, this procedure continued till desired sample size was achieved informed written consent was taken before enrollment. Finally, 25 neonates were in ODD group and 25 in TDD group of gentamicin. All these neonates were diagnosed as suspected or culture proven sepsis and were treated with gentamicin and ampicillin. Neonates with post natal age 0- ≤28days and gestational age ≥32 weeks were included in the study. Newborns with perinatal asphyxia required resuscitation, gross congenital anomalies, renal impairment due to any cause were excluded. Suspected sepsis with presence of at least two risk factors of sepsis, which leaded to commence antibiotics (as per unit protocol for starting antibiotics) and proven sepsis was defined by the presence organism in blood culture or other body fluid or tissue culture. Patien′s demographic information were gathered including gestational age, birth weight, length, post natal age and weight at the time of therapy, maternal and baby′s risk factors for sepsis were also collected. Baseline investigations for sepsis were sent before commencement of treatment along with baseline serum creatinine was also done. Gentamicin was given, in ODD group 5mg/kg and in TDD group 2.5mg/kg 12 hourly. Both groups were concomitantly treated with ampicillin 50mg/kg 12 hourly.The required dose, was given as a one minute bolus into existing intravenous lines, followed by a flush with 0.5 ml normal saline. Serum trough gentamicin concentration was obtained before 3rd dose for ODD group and before 5th dose of TDD group. Peak concentration was collected one hour after gentamicin injection. At the same time, blood were collected for CBC, CRP, IT, PBF and for blood culture sensitivity and for serum creatinine. One ml of blood was collected through butterfly needle for analysis of peak and trough level of gentamicin. Peak and trough concentration was measured in the Biochemistry Department of the Bangabandhu Sheikh Mujib Medical University, to observe the primary outcome. Serum creatinine level was measured twice, once at admission and 2nd one at discharge, to observe renal function (as secondary outcome) and creatinine level raise of 50% from the baseline was define as renal function impairment.
Hearing test was done by otoacuastic emission test (OAE) at the ENT Department at discharge of the patient and hearing impairment was defined, if fails to pass OAE. Ethical approval was taken from the Institutional Review Board. SPSS software (version 19) was used for data analysis. Chi square test for comparison of demographic variable and qualitative data; unpaired t test for comparison of serum gentamicin concentration and paired t test was performed to compare serum creatinine. Duration of treatment was continued as per protocol of NICU.
Variables |
ODD Group |
TDD Group |
p value |
Age |
19(76) |
21(84%) |
0.47 |
Sex |
15(40) |
17(68) |
0.33 |
Gestational age |
40% |
40% |
0.93 |
Clinical Features |
80% |
84% |
0.99 |
Baseline lab. Features WBC |
15(60) |
16(40) |
0.46 |
Variable |
Once daily dose(ODD) |
Twice daily dose(TDD) |
p value |
Peak concentration |
7.19±1.7 |
4.814±1.8 |
0.001 |
Trough concentration |
1.5±0.78 |
2.00±0.90 |
0.04 |
On the other hand, trough concentrations were 1.5±0.78 micrograms/ml in ODD group and 2.0±0.9 micrograms/ml in TDD group, and the difference was not statistically significant (p=0.04) (table II). Twenty (80%) patient in ODD group and 11 (44%) patient in TDD group reached the expected peak concentration (5-10 microgram/ml). On the other hand, 2 patients (8%) patient in ODD group and 6(24%) patient in TDD group crossed the toxic trough level ≥2microgram/ml (figure1 and figure 2).
Patients serum concentration of creatinine in ODD group was 0.532±0.146mg/dl at baseline and 0.568±0.106 mg/dl at discharge, and in TDD group, it was 0.532±0.151mg/dl at baseline and 0.556±0.112 mg/dl at discharge.
The differences were not statistically significant (table III). But, 2(4%) patients in TDD group had 50% raised in creatinine from the baseline but no patient in ODD group had such raised creatinine.
p>Variables |
Serum creatinine (mg/dl) |
|
At admission |
At discharge |
|
ODD group |
0.568±0.106 |
0.532±0.131 |
TDD group |
0.532±0.146 |
0.55±0.11 |
|
(p 0.29) |
(p 0.59) |
During discharge AOE was done, and only 4% patient in ODD group and 8% in TDD group has ototoxicity (Refer, means screening positive by OAE) it was non-significant statistically (table IV), but it was not followed-up for further assessment of hearing on subsequent visit.
OAE |
ODD |
TDD |
p value |
Pass |
24(96) |
23(92) |
0.55 |
Refer |
1(4) |
2(8) |
Discussion
A total of 50 newborns were included with suspected or culture positive sepsis. The number of male babies was higher than the female (male: female = 1.8: 1), which was consistent with other study.22 In this study, the peak concentration of gentamicin was significantly higher (p < 0.001) in once-daily group (7.19±1.7) microgram/dl compared to twice daily group (4.81±1.8). In addition, the peak concentration of gentamicin in ODD group remained significantly higher than the TDD group Several studies also reported higher peak concentration of gentamicin in ODD group.23 However, in one study reported no difference in peak concentration between ODD and TDD groups.24 In this study, no difference was to be found in serum concentration creatinine in between the groups rather tough concentration of gentamicin was higher in the twice daily dose group. This study had several strengths; the first strength was its design: Patients were allocated to each of the two treatment groups alternately, i.e. the first eligible patient was assigned to one study group then the next eligible patient was assigned to the other group. This sequence was followed until obtaining the total samples. As a result, the demographic and clinical characteristics of patients at enrollment were distributed evenly between the two treatment groups. The treatment effects those were observed the mean peak concentration of gentamicin was higher and the mean trough concentration was lower in the once-daily dose group is likely to be real. The second strength was that the outcomes were determined from biochemical analysis; hence, one of the objectives, assessment of the outcome had a high-level of accuracy. Furthermore, the study assessment included covariates, such as weight and gestational age, which were potentially strong confounders of the assessed relationship of dose and bioavailability of gentamicin. In contrast, limitations of the study included, firstly, sample size of the study was small; secondly, the assessment of sepsis clearance was under powered. Only a fraction of patients had sepsis at the time of enrollment. Although, more patients in the once-daily dose group had have sepsis clearance than the patients in the twice-daily dose group. The absolute number in each group was very small. Hence, the chi-square estimates were not likely to be valid. Thirdly, the study duration was short. The study did not include any long-term follow-up on patient′s vital status. For example, patients died after the study ended.References