the results of imaging studies are negatively affected by patients movements ; hence , patient s cooperation is required during imaging .
children s movements and lack of cooperation are common indications for pediatric procedural sedation during imaging studies such as computed tomography ( ct ) scans ( 1 )
. different rates of success have been achieved by various sedation regimens such as diphenhydramine , propofol , ketamine , midazolam ( 2 ) , chloral hydrate ( 3 ) , pentobarbital ( 4 ) , and dexmedetomidine ( 5 ) ; therefore , the efforts to find an ideal regimen are continued .
the selected sedative should have a rapid onset of action , few adverse effects , short and sufficient duration of action , self - maintenance of a patent airway , minimal effects on respiration or hemodynamics , and rapid recovery ( 6 ) . over the last few years
, researchers have shown a special interest in finding effective , nonparenteral , sedative agents that do not have injection problems ( 3 ) .
ketamine is a noncompetitive antagonist of the n - methyl - d - aspartate receptor ( nmdar ) , which is used for premedication , sedation , and induction as well as maintenance of general anesthesia .
quick onset , short duration of action , and maintenance of laryngeal reflexes have made it a popular sedative choice for pediatric patients in the emergency department ( 7 ) . although ketamine is known as a parenteral agent , some researchers have successfully used it as an oral sedative drug ( 8 , 9 ) .
midazolam is a potent benzodiazepine with rapid onset and offset effects as well as anxiolytic and amnestic properties , which can be administered through different routes ( i.e. oral , intravenous , intramuscular , rectal , sublingual , and intranasal ) .
oral midazolam ( om ) is a safe and effective choice for sedation in children ( 10 ) . in previous studies ,
the authors have used a combination of oral midazolam and ketamine ( omk ) as premedication and sedative regimens ; besides , some studies reported that combination therapy has higher efficacy without any additional adverse effects in comparison to the methods using each drug alone ( 11 , 12 ) .
to the best of our knowledge , limited number of studies have reported the use of om during imaging , which had reported lower effectiveness rate in comparison with chloral hydrate ( 13 , 14 ) ; however , omk has not been used for this purpose , yet .
therefore , this study was conducted to compare the effects of omk with om as procedural sedatives in pediatric patients undergoing ct imaging .

 study design and setting 
  this randomized , double - blinded , clinical trial was conducted from november 2012 to november 2013 in two teaching hospitals ( ayatollah kashani hospital and alzahara hospital ) affiliated to isfahan university of medical sciences , isfahan , iran .
the study protocol was approved by ethics committee of the isfahan university of medical sciences . all parents or guardians
were informed of the study 's protocol , risks , and benefits and were asked to sign an informed written consent .
we included six - month to six - year old children with medium - risk minor head trauma who were scheduled to undergo brain ct scan ( 15 ) .
medium - risk minor head trauma was defined as initial glasgow coma scale score of 15 with any history of brief loss of consciousness , posttraumatic amnesia , vomiting , headache , or intoxication .
all of these patients were classified as status i or ii according to american society of anesthesiologists ( asa ) physical status classification . children with neurological disorders , anomalies of the cardiovascular system , known allergy to midazolam , gastritis , any serious systemic diseases , those on long - term treatment with hepatic enzyme - inducing drugs or those receiving erythromycin concurrently ( due to drug interaction ) , and patients who had received medication within the preceding 48 hours were excluded .  
patients were randomly allocated to two groups ; om group received 0.5 mg / kg midazolam ( produced by ; tehran shimi , tehran , iran ) orally and omk group received 0.2 mg / kg midazolam and 5 mg / kg ketamine ( produced by ; rotexmedica , trittau , germany ) orally .
demographic and basic characteristics such as age , height , gender , weight , body mass index ( bmi ) , and history of any medical condition were recorded before administration of study drugs .
then a nurse , who was blinded to the study , mixed both of the medications with 5 ml of sugar syrup to make it palatable .
pulse rate and oxygen saturation ( sao2 ) were continuously monitored by a portable pulse oximeter .
blood pressure , heart rate , respiratory rate , and sao2 were recorded at baseline ( just before drug administration ) and every 30 minutes until the patient was discharged from the radiology department .
the level of sedation of patients after drug administration was assessed using ramsay sedation scale ( rss ) ( 16 ) .
patients who did not show satisfactory response to the sedative drugs within 40 minutes and those who were awakened or moved during the imaging were excluded from further analysis .
the interval between administration of sedative drugs and achieving rss of four was considered as the time to achieve adequate sedation .
once the patients achieved adequate sedation , they were transferred to a scanner room and the imaging was performed according to the protocol .
after the scan , the patients were transferred to another room in the radiology department to monitor and observe their conditions .
the time to discharge from radiology department was defined as the interval between the start of sedative administration and return to the baseline alertness and spontaneous breathing . 

statistical analyses 
  all statistical analyses were performed using the spss 19.0 ( spss inc . ,
two - way anova was used to compare changes of vital signs during 180 minutes after drug administration between two groups .
consort flow diagram of study inter - group differences of vital signs at baseline and at various time points after administration of midazolam and combination of midazolam - ketamine ( df : 18 , p > 0.05 for all comparisons )
. demographic characteristics of the participants a , data are presented as mean  standard deviation .
the outcomes of patients in midazolam and midazolam - ketamine groups om : oral midazolam ; omk : combination of oral midazolam - ketamine ; rd : radiology department .  
the mean age of participants was 2.8  1.6 years ( range : 6 months to 6 years ) and 54.5% of the participants were male .
table 1 shows the basic characteristics of patients . there was no significant difference between the two groups in age , height , weight , and male to female ratio ( table 1 ) .
adequate sedation ( rss of 4 ) was achieved in five patients ( 15.2% ) in the om group and 15 patients ( 45.5% ) in the omk group , which showed a statistically significant difference ( p = 0.015 ) .
no significant difference was found between the groups in time of achieving adequate sedation ( p = 0.854 ) and the time of discharging from radiology department ( p = 0.223 ) .
adverse effects observed in two patients ( one with nausea and another with vomiting ) in the om group and three patients ( two with nausea and one patient with vomiting ) in the omk group .
complications were minor and transient and did not differ between study groups ( p > 0.05 ) .
systolic blood pressure , sao2 level , pulse rate , and respiratory rate showed no significant inter - group differences at baseline and at various time points after administration of the drugs ( for all analysis : df = 18 , p > 0.05 , figure 2 ) .
our investigation showed that in comparison to om , omk successfully induced sedation in 45% of the patients .
om failed to sedate the patient in 85% of the cases and led to administration of additional medication and longer time to obtain the scan .  
ketamine is used for premedication , sedation , and induction as well as maintenance of general anesthesia with minimal effect on respiration and tendency to preserve autonomic reflexes ( 7 ) .
it has been reported that 10 mg / kg of ketamine provides effective sedation and analgesia in young children undergoing wound repair processes ( 9 ) . moreover , 6 mg / kg of ok was reported to be effective in sedation for outpatient pediatric dental surgeries ( 10 ) .
om is the most commonly used premedication in the united states ( 18 ) , which has been used as a safe and effective sedative in pediatrics , mainly in pediatric dentistry ( 10 , 17 ) ; however , intravenous midazolam has been found to induce more sedation ( 18 ) . intravenous or nasal midazolam has gained widespread popularity as a sedative for children undergoing radiographic studies such as ct scan ( - ) . the omk and om alone are safe , effective , and practical approach to manage children for minor dental procedures ( 22 , 23 ) .
the efficacy of om and ketamine , alone or in combination has been studied in pediatric dentistry sedation and premedication ( - ) .
reported better sedative effects during suturing lacerations with ok ( 10 mg / kg ) in comparison to om ( 0.7 mg / kg ) ( 27 ) .
although our study was consistent with the previous studies regarding the higher efficacy of omk in comparison to om , most of the previous studies reported success rates of 60% to 90% for om ( 11 , 17 , 28 ) and 46% to 95% for omk ( 11 , 22 ) .
showed that the combination of oral midazolam ( 0.5 mg / kg ) and ketamine ( 5 mg / kg ) led to deeper sedation in comparison with om ( 0.5 mg / kg ) alone in children requiring laceration repair .
in addition , 27% of patients in the om group and 6% in the omk group needed further intravenous sedation ( 11 ) .
( 12 ) compared the efficacy of om ( 1 mg / kg ) and the omk ( midazolam , 0.5 mg / kg ; and ketamine , 3 mg / kg ) for guiding the behavior of children undergoing dental treatment and reported higher efficacy of omk . on the other hand ,
there are several studies reporting lower success rate , which are similar to our findings .
( 6 ) compared the sedative effects of intravenous midazolam with pentobarbital during brain ct imaging in children aged six months to six years .
they administered pentobarbital to 29 patients ( 53% ) and midazolam ( mean dose , 0.2  0.03 mg / kg ) to 26 patients ( 47% ) . in the midazolam group , only five patients ( 19% )
were successfully scanned with midazolam alone and the remaining 21 patients ( 81% ) required additional medication and took a longer time to scan .
another investigation reported a failure rate of 60% in administrating intranasal midazolam ( 0.2 mg / kg ) for sedation of children undergoing ct scan ( 3 ) .
( 29 ) used 0.4 mg / kg of om 20 minutes before the induction of general anesthesia and reported a mild or no sedative effect in 76% to 84% of patients . in this study ,
the onset time of adequate sedation was 33 minutes in om group and 32 minutes in omk group .
( 27 ) reported an onset time of 20 minutes for ok and 43 minutes for om .
other studies reported that the time to reach optimal sedation level would be 15 minutes for om ( 10 , 17 ) .
studies , which used om ( 0.5 - 1 mg / kg ) as premedication reported that the best time for optimal preoperative sedation would be 30 to 45 minutes before scan ( 30 ) .
barkan observed that the needed time to achieve adequate sedation was 17 minutes for om and 14 minutes for omk .
the patients ' blood pressure , respiratory rate , pulse rate , and sao2 levels did not show any significant changes during the sedation .
although ketamine and midazolam affect the respiratory and hemodynamics responses ( 11 ) , our results were in line with the findings of previous studies that reported minimal effects of low - dose om and ok on these parameters ( 17 , 31 ) .
although further studies are needed to confirm or refute our results and attention to the pharmacological aspects is necessary , lower efficacy of om in this study could be explained as follows : first , we used these drugs for ct imaging that needs a deeper level of sedation in comparison with some other studies that used those drugs in other settings as premedication .
second , in the previous studies , intravenous forms of these drugs were used , which might bring about unexpected results ; the same drugs in different studies should be compared with caution .
third , the ethnic differences in response to these sedative agents might affect the results .
a major cause of variations in drug responses is hepatic cytochrome p450 oxidase ( cyp450)-mediated drug metabolism ( 29 ) .
midazolam is almost exclusively metabolized by cyp450 3a ( cyp3a ) isoenzymes ( 32 ) .
although previous studies have shown that these parenteral forms can be used orally , the oral form of drugs might bring about results that are more precise .
second , the number of participants who were included in the final analysis ( as sedated patients ) was small .
this study demonstrated that in comparison with om , omk was more effective in producing a satisfactory level of sedation in children undergoing ct examinations without additional complications ; however , none of these two regimens fulfilled clinical needs for procedural sedation .
all authors passed four criteria for authorship contribution based on recommendations of the international committee of medical journal editors .
 introduction : motion artifacts are a common problem in pediatric radiographic studies and are a common indication for pediatric procedural sedation . 
 this study aimed to compare the combination of oral midazolam and ketamine ( omk ) with oral midazolam alone ( om ) as procedural sedatives among children undergoing computed tomography ( ct ) imaging . 
 methods : the study population was comprised of six - month to six - year old patients with medium - risk minor head trauma , who were scheduled to undergo brain ct imaging . patients 
 were randomly allocated to two groups : one group received 0.5 mg / kg midazolam ( om group ; n = 33 ) orally and the other one received 0.2 mg / kg midazolam and 5 mg / kg ketamine orally ( omk group ; n=33 ) . 
 the vital signs were monitored and recorded at regular intervals . 
 the primary outcome measure was the success rate of each drug in achieving adequate sedation . 
 secondary outcome measures were the time to achieve adequate sedation , time to discharge from radiology department , and the incidence of adverse events . 
 results : adequate sedation was achieved in five patients ( 15.2% ) in om group and 15 patients ( 45.5% ) in omk group , which showed a statistically significant difference between the groups ( p = 0.015 ) . 
 no significant difference was noted between om and omk groups with respect to the time of achieving adequate sedation ( 33.80  7.56 and 32.87  10.18 minutes , respectively ; p = 0.854 ) and the time of discharging from radiology department ( 89.60  30.22 and 105.27  21.98 minutes , respectively ; p=0.223 ) . 
 the complications were minor and similar among patients of both groups . 
 conclusion : this study demonstrated that in comparison with om , omk was more effective in producing a satisfactory level of sedation in children undergoing ct examinations without additional complications ; however , none of these two regimens fulfilled clinical needs for procedural sedation . 
Introduction:
Methods:
Results
Discussion:
Conclusion:
Conflict of interest:
Funding support:
Authors contributions: