the cytokine response to surgery involves 
 inflammation , immune and pituitary hormonal responses , 
 hematopoiesis , and tissue repair .
the major cytokine synthesized after surgery is 
 interleukin-6 and this stimulates acute phase protein ( app ) synthesis in 
 the liver .
concentrations of apps rise significantly during acute 
 inflammation owing to surgery , myocardial infarction , infections , 
 and tumors [ 1 , 2 , 3 , 4 ] .
c - reactive protein ( crp ) is one of the plasma acute phase proteins 
 with the largest and earliest rise .
increase in the synthesis of 
 apps is accompanied by a decrease in the synthesis of some 
 proteins called negative app .
albumin ( alb ) is a negative app and 
 albumin values fall in the presence of inflammatory cytokines 
 [ 1 , 3 ] . except for ritual circumcision
, boys are circumcised because of 
 medical indications such as recurrent balanitis , severe phimosis , 
 and paraphimosis .
circumcision prevents urinary tract infections , 
 reduces the incidence of penile carcinoma , also reduces the spread 
 of hiv and other sexually transmitted diseases [ 5 , 6 , 7 ]
some physicians performing circumcision without any form of 
 analgesia , believe that neonates do not feel or remember pain 
 , but local anaesthesia including topical application of 
 cream , emulsion or jel , or dorsal penile nerve block , and penile 
 ring block are recommended for neonatal circumcision [ 5 , 9 ] . 

although circumcision can be 
 performed under local anaesthesia even in older boys , general 
 anaesthesia is required in children older than six months of age 
 . in our society ,
the parents choose the 
 anesthesia type but at the departments of pediatric surgery , 
 general anesthesia is preferred .
there are several studies reporting the effects of the type of 
 anaesthesia on acute phase response [ 2 , 3 , 11 , 12 ] .
khilnani et al hypothesized that 
 children have a different stress response to surgery than adults 
 and they found that hormonal responses to surgical stress in 
 children were not affected by age , length of surgery , and 
 anaesthetic technique . to our knowledge acute phase 
 response ( crp and albumin ) to circumcision has not been previously 
 studied .
the purpose of this study was to confirm the acute phase 
 protein response to circumcision and investigate the effects of 
 anaesthesia on this response .
we obtained local hospital ethics committee approval and written 
 informed consent from the parents of 115 children , aged 1 to 13 
 years .
children with malnutrition , suspected infection , or chronic 
 inflammatory conditions and receiving medications known to 
 interfere with stress response were excluded .
after 6 hours fasting all patients were premedicated with 
 midazolam 0.1  mg / kg intramuscularly or 0.3  mg / kg rectally 
 and monitored via electrocardiogram , 
 noninvasive arterial blood pressure , and pulse oximetry 
 ( cardiocap/5 , datex ohmeda , louisville , colo , usa ) during the 
 operation .
the type of 
 anaesthesia was determined according to the parents and the 
 surgeons ' preference .
the children in group 1 ( itga : intratracheal 
 general anaesthesia , n = 40 ) received sevoflurane 2% via mask , fentanyl 
 1  g / kg intravenously ( iv ) for induction , 
 and rocuronium bromide 0.5  mg / kg iv was 
 given as muscle relaxant .
after endotracheal intubation , 50% 
 nitrous oxide in oxygen with 2% sevoflurane was used for 
 maintenance . in group 2 ( general anaesthesia with mask ,
n = 20 ) , 
 children received 50% nitrous oxide in oxygen with sevoflurane 
 2%-3% via mask and fentanyl 1  g / kg iv .
ketamine 
 1 - 2  mg / kg iv was used in group 3 ( intravenous anaesthesia 
 with ketamine , n = 20 ) . in group 4 ( local anaesthesia ,
n = 35 ) , 
 dorsal penile nerve block or penile ring block ( 1 - 2 or 
 24  ml of lidocaine 20  mg / ml and epinephrine 
 0.0125  mg / ml , subcutaneously ) was used for circumcision .
the distal incision was marked 
 and created carrying sharply down to buck 's fascia .
after 
 frenuloplasty , the proximal incision was marked and carried down 
 deeply into the dartos fascia .
the sleeve of tissue was divided in 
 the midline and the redundant tissue was excised .
blood samples for protein analysis were obtained by venipuncture 
 from children 24 hours before circumcision during preoperative 
 evaluation ( sample 1 ) , on admission to hospital , after 
 premedication ( sample 2 ) , and 24 hours after circumcision ( sample 
 3 ) .
three ml of blood were centrifuged , serum collected and stored 
 at 20c until assayed .
serum crp and albumin values 
 were determined by immunoturbidimetric and colorimetric methods , 
 respectively , with sigma kits ( sigma diagnostics , fla , usa ) using 
 hitachi 717 auto analyzer ( boehringer mannheim , germany ) .
crp concentrations remained 
 inferior to the detection limit of assay used were accepted as 
 zero .
the parameters among the four groups were compared by anova test 
 ( a value of p < .05 was considered as significant ) .
the 
 differences in the values of crp and albumin during the study were 
 analyzed with repeated measures anova .
statistical significance 
 was considered at p < .05 . results were given as mean ( sd ) .
there were no significant differences in children profile ( age , 
 weight ) and operation time among the groups ( table 1 ) .
crp values before surgery ( samples 1 and 2 ) were comparable for all 
 groups . in group 1 ( itga ) ,
crp increased on admission , and 
 decreased after circumcision but the changes were not significant . 

there was a little increase of samples 2 and 3 of crp in group 3 
 ( ketamine ) ( p > .05 ) . in group 2 ( mask ) and
group 4 ( local 
 anaesthesia ) , the same crp values were obtained before surgery .
we 
 observed no increase in crp values after circumcision in four 
 groups ( table 1 ) .
the albumin values 24 hours before surgery ( sample 1 ) and on 
 admission ( sample 2 ) were similar for all groups , and the values 
 remained steady throughout the study .
the common age period of cultural circumcision is 1 to 8 years , in 
 our country .
although circumcision is usually performed under 
 local anesthesia including dorsal penile nerve block or penile 
 ring block and topical anesthesia , pediatric surgeons prefer 
 general anaesthesia . during cytokine response to surgery , acute phase proteins , 
 including crp , are synthesized in the liver , but plasma 
 concentrations of some visceral proteins such as albumin , termed 
 the negative phase reactant , decrease , because of alteration in 
 synthesis rate or increased catabolism [ 1 , 3 ] .
the effects of anaesthesia on acute phase response to surgery have 
 been studied in adults .
it was found that the cytokine production 
 in cardiac surgery was not affected by type of anaesthesia , 
 thoracic analgesia combined with inhalation anaesthesia or high 
 dose opioid anaesthesia . in this study
, types of 
 anaesthesia ( general or ketamine ) did not affect the response .
we 
 obtained similar results in our previous study investigating the 
 effects of anaesthetic techniques and delivery types on crp and 
 albumin values during uncomplicated delivery .
no influence of 
 anaesthetic techniques was found except haemodilution due to 
 volume loading in regional anaesthesia .
eleven proteins were studied by simpson et al , to investigate the 
 influences of halothane and different doses of fentanyl ( 2 - 3 and 
 12  /kg ) on acute phase response to elective 
 cholecystectomy .
they could not find any 
 evidence of variation in stress suppression related to 
 anaesthesia .
the supplementation of isoflurane anaesthesia with 
 different doses of fentanyl ( 3 and 15  g / kg ) did not 
 modify the cytokine response to abdominal hysterectomy .
crp 
 increased after 24 hours , but there was no significant difference 
 between the groups . in our study , the children in group 1 
 ( itga ) and group 2 ( mask ) received sevoflurane anaesthesia with 
 fentanyl ( 1  g / kg ) .
we did not observe any difference in 
 crp and alb as acute phase protein response to circumcision , 
 between these groups and the other groups .
bourguignat et al suggested that there was incomplete or absent 
 acute phase response in some postoperative patients . 

there was no increase of crp after osteosynthesis in their 5 of 74 
 patients .
these five patients had no hepatic insufficiency or 
 protein malnutrition , and no infection was observed during the 
 survey period .
they interpreted the results as an apparent lack of 
 crp response because of the limit of detection of the assay . in 
 their study and our study ,
crp detection limit was 0.05  mg / dl 
 and crp concentrations ( < 0.05  mg / dl ) were undetectable .
preoperative fear , anxiety , starvation , length , and type of surgery 
 and premedication are the factors affecting the hormonal response 
 .
we used the same premedication ( midazolam 0.1  mg / kg 
 intramuscularly or 0.3  mg / kg rectally ) for all children and 
 there was no difference in the length and type of surgery .
no 
 change was observed between the values 24 hours before surgery 
 ( sample 1 ) and on admission to hospital ( sample 2 ) .
we think that 
 adequate preoperative sedation with midazolam may prevent acute 
 phase response , by decreasing preoperative fear and anxiety . 

the doses we have used provide good sedation and make 
 the children drowsy or sleepy .
booker et al showed that most infants had an increase in alfa-1 
 acid glycoprotein ( aag ) in response to major surgicaltrauma .
the 
 type of surgery in our study may be the reason of observing no 
 significant changes in preoperative and postoperative values of 
 crp and albumin .
circumcision is not a major surgery , but in an 
 earlier study , acute phase changes were observed in children 
 recovering from minor surgery ( inguinal hernia , undescended 
 testis ) .
there was no difference in albumin values on 
 postoperative days when compared with preoperative values .
it was 
 concluded that prognostic inflammatory and nutritional index 
 ( pini ) was more valuable for monitoring stress response .
a 
 physiologic stress including increases in heart rate and blood 
 pressure can be reduced if analgesia is employed and local 
 anaesthesia can relieve the distress seen during circumcision 
 . in one study by stang et al , dorsal penile nerve block 
 was found to be effective in reducing behavioral distress and 
 modifying the adrenocortical stress response .
it was 
 reported that the injection itself did not increase stress and did 
 not offset the beneficial effects of anaesthesia .
the langerhans cells are an epithelial component of the immune 
 system and lack of the epidermal langerhans cells at the inner 
 surface of the prepuce may produce reduced immunological response 
 to cutaneous antigens .
perhaps this histological 
 difference between the inner and outer surface of the prepuce may 
 cause reduced cytokine response to sleeve of foreskin and 
 incision .
the macrophages and monocytes start acute phase response at the 
 site of tissue injury by releasing the mediators .
cytokine 
 response to surgery reflects the extent of tissue injury and is 
 decreased with minimally invasive techniques . 

wolff et al evaluated the possible tissue damage during 
 extra corporeal shock wave lithotripsy and observed no marked crp 
 elevations because of minimal tissue damage . in 
 circumcision ,
the size of injured tissue is small and the systemic 
 absorption of mediators may be decreased because the penis is an 
 end organ . in conclusion , there was no change in crp and albumin values as 
 acute phase protein response to circumcision and type of 
 anaesthesia did not affect this response .
although undetectable 
 changes at crp and albumin concentrations may occur , no stress 
 response to circumcision may be explained with the size of injured 
 tissue or anatomical ( end organ ) and histological type of the 
 prepuce .
 concentrations of acute phase proteins ( crp : c - reactive protein , 
 albumin ) change during surgery . 
 we investigated the acute phase 
 response to circumcision and the effects of anaesthesia on this 
 response . 
 the children were divided into four groups ; group 1 
 ( intratracheal general anaesthesia , n = 40 ) , group 2 ( general 
 anaesthesia with mask , n =   20 ) , group 3 ( ketamine , n = 20 ) , group 
 4 ( local anaesthesia , n = 35 ) . 
 blood samples were obtained , 24 
 hours before circumcision , after premedication , and 24 hours after 
 circumcision . 
 crp and albumin before circumcision were comparable 
 for all groups . 
 there was no increase in crp , and albumin remained 
 steady throughout the study . 
 no difference was observed among the 
 groups , and related to anaesthesia . 
 no responsiveness may be 
 explained with the size of injured tissue or anatomical and 
 histological type of preputium . 
INTRODUCTION
MATERIAL AND METHODS
RESULTS
DISCUSSION