from august 1 to 31 , 2007 all patients scheduled for percutaneous rfa for treatment of hepatic cancer or metastases were recruited for this explorative prospective cohort study .
the investigative protocol was approved by the institutional review board and informed consent was obtained from every patient before enrollment .
seventeen patients ( m : f = 9:8 ; mean age , 61.511.7 ; range , 38 - 78 years ) treated by ct - guided rfa for non - resectable hepatocellular carcinoma ( hcc ; n = 4 ) and liver metastases from colorectal cancer ( n = 7 ) , breast cancer ( n = 3 ) , gastric cancer ( n = 1 ) , uterine cancer ( n = 1 ) , and leiomyosarcoma ( n = 1 ) were included in this study .
patients suffered from a variable number of lesions of different sizes , with a total of 28 lesions treated in 20 treatment sessions . the general condition and anesthesiarelated risks
were classified according to the american society of anesthesiology ( asa ) grading system ( table 1 ) .
all patients with metastatic disease had undergone resection of the primary tumor , and 14 patients had been pre - treated , either by chemotherapy ( n = 6 ) , combined surgical resection of liver metastases plus chemotherapy ( n = 3 ) , or surgical resection of liver metastases without chemotherapy ( n = 5 ) .
none of the patients had undergone systemic chemotherapy within four weeks prior to the intervention .
after informed consent had been obtained , patients were enrolled 48 hours before the intervention .
inclusion criteria included less than five metastatic or three hcc lesions per lobe , a tumor size of less than 5 cm , and no extrahepatic tumor ( 13 ) .
exclusion criteria were portal vein thrombosis and contraindications to percutaneous puncture , i.e. ascites , or coagulopathy with an international normalized ratio ( inr ) > 1.5 or a platelet count < 50,000 ( 10/l ) .
after enrollment , patient vital signs , body temperature , and blood samples were obtained .
four measurement time points ( t1-t4 ) were defined as follows : 
 t1 = pre - interventionally after induction of anesthesia , t2 = intra - interventionally , 90 min after initiation of rfa , t3 = post - interventionally after finishing the procedure , andt4 = post - interventionally the following day ( 22 - 24 h after initiation of rfa ) . 
  t1 = pre - interventionally after induction of anesthesia , t2 = intra - interventionally , 90 min after initiation of rfa , t3 = post - interventionally after finishing the procedure , and t4 = post - interventionally the following day ( 22 - 24 h after initiation of rfa ) .
hemodynamic measurements , body temperature ( infrared ear - thermometer , first temp genius , sherwood medical , uk ) , and blood samples were obtained at all time points t1-t4 . all blood samples were immediately cooled down to 4 and centrifuged .
plasma samples were assayed by elisa ( immulite 1000 , dpc biermann , bad nauheim , germany ) for tnf , il-6 , il-8 , and il-10 .
serum samples for catecholamines ( adrenaline , noradrenaline ) were stored on ice and transferred to the laboratory for prompt high pressure liquid chromatography ( hplc ) analysis ( alliance hplc systems , waters corporation , milford , ma ) .
blood samples for liver enzymes , creatine kinase ( ck ) and lactate were taken at the same time .
all procedures were performed under general anesthesia according to our hospital routine protocol , including oral premedication with 0.1 mg / kg midazolam ( midazolam ratiopharm , ratiopharm , ulm , germany ) and monitoring of ecg , invasive blood pressure , pulse oximetry , and capnometry .
pre - oxygenation anesthesia was induced by the injection of 0.1 mg / kg piritramide ( dipidolor , janssen - cilag , neuss , germany ) , 1 - 2 mg / kg propofol ( propofolratiopharm , ratiopharm ) and 0.2 mg / kg cisatracurium ( nimbex , glaxosmithkline uxbridge , uk ) . the patient 's trachea was intubated and anesthesia was maintained intravenously with 5 - 10 mg / kg / h propofol ( propofolratiopharm , ratiopharm ) and 0.1 - 0.3 g / kg / min remifentanil ( ultiva , glaxosmithkline ) .
patients were mechanically ventilated ( servo 900c , siemens elema , solna , se ) , in the volume controlled mode , with a tidal volume of 8 ml / kg and a respiratory rate to target an end - tidal partial carbon dioxide pressure ( etco2 ) of 34 - 40 mmhg . for hemodynamic management , 2 ml / kg / h of ringer 's solution were infused .
a foley catheter was placed in the bladder ( rsch sensor silicon , rsch , belp , ch ) to measure body temperature and fluid balance . with removal of the rf probe ,
upon emergence from anesthesia , the patient was extubated and brought to the post - anesthetic care unit until full recovery .
first , a standardized non - contrast ct ( somatom volume zoom , siemens , forchheim , germany ) of the liver was performed to visualize the lesion ( 42.5 mm , 120 kv , 150 maseff ) .
next , the rf - probe was placed under ct - guidance using 3 mm sequential images .
two different generators , rf-3000 ( boston scientific , natick , ma ) and elektrotom hitt 106 ( integra , plainboro , nj ) were used ( table 1 ) .
the probes used were either mechanically expandable ( leveen , boston scientific , natick , ma ) or employed saline infusion ( hitt needle electrode , integra , plainboro , nj ) .
ablation was performed according to the protocols recommended by the vendors at two positions using the so called pullback technique ( 12 , 14 ) . at the end of the procedure ,
the probe was slowly withdrawn while tract ablation was performed . in the rf-3000 system ,
the applied energy was estimated as the product of time ( s ) and power ( w ) , while it was displayed on the hitt106 system .
a repeated measures anova was performed to test for differences . in case of significant results
all statistical operations were performed using spss for windows 17.0 ( spss inc , chicago , il ) .
seventeen patients ( m : f = 9:8 ; mean age , 61.511.7 ; range , 38 - 78 years ) treated by ct - guided rfa for non - resectable hepatocellular carcinoma ( hcc ; n = 4 ) and liver metastases from colorectal cancer ( n = 7 ) , breast cancer ( n = 3 ) , gastric cancer ( n = 1 ) , uterine cancer ( n = 1 ) , and leiomyosarcoma ( n = 1 ) were included in this study .
patients suffered from a variable number of lesions of different sizes , with a total of 28 lesions treated in 20 treatment sessions . the general condition and anesthesiarelated risks
were classified according to the american society of anesthesiology ( asa ) grading system ( table 1 ) .
all patients with metastatic disease had undergone resection of the primary tumor , and 14 patients had been pre - treated , either by chemotherapy ( n = 6 ) , combined surgical resection of liver metastases plus chemotherapy ( n = 3 ) , or surgical resection of liver metastases without chemotherapy ( n = 5 )
. none of the patients had undergone systemic chemotherapy within four weeks prior to the intervention .
after informed consent had been obtained , patients were enrolled 48 hours before the intervention .
inclusion criteria included less than five metastatic or three hcc lesions per lobe , a tumor size of less than 5 cm , and no extrahepatic tumor ( 13 ) .
exclusion criteria were portal vein thrombosis and contraindications to percutaneous puncture , i.e. ascites , or coagulopathy with an international normalized ratio ( inr ) > 1.5 or a platelet count < 50,000 ( 10/l ) . after enrollment , patient vital signs , body temperature , and blood samples
four measurement time points ( t1-t4 ) were defined as follows : 
 t1 = pre - interventionally after induction of anesthesia , t2 = intra - interventionally , 90 min after initiation of rfa , t3 = post - interventionally after finishing the procedure , andt4 = post - interventionally the following day ( 22 - 24 h after initiation of rfa ) . 
 
t1 = pre - interventionally after induction of anesthesia , t2 = intra - interventionally , 90 min after initiation of rfa , t3 = post - interventionally after finishing the procedure , and t4 = post - interventionally the following day ( 22 - 24 h after initiation of rfa ) .
hemodynamic measurements , body temperature ( infrared ear - thermometer , first temp genius , sherwood medical , uk ) , and blood samples were obtained at all time points t1-t4 .
plasma samples were assayed by elisa ( immulite 1000 , dpc biermann , bad nauheim , germany ) for tnf , il-6 , il-8 , and il-10 .
serum samples for catecholamines ( adrenaline , noradrenaline ) were stored on ice and transferred to the laboratory for prompt high pressure liquid chromatography ( hplc ) analysis ( alliance hplc systems , waters corporation , milford , ma ) .
blood samples for liver enzymes , creatine kinase ( ck ) and lactate were taken at the same time .
all procedures were performed under general anesthesia according to our hospital routine protocol , including oral premedication with 0.1 mg / kg midazolam ( midazolam ratiopharm , ratiopharm , ulm , germany ) and monitoring of ecg , invasive blood pressure , pulse oximetry , and capnometry . pre - oxygenation anesthesia was induced by the injection of 0.1 mg / kg piritramide ( dipidolor , janssen - cilag , neuss , germany ) , 1 - 2 mg / kg propofol ( propofolratiopharm , ratiopharm ) and 0.2 mg / kg cisatracurium ( nimbex , glaxosmithkline uxbridge , uk ) . the patient 's trachea was intubated and anesthesia was maintained intravenously with 5 - 10 mg / kg / h propofol ( propofolratiopharm , ratiopharm ) and 0.1 - 0.3 g / kg / min remifentanil ( ultiva , glaxosmithkline ) .
patients were mechanically ventilated ( servo 900c , siemens elema , solna , se ) , in the volume controlled mode , with a tidal volume of 8 ml / kg and a respiratory rate to target an end - tidal partial carbon dioxide pressure ( etco2 ) of 34 - 40 mmhg . for hemodynamic management , 2
a foley catheter was placed in the bladder ( rsch sensor silicon , rsch , belp , ch ) to measure body temperature and fluid balance . with removal of the rf probe ,
upon emergence from anesthesia , the patient was extubated and brought to the post - anesthetic care unit until full recovery .
first , a standardized non - contrast ct ( somatom volume zoom , siemens , forchheim , germany ) of the liver was performed to visualize the lesion ( 42.5 mm , 120 kv , 150 maseff ) .
next , the rf - probe was placed under ct - guidance using 3 mm sequential images .
two different generators , rf-3000 ( boston scientific , natick , ma ) and elektrotom hitt 106 ( integra , plainboro , nj ) were used ( table 1 ) .
the probes used were either mechanically expandable ( leveen , boston scientific , natick , ma ) or employed saline infusion ( hitt needle electrode , integra , plainboro , nj ) .
ablation was performed according to the protocols recommended by the vendors at two positions using the so called pullback technique ( 12 , 14 ) . at the end of the procedure ,
the probe was slowly withdrawn while tract ablation was performed . in the rf-3000 system ,
the applied energy was estimated as the product of time ( s ) and power ( w ) , while it was displayed on the hitt106 system .
a repeated measures anova was performed to test for differences . in case of significant results ,
all statistical operations were performed using spss for windows 17.0 ( spss inc , chicago , il ) .
stable tiva was achieved in all patients and rfa was successfully completed . total procedure time and duration of energy deposition
were 152  22 ( 113 - 186 ) minutes and 101  7 ( 92 - 112 ) minutes , respectively .
another patient with previously known severe hepato - pulmonary syndrome developed an intra - hepatic abscess and died despite adequate percutaneous drainage 33 days after the procedure from septic multi - organ failure . in one patient ,
a fully reversible paresis of the right arm occurred , which was due to the positioning of the arm above the head . in two patients treated with the rf-3000 system
there were no significant changes in heart rate during the interventions , but heart rate was significantly increased on the first post - interventional day ( p = 0.038 ) .
mean arterial blood pressure was significantly lower after induction of anesthesia at t1 , when compared to all other points ( p < 0.001 ) .
body temperature increased significantly during the procedure , but was normal again in the post - anesthetic care unit .
temperature was again slightly elevated on the first post - interventional day ( p < 0.001 ) ( table 2 ) .
il-6 increased during ( t2 ; p > 0.05 ) and after ( t1 vs. t3 ; p = 0.003 ) the intervention and remained high at the next day ( t1 vs. t4 ; p = 0.001 ) .
il-10 increased significantly between t1-t3 ( p = 0.007 ) and t2-t3 ( p = 0.014 ) , and started to decrease the following day ( t4 ) , but remained above the pre - interventional level ( p = 0.019 ) ( fig . 1 , table 3 ) .
post - interventional il-6 levels strongly correlated with the applied energy ( r = 0.837 , p = 0.01 ) .
there was also a weak correlation between the plasma levels of adrenaline and the anti - inflammatory cytokine il-10 after the intervention ( r = 0.583 , p = 0.022 ) .
post - interventional adrenaline levels were significantly elevated in the recovery room ( t1 vs. t3 ; p < 0.001 ) , but decreased to pre - interventional levels on the next day .
in contrast , noradrenaline was elevated on the first post - interventional day only ( p < 0.001 ) ( fig .
2 , table 3 ) . aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) levels increased during the procedure ( p = 0.021 ) , and continued to further increase the next day ( p < 0.001 ) .
lactate dehydrogenase ( ldh ) increase was delayed to the first post - interventional day ( p < 0.001 ) .
no significant changes could be demonstrated for alkaline phosphatase ( ap ) , pseudocholinesterase ( pche ) , and glutamate dehydrogenase ( gldh ) levels .
there was an increase in ck , starting directly after the procedure ( t1 vs. t4 ; p = 0.001 ) .
lactate was slightly , but significantly greater the day after the procedure ( t4 ; p = 0.007 ) ( table 4 ) .
there were no significant changes in heart rate during the interventions , but heart rate was significantly increased on the first post - interventional day ( p = 0.038 ) .
mean arterial blood pressure was significantly lower after induction of anesthesia at t1 , when compared to all other points ( p < 0.001 ) .
body temperature increased significantly during the procedure , but was normal again in the post - anesthetic care unit .
temperature was again slightly elevated on the first post - interventional day ( p < 0.001 ) ( table 2 ) .
il-6 increased during ( t2 ; p > 0.05 ) and after ( t1 vs. t3 ; p = 0.003 ) the intervention and remained high at the next day ( t1 vs. t4 ; p = 0.001 ) .
il-10 increased significantly between t1-t3 ( p = 0.007 ) and t2-t3 ( p = 0.014 ) , and started to decrease the following day ( t4 ) , but remained above the pre - interventional level ( p = 0.019 ) ( fig . 1 , table 3 ) .
post - interventional il-6 levels strongly correlated with the applied energy ( r = 0.837 , p = 0.01 ) .
there was also a weak correlation between the plasma levels of adrenaline and the anti - inflammatory cytokine il-10 after the intervention ( r = 0.583 , p = 0.022 ) .
post - interventional adrenaline levels were significantly elevated in the recovery room ( t1 vs. t3 ; p < 0.001 ) , but decreased to pre - interventional levels on the next day .
in contrast , noradrenaline was elevated on the first post - interventional day only ( p < 0.001 ) ( fig .
aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) levels increased during the procedure ( p = 0.021 ) , and continued to further increase the next day ( p < 0.001 ) .
lactate dehydrogenase ( ldh ) increase was delayed to the first post - interventional day ( p < 0.001 ) .
no significant changes could be demonstrated for alkaline phosphatase ( ap ) , pseudocholinesterase ( pche ) , and glutamate dehydrogenase ( gldh ) levels .
there was an increase in ck , starting directly after the procedure ( t1 vs. t4 ; p = 0.001 ) .
lactate was slightly , but significantly greater the day after the procedure ( t4 ; p = 0.007 ) ( table 4 ) .
this study demonstrated a persistent increase in pro - inflammatory ( il-6 ) and a transient increase in anti - inflammatory cytokines ( il-10 ) , with the increase in il-6 being correlated with the amount of applied energy .
this indicates a concomitant inflammatory response beyond mechanistic heating ( 9 , 10 , 15 ) .
a cryoablation associated systemic inflammatory response syndrome ( sirs ) , with high mortality ( 35% ) ( 6 , 9 , 15 ) , which was characterized by multi - organ failure and coagulopathy , could not be detected in any of these rfa patients , and has not yet been reported after rfa .
therefore , the inflammatory and stress response measured in this cohort of patients undergoing percutaneous rfa of hepatic tumors has to be interpreted in the context of procedural , anesthetic and general considerations .
extent and time course of the increase in liver enzymes and ldh are in agreement with previously published data , reflecting the response to the liver injury caused by ablation ( 16 ) .
consistent with previous studies , we observed a significant increase in body temperature during and after percutaneous ' hepatic rfa ' ( 17 ) .
however , a clear correlation between applied energy and increase in body temperature could not be established in this small patient population .
the hypothesis of local hepatic hyperthermia , leading to systemic heating via intra - hepatic blood flow , comparable to a ' heat exchanger ' ( 17 ) , is supported by the transient normalization of body temperature measured immediately after the procedure .
however , differences in tumor location and vascularization make it impossible to predict the systemic warming effect from the total amount of applied energy . of note
the liver is a significant source of cytokines , which are produced in kupffer cells ( 18 - 20 ) .
the release of cytokines may be depending on several conditions including the ablation technique and type of anesthesia . in a rat model ,
chapman et al . ( 21 ) described a significantly higher increase in tnf at 24 hrs after performing hepatic cryoablation when compared to rfa - treated animals .
( 22 ) demonstrated that systemic inflammation induced by rfa or open partial liver resection are of the same moderate magnitude and not as exaggerated as frequently observed after cryoablation .
the moderate inflammatory reaction observed in this study supports the findings of schell et al .
( 10 ) , indicating that the course of systemic inflammation after percutaneous rfa is typically moderate .
cryoablation induces a rupture of the plasma membrane , resulting in a dispersion of intact cellular structures into the space of disse and leading to a systemic spreading .
rfa , in contrast , induces the coagulative destruction of intra cytoplasmatic structures and does not touch cellular surface integrity
. moreover , rfa results in local vessel occlusion , limiting the local and systemic spread of proinflammatory cytokines .
interestingly , cytokine release is known to be influenced by the type of anesthesia and the ventilatory regimen .
there is a significant correlation between balanced inhalational anesthesia and the increase of pro - inflammatory il-6 .
the increase of il-6 with tiva has been reported to be markedly less when compared with the results observed in this study ( 23 , 24 ) . therefore , the pro - inflammatory effect in this study effect is likely due to rfa .
tiva is also known to induce a significant increase of anti - inflammatory cytokines ( 25 ) .
the use of propofol and remifentanil in this study might have caused an anti - inflammatory effect , although both il-6 and il-10 activation were present .
the notable stress response is likely to have been attenuated by anesthesia . in previous investigations , maximum levels of stress hormones
have been measured not during the surgical procedure , but immediately after termination of general anesthesia .
this was attributed to the onset of postoperative pain , centralization , and shivering ( 26 - 29 ) .
one purpose of anesthesia is the modification of stress response to avoid surplus endocrine reactions and to preserve the compensatory mechanisms ( 26 , 30 ) .
the mode of anesthesia is relevant , as endocrine stress response varies in different anesthetic regimens .
it was found to be less attenuated with tiva , compared with inhalation anesthesia ( 31 ) . in this study ,
catecholamine levels were normal during the procedure , but increased post - interventionally , indicating that the stress response has been sufficiently suppressed during the procedure .
interestingly , the time courses of adrenaline and noradrenaline were different , peaking at different times .
this might have affected the suppression of noradrenaline production in the early post - interventional period , but not the first post - interventional day .
first , only a small number of patients with a broad variety of hepatic neoplasms were included in this explorative study .
second , all procedures were performed under general anesthesia and there is no data on conscious sedation .
considering the effects on inflammatory and stress reaction , it has to be recognized that general anesthesia per se is not known to induce inflammation , and stress reaction is lowest with tiva .
thus , the observed effects have to be considered to be due to the ablation procedure
. however , we can only speculate if the results would be different in patients treated under conscious sedation .
finally , the energy applied with the rf-3000 system could only be estimated with incomplete data on energy deposition in two procedures . in conclusion ,
rfa of hepatic malignancies causes inflammatory and endocrine activation , similar to sirs . in choosing the best management strategy
, one has to consider that the extent of this response is extremely variable and is modulated by additional factors such as the type of anesthesia . as percutaneous rfa
is often employed in fragile patients , these systemic reactions have to be taken into account when dealing with patients susceptible to sepsis or multi - organ failure .
 objectiveto investigate the effects of hepatic radiofrequency ablation ( rfa ) in patients with malignant liver disease with respect to inflammation activation and stress response.materials and methodsin an observational trial , we investigated the physiologic parameters of 17 patients ( 20 interventions ) who underwent percutaneous rfa under general anesthesia after applying total intravenous anesthesia . 
 tnf , il-6 , il-8 , il-10 , adrenaline and noradrenaline , liver enzymes , lactate and creatine kinase were determined pre - interventionally after induction of anesthesia ( t1 ) , 90 minutes after initiation of rfa ( t2 ) , immediately after the conclusion of the procedure ( t3 ) , and 24 hours after the procedure ( t4).resultsa significant increase in body temperature ( p < 0.001 ) , and mean arterial pressure ( p = 0.001 ) were measured intraoperatively ( t2 ) and the day after the procedure ( t4 ) . 
 increased levels of il-6 were measured at t3 and t4 ( p = 0.001 ) . 
 il-10 increased immediately after the procedure ( t3 ; p = 0.007 ) . 
 il-6 levels correlated well with the total energy applied ( r = 0.837 ) . 
 significant increases in the levels of adrenaline and noradrenaline were present at t3 and t4 ( p < 0.001 ) . the rfa - induced destruction of hepatic tissue was associated with increased levels of ast , alt , gldh and ldh.conclusionpercutaneous rfa of hepatic malignancies causes an inflammatory and endocrine activation , similar to the systemic inflammatory response syndrome . 
 these effects have to be taken in account when dealing with patients susceptible to sepsis or multi - organ failure . 
MATERIALS AND METHODS
Demographics
Study Protocol
Biochemical Analysis
Anesthesia Management
Radiofrequency Ablation Procedure
Statistics
RESULTS
Clinical Parameters
Cytokine Levels
Catecholamine Levels
Serum Chemistry
DISCUSSION