this effect is associated with adverse outcomes including impaired coagulation ( 3 ) , increased incidence of surgical wound infections , prolonged hospitalization ( 4 ) , and myocardial ischemia ( 5 ) . despite the absence of environmental exposure of a wound or abdominal viscera ,
exposure of the abdominal cavity to large volumes of cold , dry carbon dioxide gas used for insufflation has been implicated as a potential source of heat loss during laparoscopy ( 6 , 7 , 8) .
therefore , the effects of aminophylline ( 85% theophylline , 15% ethylendiamine ) are similar to those of caffeine .
aminophylline has been shown to elicit thermogenesis and improve cold tolerance in rats ( 9 , 10 ) and increase the metabolic rate in lambs during cold stress ( 11 ) . since there have been no reports on the thermogenic effects of aminophylline in humans , we tested the hypothesis that aminophylline reduces the decrease in core body temperature during laparoscopic vaginal hysterectomy ( lvh ) requiring pneumoperitoneum .
this was a prospective , randomized , blinded clinical trial . after obtaining written informed consent from all patients , fifty patients scheduled for elective lvh
were enrolled between 40 to 60 yr of aged with american society of anesthesiologists ( asa ) physical status i or ii .
patients with a history of cardiovascular , pulmonary , or thyroid disease ; dysautonomia ; fever ; aminophylline intake within a day before surgery ; or who were transfused were excluded from this study .
the patients were randomly divided into an aminophylline group ( n=25 ) and a saline control group ( n=25 ) using a computer - generated randomization list .
the ambient operating room ( or ) temperature was maintained around 21 ( 12 ) .
upon arrival in the operating room , standard anesthetic monitors were applied , including ecg , a non - invasive blood pressure monitor , and pulse oximetry . to evaluate the depth of anesthetization , bis monitor ( a-3000 bis monitor , aspect medical system , covidien , ma , usa ) sensors ( bistm quatro ,
aspect medical system , norwood , ma , usa ) were attached to the patient 's forehead and temple .
a skin temperature probe was attached to the index finger of the non - infused arm .
after induction , a urinary catheter was inserted to measure hourly urine output . to prepare the study drug , aminophylline ( 10 mg / kg )
was mixed with saline in a syringe to a volume of 100 ml by an independent researcher .
fifteen minutes before inducing anesthesia , 10 ml ( 1 mg / kg ) of the study drug was administered intravenously over 1 min as an initial infusion .
an esophageal temperature probe was inserted into the lower esophagus immediately after intubation in order to measure the core temperature .
the remaining 90 ml of the study drug was administered intravenously at a rate of 50 ml / hr for next 108 min using a syringe pump .
anesthesia was maintained with 1 - 3 vol% of sevoflurane and 2 l / min each of nitrous oxide and oxygen to obtain bis values between 45 and 55 .
the lungs were ventilated with a tidal volume of 7 - 10 ml / kg and a respiratory rate of 8 - 12 breaths / min to maintain an end - tidal carbon dioxide ( etco2 ) value between 30 and 35 mmhg .
the pneumoperitoneal pressure was maintained at 12 mmhg to decrease the risk of venous carbon dioxide embolism .
the average temperature of inflow gas was 21 , and the temperature of the outflow was 32. the tidal volume and respiratory rate were set to maintain an etco2 between 35 - 40 mmhg after pneumoperitoneum .
ephedrine was given slowly , and additional doses were given at 10 min intervals , as needed .
lactated ringer 's solution and 6% hydroxyethyl starch in normal saline ( ns ) solution ( voluven , fresenius kabi , bad homberg , germany ) were administered at a maximum dose of 50 ml / kg .
lactated ringer 's solution was infused at a constant rate of 6 ml / kg / hr . body temperature was measured in the post - anesthesia care unit ( pacu ) using a tympanic thermometer ( thermoscan irt 1020 , braun , germany ) . in the pacu , a bair hugger forced - air warmer ( augustine medical inc . , eden prairie , mn , usa ) was applied to patients who had a tympanic temperature below 36. the skin temperature , mean blood pressure , and heart rate were recorded 15 min before inducing anesthesia ( t-15 ) , immediately after intubation ( tintu ) , and at 15 min intervals ( t15-t105 ) after intubation .
esophageal temperature was recorded immediately after intubation ( tintu ) and at 15 min intervals ( t15-t105 ) afterward . the room temperature , fluid intake , urine output , and estimated blood loss were recorded at t105 . to estimate
the sample size needed , a pilot study was conducted measuring core body temperature of ten control patients .
for the power calculation , we assumed an equal standard deviation for the aminophylline infusion group .
a sample size of 22 patients per group provided 80% power with a two - tailed =0.05 to show a difference of 0.3 between groups . to compensate for an estimated dropout rate of 10% ,
continuous data within the groups , such as temperature and hemodynamic variables , were compared with repeated measures of anova followed by paired t - tests with bonferroni correction for multiple comparisons .
student 's t - test or chi - square test was used to compare variables between the groups , where appropriate . in all tests ,
the study protocol was approved by the institutional review board for human research at the catholic university of korea st .
the nature of the study was explained to all patients , each of whom provided written informed consent before the beginning of the study , in accordance with the principles of the declaration of helsinki ( revision of edinburgh , 2000 ) .
the study protocol was approved by the institutional review board for human research at the catholic university of korea st .
the nature of the study was explained to all patients , each of whom provided written informed consent before the beginning of the study , in accordance with the principles of the declaration of helsinki ( revision of edinburgh , 2000 ) .
patient characteristics and perioperative data , including room temperature , fluid intake , urine output , and blood loss , did not differ significantly between the groups . in the aminophylline group ,
esophageal temperatures at t45 , t60 , t75 , t90 , t105 ( p values are in the order of 0.024 , 0.053 , 0.025 , 0.011 , 0.017 ) and index finger temperatures at t15 , t30 , t45 , t60 , t75 , t90 , t105 ( p values are in the order of 0.001 , 0.029 , 0.020 , 0.010 , 0.028 , 0.042 , 0.024 ) were significantly higher than in the saline control group ( table 1 ) ( fig .
the esophageal temperatures decreased significantly from tintu at t15-t105 in the saline control group ( p values were in the order of 0.040 , 0.006 , < 0.001 , < 0.001 , < 0.001 , < 0.001 , < 0.001 ) and at t45-t105 in the aminophylline group ( p values were in the order of 0.039 , 0.011 , 0.002 ,
the index finger temperature at t105 in the saline control group decreased significantly from tintu ( p=0.045 ) ( fig .
heart rates in both groups were significantly higher at tintu than at t-15 ( p=0.025 in the saline control group , p=0.014 in aminophylline group ) .
mean blood pressures in the aminophylline group were significantly lower at t45-t105 than at t-15 ( p<0.001 ) ( fig .
this study demonstrated that an aminophylline infusion reduced the changes in core and skin temperature compared to a saline control during lvh requiring pneumoperitoneum .
aminophylline , like caffeine , is a methylxanthine that has been shown to elicit thermogenesis and improve cold tolerance in rats ( 9 , 10 ) .
it has also significantly improved cold tolerance in lean sprague - dawley rats , regardless of age or thermogenic capacity .
aminophylline ( 18.7 mg / kg intraperitoneal ) significantly improved thermogenesis and cold tolerance in both lean and corpulent rats without any age - related difference ( 13 ) .
( 11 ) reported that aminophylline has potential as a treatment for hypothermia or to improve recovery from hypothermia in lambs by increasing metabolic rate during cold stress at 16 and 32 mg / kg doses .
vestal et al . ( 14 ) reported that methylxanthine derivatives , such as caffeine and theophylline , stimulated epinephrine and norepinephrine release from the sympathoadrenal system . in six healthy males ,
a 262% increase in plasma epinephrine and a 64% increase in plasma norepinephrine during a high - dose infusion of theophylline ( plasma theophylline level of 20 g / ml ) resulted in dose - dependent cardiovascular and metabolic effects .
plasma concentrations of glucose and free fatty acids ( ffas ) also increased , but insulin secretion was inhibited ( 14 ) .
caffeine ( 15 ) and aminophylline also block adenosine receptors ( 16 ) , which is an effect that may have a greater impact on metabolism than the inhibition of phosphodiesterase ( 17 ) .
the combined effects are expected to enhance lipolysis , glycogenolysis and gluconeogenesis and hence contribute to enhanced maximal thermogenesis ( 10 ) .
after anesthesia is induced , core hypothermia is largely caused by a redistribution of body heat from the core to the periphery ( 1 ) .
most anesthetics cause arterial and venous dilation as well as thermoregulatory vasodilation in the arteriovenous shunt ( 18 , 19 ) .
ikeda et al . ( 20 ) stated that hypothermia during general anesthesia develops in three distinct phases : 1 ) an initial , rapid decrease in core temperature , resulting largely from an internal core - to - peripheral redistribution of body heat ; 2 ) a slower , linear decrease in core temperature that results from heat loss exceeding metabolic heat production ( 21 ) ; and 3 ) a core - temperature plateau resulting from decreased cutaneous heat loss ( 22 ) and metabolic heat constrained to the core thermal compartment in patients becoming sufficiently hypothermic to trigger thermoregulatory vasoconstriction ( 23 ) . in this study ,
the core temperature gradients in the aminophylline group during sevoflurane anesthesia decreased significantly less than in the saline control group .
these data suggest that aminophylline effectively maintained the core temperature through a thermogenic effect despite reduced peripheral thermoregulatory vasoconstriction .
since there are no data on the thermogenic effect in humans , we can not determine the therapeutic range of aminophylline infusion doses .
( 11 ) reported that , in lambs , a dose of more than 16 mg / kg of aminophylline can improve recovery from hypothermia by increasing metabolic rate during cold stress , whereas 8 mg / kg of aminophylline did not affect metabolic rate .
although this was the first study to report the thermogenic effect of aminophylline in humans , we hoped positive results . therefore , we chose an aminophylline dose high in the therapeutic range ( 10 mg / kg ) .
1 mg / kg of aminophylline was administered as an initial infusion at 15 min before inducing anesthesia , and the remaining 9 mg / kg was administered intravenously after intubation at a rate of 50 ml / hr for 108 min using a syringe pump .
another limitation is that the study was performed only in women that underwent laparoscopic gynecologic surgery requiring pneumoperitoneum .
other types of surgeries in both sexes should be investigated further . in summary , this is the first study to report the thermogenic effect of aminophylline in humans .
we found that an intraoperative infusion of aminophylline reduced the decreases in core and skin temperature during lvh requiring pneumoperitoneum .
these data suggest that aminophylline maintains core temperature through a thermogenic effect despite reduced peripheral thermoregulatory vasoconstriction .
aminophylline , therefore , may be a useful and supplemental thermogenic agent to prevent hypothermic conditions when limited facilities are available to provide supplemental heat .
 aminophylline can elicit thermogenesis in rats or increase metabolic rate during cold stress in lambs . 
 we tested the hypothesis that aminophylline would reduce the change in core body temperature during laparoscopic abdominal surgery requiring pneumoperitoneum . 
 fifty patients were randomly divided into an aminophylline group ( n=25 ) and a saline control group ( n=25 ) . 
 esophageal temperature , index finger temperature , and hemodynamic variables , such as mean blood pressure and heart rate , were measured every 15 min during sevoflurane anesthesia . in the aminophylline group , esophageal temperatures at t45 ( 36.10.38 vs. 35.70.29 , p=0.024 ) , t60 
 ( 36.00.39 vs. 35.60.28 , p=0.053 ) , t75 
 ( 35.90.34 vs. 35.50.28 , p=0.025 ) , t90 ( 35.80.35 vs. 35.30.33 , p=0.011 ) , and t105 ( 35.80.36 vs. 35.10.53 , p=0.017 ) and index finger temperatures at t15 ( 35.80.46 vs. 34.90.33 , p<0.001 ) , t30 ( 35.70.36 vs. 35.00.58 , p=0.029 ) , t45 
 ( 35.80.34 vs. 35.20.42 , p=0.020 ) , t60 ( 35.70.33 vs. 34.90.47 , p=0.010 ) , t75 
 ( 35.60.36 vs. 34.80.67 , p=0.028 ) , t90 ( 35.40.55 vs. 34.40.89 , p=0.042 ) , and t105 
 ( 34.90.53 vs. 33.90.85 , p=0.024 ) were significantly higher than in the saline control group . 
 aminophylline is effective in maintaining the core temperature through a thermogenic effect , despite reduced peripheral thermoregulatory vasoconstriction.graphical abstract 