{"paper_id":"0a50b1d8-79d3-4543-8531-287fe0d5cf87","body_text":"Vol:.(1234567890)\nSurgical Endoscopy (2022) 36:4154–4170\nhttps://doi.org/10.1007/s00464-021-08742-1\n1 3\nWarm and humidified insufflation gas during gynecologic \nlaparoscopic surgery reduces postoperative pain in predisposed \npatients—a randomized, controlled multi‑arm trial\nMarkus Breuer1 · Julia Wittenborn2 · Rolf Rossaint1 · Julia Van Waesberghe1 · Ana Kowark1 · Deborah Mathei2 · \nAndrás Keszei3 · Svetlana Tchaikovski2 · Magdalena Zeppernick2,4 · Felix Zeppernick2,4 · Elmar Stickeler2 · \nNorbert Zoremba5 · Ivo Meinhold‑Heerlein2,4 · Christian Bruells1\nReceived: 23 February 2021 / Accepted: 20 September 2021 / Published online: 1 October 2021 \n© The Author(s) 2021\nAbstract\nBackground Postoperative pain remains a common problem in gynecologic laparoscopy, especially in head zone-related \nregions, triggered by intra-abdominal pressure during capnoperitoneum. Humidified and prewarmed insufflation gas may \nameliorate pain and be beneficial.\nMethods This prospective randomized controlled parallel group multi-arm single-center study investigated the effects of \ntemperature and humidity of insufflation gas on postoperative pain during gynecologic laparoscopy with a duration ≥ 60 min. \nFemale participants (18—70 years) were blinded and randomly assigned—computer generated—to either insufflation with \ndry cold  CO2 with forced air warming blanket (“AIR”), humidified warm gas without forced air warming blanket (“HUMI”), \nor humidified warm gas with forced air warming blanket (“HUMI +”). We hypothesized that using humidified warm gas \nresulted in lower pain scores and less analgesic consumption. The primary endpoint postoperative pain was assessed for dif-\nferent pain localizations every 12 h during 7 days after surgery. Secondary endpoints were demand for painkillers and epidural \nanesthetics, length of stay in recovery room, and hospital stay. (Registration: ClinicalTrials.gov NCT02781194—completed).\nResults 150 participants were randomized. Compared to group “AIR” (n  = 48), there was significantly less pain in group \n“HUMI +” (n = 48) in the recovery room (− 1.068; 95% CI − 2.08 to − 0.061), as well as significantly less ibuprofen use at \nday two (− 0.5871 g ± 0.258; p-value = 0.0471). Other variables did not change significantly. Stratification for presence of \nendometriosis or non-previous abdominal surgery in patient history revealed significantly less pain in both groups “HUMI” \n(n = 50) and “HUMI +” versus group “AIR.” Related side effects were not noted.\nConclusion In the overall population, the use of warm, humidified insufflation gas did not yield clinically relevant effects; \nhowever, in predisposed patients with endometriosis and who could otherwise expect high pain levels, warm and humidified \ngas may be beneficial.\nKeywords Laparoscopy · Gynecology · Postoperative pain · Warm humidified insufflation gas\nSince its invention, laparoscopic surgery became the gold \nstandard in various surgical disciplines with a wide range \nof indications [ 1]: the majority of gynecological surgeries \nare currently performed using minimally invasive technique \ndue to its benefits compared with open access. Patients \nundergoing laparoscopic surgery benefit from a faster recov-\nery, a reduced hospital stay, and a quicker return to normal \nactivities [1 , 2], resulting in increased patient satisfaction \n[3]. Until 2018, the frequency of laparoscopic appendec-\ntomy, cholecystectomy, and hysterectomy was reported to \nhave increased worldwide [4].\nDespite these benefits and the rising numbers of laparo-\nscopic procedures, postoperative pain remains a common \nproblem [5]. Gerbershagen et al. showed that unexpectedly \nhigh levels of postoperative pain occur even in some minor-\nto medium level surgical procedures using the laparoscopic \napproach [6]. In addition to wound-related pain, up to 80% \nand Other Inte rventional Techniques \nMarkus Breuer, Julia Wittenborn, Ivo Meinhold-Heerlein, and \nChristian Bruells have contributed equally to this work.\n * Christian Bruells \n cbruells@ukaachen.de\nExtended author information available on the last page of the article\n\n4155Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nof patients undergoing laparoscopic procedures also com-\nplain about shoulder tip pain [7 ] that is often perceived to \nbe more hampering and disabling than the wound pain. The \nseverity of the postoperative pain is dependent not only on \nthe type and conditions of the surgical procedure but is also \ninfluenced by the preoperative patient characteristics. For \ninstance, the severity of pre-existing dysmenorrhea, a com-\nmon symptom of endometriosis [8 ], predicts significantly \nhigher levels of postoperative pain [5 ], which results in \npatients’ discomfort, a longer stay in the hospital, and higher \nconsumption of analgesics, thereby increasing the frequency \nof their side effects [9, 10].\nThere are several approaches proposed to reduce post-\noperative pain, especially shoulder tip pain, in gynecologi-\ncal laparoscopy. One of the proposed methods is the use of \nwarmed and humidified carbon dioxide (WHCD) for estab-\nlishing the capnoperitoneum. Animal studies have shown \nthat the use of WHCD during laparoscopy results in less \ndesiccation and cell alteration and therefore less peritoneal \ndamage and inflammation as compared to cold and dry gas \n[11–13]. Dry gas causes peritoneal tissue drying, cell death, \nand the loss of peritoneal surface continuity [14]. There is \nalso evidence for a rapid and significant induction of HIF-1α \nby cold and dry  CO2 compared with WHCD [15].\nConsequently, Binda concluded in her review that both \npain and tissue damage can be prevented using humidified \ngas [16]. However, recent meta-analyses investigating the \neffects of WHCD on postoperative pain report contradictory \nresults due to the small sample size of the available studies, \nvarying duration of operation time, and the comparison of \ndifferent surgical procedures, e.g., visceral and gynecologi-\ncal [17–19]. One key factor of the STP incidence after lapa-\nroscopy seems to be the duration of the surgical procedure \nper se [5, 20].\nWe therefore decided to investigate the impact of WHCD \non postoperative pain course following gynecological lapa-\nroscopic procedures with a duration of more than 60 min in a \nprospective, randomized, controlled monocentric multi-arm \ntrial (A prospective, randomized, controlled, double-blinded \nstudy investigating intraoperative temperature and postop-\nerative pain course following gynecological laparoscopy—\nTePaLa (Temperature and Pain in Laparoscopy)). This arti-\ncle describes parts of this TePaLa trial (the effects on body \ntemperature have not been published yet). The TePaLa trial \nis based on a retrospective pilot study showing the preven-\ntive effect of body temperature and humidified  CO2 on intra-\noperative hypothermia compared to room temperature and \ndry gas in laparoscopy that lasted at least 60 min [ 21]. As \nperception of postoperative pain was likely to be influenced \nby pre-existing endometriosis, the data were stratified for \nthis disorder.\nWe hypothesized that using WHCD compared to cold \nand dry carbon dioxide resulted in lower pain scores, \nespecially shoulder pain, and less analgesic consumption. \nSince patients suffering from endometriosis are more prone \nto having severe postoperative pain, we suggested that they \ncould profit more from this kind of insufflation technique \nas compared to women who underwent surgery because of \nother gynecological diseases. In a combined three-arm study \ndesign investigating pain and temperature management, \npatients were either warmed with a forced air warming blan-\nket, with the use of WHCD, or with a combination of both.\nThe aim of this section of the study was to assess the \nimpact of forced air warming or WHCD on postoperative \npain course following gynecological laparoscopic proce-\ndures with a duration of more than 60 min.\nMethods\nTrial design\nThe study was designed as a monocentric, prospective, ran-\ndomized, double-blinded controlled trial with three parallel \nintervention arms. Before trial commencement, the study \ndesign was changed to be a single-blinded trial because the \nsurgeons and study staff could not be effectively blinded \nwith respect to the devices used during the laparoscopic \nprocedure. All patients and ward staff were not aware of the \nmethod used during laparoscopy.\nThe methods and trial are described in detail in supple-\nment 2.\nParticipants\nThe study included 150 participants with an indication to \na laparoscopic gynecological surgery. It was conducted at \nthe Department of Anesthesiology and the Department of \nGynecology and Obstetrics, University Hospital Aachen, \nGermany between July 2016 and September 2018.\nThe participants were randomized in 3 groups of 50 sub-\njects each. In group “AIR” (control group “AIR”), a forced \nair warming blanket and cold and dry insufflation gas was \nused during surgery. In group “HUMI”, insufflation was \nperformed with warm and humidified insufflation gas and \nno warming blanket was used (“HUMI”). Group “HUMI +” \nwas treated with a combination of a forced air warming blan-\nket and warm, humidified gas (“HUMI +”).\nInclusion criteria\nEligible patients were female, aged between 18 and 69 years \nwith a body mass index under 35, admitted to the hospital \nfor laparoscopic surgery with a planned duration of more \nthan 60 min.\n\n4156 Surgical Endoscopy (2022) 36:4154–4170\n1 3\nExclusion criteria\nExclusion criteria were patients who were pregnant or not \nusing sufficient contraception, who were breastfeeding, \nwho were engaged in alcohol or drug abuse, who were \neither expected not to comply with instructions or with \nlimited ability to comply with instructions for this study, \nwho were unwilling or unable to give informed consent, \nwho participated in another interventional study within \nthe last 3 months, who are committed to an institution \nand/ or penitentiary by judicial or official order, and who \nare employees of the investigator cooperation companies.\nInterventions\nIntraoperative procedures\nIf epidural anesthesia was indicated and desired by the \npatient, an epidural catheter was placed according to \nstandard operating procedures. All patients received gen-\neral anesthesia as total intravenous anesthesia or low flow \n(< 1 l/ min)-balanced anesthesia. After the induction of \nanesthesia, patients of group “AIR” and group “HUMI  +” \nreceived forced air warming and patients of group “HUMI” \nwere only covered with cotton sheets. According to ran-\ndomization, capnoperitoneum was established and main-\ntained either with cold and dry  CO2 (21.0 °C room tem-\nperature/ 0% humidity) in group “AIR” or with warm and \nhumidified  CO2 (depending on flow rate > 38.6 °C/ > 98%) \n[22] in group “HUMI” and group “HUMI +”. The actively \nheated tube maintained the temperature and humidity \nof the gas until it was delivered to the patient interface \n(37.0 °C ± 0.8/ 100.0% ± 0.05) [23].\nPost‑surgical data acquisition\nAfter the patient’s arrival in PACU, the pain score was \ndetermined with the visual analogue scale (VAS) for pain \nfrom the abdominal area, pain in the shoulder, pain upon \nmovement, and pain upon coughing. Pain scores were also \nrecorded before transfer to the ward, on the day of surgery \nat 8 p.m., and on postoperative days 1 to 7 at 8 a.m. and 8 \np.m. until the day of the patient’s dismissal from the hos-\npital. All patients were instructed to use VAS on the day \nbefore surgery, and the pain questionnaire was filled out \nby the patient alone to avoid observer bias. Postoperative \npain management was standardized and followed a three-\nstep analgesic ladder, based on the WHO guidelines for \nthe pharmacological and radiotherapeutic management of \ncancer pain in adults and adolescents [24].\nOutcomes\nThe primary endpoint was postoperative pain recorded by \nthe visual analogue scale upon arrival in the recovery room, \nbefore transfer to the ward, at 8 p.m. on the day of surgery, \nat 8 a.m. and 8 p.m. on postoperative days 1 to 7 specifically \nfor abdominal pain, pain in the shoulders, pain upon move-\nment, and pain upon coughing. Secondary endpoints were \nanalgesic consumption, the duration of epidural anesthesia, \npostoperative nausea and vomiting, differences in activities \nof daily living (ADL), the length of stay in post-anesthesia \ncare unit (PACU), and the total length of the hospital stay.\nSample size\nThis study was designed to address heating capabilities and \npain reduction. Three groups were constructed, and sample \nsize and statistical power were calculated to detect a differ-\nence in core body temperature. In a Cohen's delta effect size \npower analysis, a sample size of 50 in each of the treatment \ngroups would give a power of 0.8 to detect a difference of at \nleast 0.2 °C between groups in a balanced design. The effects \non body temperature have not been published yet.\nRandomization\nAfter patients were enrolled by the study team and writ -\nten informed consent was obtained, study participants were \nrandomized with equal allocation ratios to the three inter -\nventions using permuted block randomization (block size \n6) stratified by endometriosis (Yes/No). Computer-gener -\nated sequences were used. To maintain allocation conceal-\nment, the randomization sequence and the block size were \nconcealed from the investigators and the study team until \ndatabase lock and the assignment to study participants was \ncarried out with a web-based application maintained by the \nInstitute of Medical Informatics, RWTH Aachen University.\nStatistical methods\nOutcome variables were described within each treatment \ngroup using standard descriptive statistics (frequency, mini-\nmum, maximum, quartiles, mean, and standard deviation). \nDescriptive statistics for pain scores were also calculated \nseparately for each measurement timepoint. Analyses of pain \nscores were performed on the maximum pain score calcu-\nlated as the maximum of the abdominal-, movement-, upon \ncoughing-, and shoulder pain scores for each subject at each \nmeasurement occasion. A linear mixed effects model was \nused to model the pain score [25, 26]. Estimated treatment \neffects at each measurement occasion were calculated from \nthe model along with nominal 95% confidence intervals. \nExplorative tests for the treatment effect on activities of daily \n\n4157Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nliving (ADL) scores and the frequency of nausea severity \nlevels on day 1 and on discharge day were conducted with \nKruskal–Wallis rank sum test and Pearson’s Chi-squared \ntests, respectively. The length of the stay in PACU was ana-\nlyzed using a general linear model with gamma-distributed \nerrors. Analyses were conducted using R [27]. Mixed mod-\nels were fitted with lme4 [28].\nResults\nStudy population\nA total of 208 patients with an indication to a laparoscopic \ngynecologic surgery were assessed for eligibility between \nJuly 2016 and September 2018. The trial ended after the \nplanned 150 interventions were completed. 58 subjects were \nnot included, as they did not meet inclusion criteria, declined \nto participate, participated in another study, or for other rea-\nsons. The 150 patients who were included in the study were \nrandomized either to the control group or to one of the two \nintervention groups, stratified by endometriosis. Seventy-\nfour women declared to suffer from endometriosis and 76 \ndid not have a diagnosis of endometriosis. Four of these \npatients were newly diagnosed with endometriosis during \nthis study.\nOne patient randomized to the control group accidently \nreceived no warming blanket, but warm humidified insuffla-\ntion gas instead of the allocated intervention with forced air \nwarming blanket alone. One patient randomized into group \n“HUMI” did not receive surgery and consequently the allo-\ncated intervention, because of a preoperative spontaneous \nrupture of the ovarian cyst that was the indication for lapa-\nroscopy. Three patients randomized into group “HUMI +” \ndid not receive the allocated intervention: in two cases \nbecause the planned surgery was not performed due to dif-\nferent reasons and the other because the patient received \na forced air warming blanket only instead of the allocated \nintervention.\nIn two cases the intervention was discontinued: one \npatient from group “AIR” because of the intraoperative indi-\ncation to a conversion of the laparoscopic procedure into \nlaparotomy and one patient from group “HUMI” because of \nthe lowering of core body temperature below 35 °C during \nthe intervention with the necessity to use in addition a forced \nair warming blanket.\nFollow-up data were available for 146 of the 150 ran-\ndomized patients. In one case from group “AIR” and one \ncase from group “HUMI  +”, follow-up data were missing, \nbecause the VAS questionnaires were not available. There \nwere also no follow-up data from the two patients without \nsurgery after randomization.\nPrimary intention-to-treat analysis was performed on the \nfull set of follow-up data (Fig.  1).\nBaseline data\nTable  1 shows the baseline characteristics of all patients who \nreceived surgery. Demographic data, risk factors for cardio-\nvascular complications, patient’s medical history, intraopera-\ntive medication, IV fluids, and insufflated  CO2, as well as \nthe type and length of operative procedures were recorded. \nSignificant differences between the groups were seen in \nASA classification and intraoperative use of paracetamol. \nNo other differences were recorded.\nOutcomes and estimation\nPrimary endpoint—Postoperative pain\nDescriptive statistics of pain perceived on each postopera-\ntive day specific for the abdominal area, shoulder pain, and \npain caused by movement or coughing is shown in Table  2 \nand Fig.  2A–D. The maximum pain was evaluated to have \na median of 6 in group “AIR” at day one during movement.\nFigure  3A shows the maximum pain score of the three \ntreatment groups for each timepoint. Estimated treatment \neffects of the two interventional groups compared to the \ncontrol group on postoperative pain scores are shown \nin Fig.  3B. The pain intensity upon arrival in PACU was \nsignificantly lower in group “HUMI +” as compared to \ngroup “AIR” (control group) (MD − 1.068; 95% CI − 2.08 \nto − 0.061), and there were no other differences between the \ngroups. Also, after correcting for the effects of intraopera-\ntive analgesic use or the presence of epidural anesthesia in \nan additional explorative analysis, the difference in the pain \nscore between group “HUMI +” and group “AIR” at arrival \nin PACU remained significant (MD − 1.068; 95% CI − 2.07 \nto − 0.069).\nSecondary endpoints\nTable  3 shows a descriptive analysis of the secondary end-\npoints, like postoperative analgesic consumption, flow rate \nand duration of epidural anesthetics, length of stay in PACU, \nand length of the hospital stay. Compared to group “AIR”, \ngroup “HUMI +” showed significantly less consumption of \nIbuprofen at day 2 (− 0.5871 g ± 0.258; p -value = 0.0471) \n(Table  4). No differences were found in the other secondary \nendpoints. Not shown are data of nausea and vomiting and \nADL scores: there was no difference in occurrence of nau-\nsea and vomiting on day 1 (p -value 0.989) or on discharge \nday (p-value 0.6362). ADL scores were the same in each \ntreatment group separately on day 1 (p -value 0.45) and on \ndischarge day (p-value 0.2117).\n\n4158 Surgical Endoscopy (2022) 36:4154–4170\n1 3\nAncillary analyses\nAdditionally, exploratory post hoc analysis of postopera-\ntive pain scores was performed. We analyzed the treatment \neffect on postoperative pain scores of the two intervention \ngroups combined, both received warm and humidified gas, \nand in comparison to the control group, which received \ncold and dry gas: no significant differences in this model \nwere detected.\nResults stratified by endometriosis are shown in Fig.  4A \nand B. Figure  4A shows pain scores stratified by endome-\ntriosis with higher pain scores in patients suffering from \nendometriosis nearly in all groups over the whole period. \nThe differences between groups “HUMI” vs “AIR” and \nFig. 1  CONSORT flow diagram. Numbers are given in brackets\n\n4159Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nTable 1  Baseline characteristics of the investigated patient groups (all participants who underwent surgery)\nGroup 1 “AIR”\nn = 49\nGroup 2 “HUMI”\nn = 50\nGroup 3 “HUMI +”\nn = 49\np-value\nAge (years) 40.4 ± 14.0 36.1 ± 11.7 38.7 ± 11.6 0.51\nBMI 24.7 ± 3.78 26.1 ± 4.71 23.0 ± 3.55 0.05\nSmoker 16 (32.7) 18 (36.0) 7 (14.3)\nCigarettes per day 13.5 ± 6.23 11.9 ± 6.82 11.1 ± 7.45 0.39\nSmoking years 16.3 ± 14.5 16.2 ± 14.6 14.2 ± 7.6 0.79\nEx-smoker 8 (16.3) 11 (22.0) 14 (28.6)\nCigarettes per day 12.5 ± 6.89 16.1 ± 6.97 11.5 ± 6.17 0.53\nSmoking years 9.57 ± 7.91 11.30 ± 9.38 9.79 ± 6.89 0.96\nRisk factors for CV complications\nHypercholesterolaemia 3 (6.1) 2 (4.0) 3 (6.1) 0.82\nHypertension 9 (18.4) 5 (10.0) 4 (8.2) 0.26\nOverweight 19 (38.8) 24 (48.0) 12 (24.5) 0.05\nCo-morbidities\nDiabetes 3 (6.1) 1 (2.0) 3 (6.1) 0.57\nArteriosclerosis 1 (2.0) 0 0 0.66\nAsthma 7 (14.3) 3 (6.0) 2 (4.1) 0.21\nThyroid dysfunction 7 (14.3) 14 (28.0) 9 (18.4) 0.22\nASA classification 0.04\nASA 1 19 (38.8) 22 (44.0) 33 (67.3)\nASA 2 25 (51.0) 26 (52.0) 15 (30.6)\nASA 3 4 (8.2) 2 (4.0) 1 (2.0)\nNot applicable 1 (2.0)\nPrevious abdominal surgery 0.31\nLaparoscopic 22 (44.9) 20 (40.0) 23 (46.9)\nAbdominal 12 (24.5) 12 (24.0) 6 (12.2)\nEpidural catheter 11 (28.2) 16 (41.0) 12 (30.8) 0.52\nAnesthetics\nPropofol (mg/h) 419 ± 59.4 (n = 20) 437 ± 86.0 (n = 14) 387 ± 68.4 (n = 22) 0.10\nSevoflurane (%) 1.57 ± 0.290 (n = 28) 1.56 ± 0.285 (n = 37) 1.55 ± 0.213 (n = 22) 0.98\nDesflurane (%) 5.00 (n = 1) 5.33 ± 0.808 (n = 3) 5.10 ± 0.316 (n = 5) 0.80\nIntraoperative opioids\nSufentanil (µg) 45.1 ± 15.1 (n = 47) 40.2 ± 13.0 (n = 50) 45.5 ± 18.3 (n = 48) 0.17\nRemifentanil (µg/ h) 43 (n = 1) 1200 (n = 1) (n = 0)\nFentanil (mg) 0.5 ± 0.1 (n = 2) (n = 0) 0.4 (n = 1)\nPiritramide (mg) 5.28 ± 2.28 (n = 29) 5.27 ± 2.33 (n = 32) 4.75 ± 2.15 (n = 23) 0.64\nIntraoperative non-opioids\nMetamizole (g) 1.20 ± 0.391 (n = 23) 1.21 ± 0.379 (n = 26) 1.19 ± 0.385 (n = 24) 0.98\nParacetamol (g) 1 ± 0 (n = 8) 1 ± 0 (n = 1) 1 ± 0 (n = 4) 0.03\nIbuprofen (g) (n = 0) 0.525 ± 0.125 (n = 2) 0.4 ± 0 (n = 2)\nIntraoperative relaxant\nRocuronium (mg) 49.9 ± 21.1 (n = 49) 53.5 ± 23.7 (n = 50) 51.4 ± 19.7 (n = 49) 0.71\nLength of anesthesia (min) 193 ± 104.0 187 ± 90.8 193 ± 94.2 0.94\nAmount of infusions (ml) 1638 ± 796 1690 ± 748 1714 ± 661 0.87\nType of surgical procedure\nEndometriosis 19 (38.8) 24 (48.0) 20 (40.8) 0.62\nHysterectomy 12 (24.5) 14 (28.0) 18 (36.7) 0.39\nMyoma enucleation 7 (14.3) 5 (10.0) 4 (8.2) 0.61\nCyst enucleation 8 (16.3) 8 (16.0) 4 (8.2) 0.41\nAdnektomia 9 (18.4) 5 (10.0) 9 (18.4) 0.41\n\n4160 Surgical Endoscopy (2022) 36:4154–4170\n1 3\n“HUMI +” vs “AIR” are shown in Fig. 4B. There were sig-\nnificantly lower pain score levels of subjects suffering from \nendometriosis in group “HUMI” and group “HUMI +” com-\npared to group “AIR” at different timepoints.\nAnalysis of data stratified by abdominal surgery showed \nsignificantly less pain scores in patients who did not undergo \nprevious abdominal surgery in both groups “HUMI” and \n“HUMI +” compared to group “AIR” at different timepoints \n(Fig.  5A and B).\nAdverse events\nA total of 109 (74%) study objects experienced adverse \nevents during study intervention. All adverse events were \nclassified as mild and they were not, or highly unlikely to be, \nrelated to the study (see Supplement, Table S1).\nDiscussion\nIn the present study, we investigated the effect of three dif-\nferent intraoperative management regimens using either \nstandard conditions with a heating blanket with forced air \nwarming and dry insufflation gas at room temperature (group \n“AIR”), no heating blanket, but warm and humidified insuf-\nflation gas (group “HUMI”) or both a heating blanket with \nforced air warming and warm and humidified insufflation gas \n(group “HUMI +”). Importantly, we could not detect clini-\ncally relevant differences over the whole patient population. \nWe could work out that patients suffering from endometrio-\nsis and patients without previous abdominal surgery profited \nfrom the use of humidified insufflation gas.\nAlthough reduced in comparison to open surgery, pain \nafter laparoscopic surgery is a common phenomenon \nexceeding the pure nociception by wounds, drains, or sore \nintra-abdominal tissue. Knowledge about “head zones” is \nwell described in several pathologies, and the occurrence \nof shoulder pain after laparoscopic surgery is common. \nSome studies have indicated that the use of dry insuffla-\ntion gas to establish the capnoperitoneum might increase \nthe nociception or, in fact, induce an inflammatory reaction \nof the peritoneal tissue [11–15].\nIn our study, we could not detect differences in postopera-\ntive pain in groups “HUMI” and “HUMI +” versus group \n“AIR” besides the timepoint “arrival at PACU” between \ngroup “HUMI +” and group “AIR.” The actual VAS score \nfor abdominal pain in group “HUMI +” was 0 (0;7) and 1.5 \n(0;9) in group “AIR” at this timepoint; therefore, we inter -\npret this significant difference as an effect of direct individ-\nual anesthesia but not of the intervention. Interestingly, there \nis no difference in the amount of postoperative analgesic \nmedication (in our hospital, mainly piritramide combined \nwith a non-opioid analgesic) which could explain this differ-\nence. Moreover, the use of analgesics on the day of surgery \ndid not differ significantly, which could have been expected, \nif pain was higher in groups “AIR” and “HUMI.” Addition-\nally, the effects were not altered when combining the groups \nreceiving warm and humidified gas with and without the \nintraoperative use of a heating blanket (group “HUMI” and \n“HUMI +”) versus the control group, where cold and dry \ninsufflation gas was applied (group “AIR”).\nAt day 2, we measured less consumption of Ibuprofen \nin group “HUMI +” compared to group “AIR,” while the \neffect did not occur in group “HUMI” versus group “AIR”; \nno other non-opioid was used differently that could have \nreplaced ibuprofen in the other group. This difference may \nsimply be due to the preferences of the treating physician \nor nurse on this day and, in our opinion, should not lead \nto the conclusion that group “HUMI +” really experienced \nless pain: in fact, in all patient groups, the VAS at day 2 \nwas moderate with a VAS of 3 at rest and not significantly \ndifferent.\nThese findings are in line with Matsuzaki and her col-\nleagues’ work that could not find differences between the \nlikelihood of higher pain intensity (VAS > 3) in the PACU \nand a significantly higher use of opioid analgesics [29]. This \nstudy, however, detected a higher likelihood of pain in the \nfirst 12 h after surgery in their 2 × 2 mixed model of high \nintra-abdominal pressure with or without WHCD and low \nintra-abdominal pressure with or without WHCD, when \nValues are given as mean ± standard deviation or number (percent)\nTable 1  (continued)\nGroup 1 “AIR”\nn = 49\nGroup 2 “HUMI”\nn = 50\nGroup 3 “HUMI +”\nn = 49\np-value\nOther 13 (26.5) 19 (38.0) 18 (36.8) 0.42\nLength of surgery (min) 169 ± 97.8 166 ± 84.6 171 ± 92.6 0.96\nAmount of intraperitoneal irrigating fluids \n(ml)\n849 ± 600 971 ± 597 976 ± 611 0.54\nLength of capnoperitoneum (min) 109 ± 78.0 109 ± 77.1 116 ± 73.1 0.88\nAmount of insufflated  CO2 (l) 294 ± 338 261 ± 237 294 ± 229 0.79\n\n4161Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nTable 2  VAS pain scores \nfrom admission to PACU until \npostoperative day seven\nGroup 1 “AIR” Group 2 “HUMI” Group 3 “HUMI +” p-value\nOperation day\nArrival in PACU \nVAS abdominal 1.5 (0 – 9) 3.5 (0 – 8) 0 (0 – 7) 0.13\nVAS on coughing 2 (0 – 9) 3 (0 – 10) 0 (0 – 8) 0.31\nVAS on movement 2 (0 – 9) 3 (0 – 10) 1 (0 – 8) 0.36\nVAS shoulder pain 0 (0 – 0) 0 (0 – 5) 0 (0 – 0) 0.15\nTransfer to ward\nVAS abdominal 2 (0 – 8) 2 (0 – 6) 2 (0 – 8) 0.86\nVAS on coughing 3 (0 – 8) 2 (0 – 8) 3 (0 – 9) 0.68\nVAS on movement 3 (0 – 8) 2 (0 – 8) 3 (0 – 8) 0.51\nVAS shoulder pain 0 (0 – 5) 0 (0 – 3) 0 (0 – 1) 0.17\n8 pm\nVAS abdominal 4 (0 – 9) 4 (0 – 10) 3 (0 – 9) 0.40\nVAS on coughing 4 (0 – 10) 5 (0 – 10) 4 (0 – 9) 0.16\nVAS on movement 5 (0 – 10) 5 (0 – 10) 4 (0 – 10) 0.21\nVAS shoulder pain 0 (0 – 9) 0 (0 – 7) 0 (0 – 10) 0.69\nDay 1\n8am\nVAS abdominal 4 (0 – 9) 3 (0 – 10) 3 (0 – 8) 0.74\nVAS on coughing 4 (0 – 10) 4 (0 – 10) 4 (0 – 9) 0.46\nVAS on movement 6 (0 – 10) 4 (0 – 10) 4 (0 – 9) 0.49\nVAS shoulder pain 0 (0 – 10) 0 (0 – 8) 0 (0 – 10) 0.74\n8 pm\nVAS abdominal 4 (0 – 8) 4 (0 – 10) 3 (0 – 9) 0.64\nVAS on coughing 4 (0 – 9) 4 (0 – 10) 4 (0 – 9) 0.51\nVAS on movement 6 (0 – 9) 5 (0 – 10) 4 (0 – 9) 0.42\nVAS shoulder pain 0 (0 – 9) 0 (0 – 7) 0 (0 – 7) 0.15\nDay 2\n8am\nVAS abdominal 3 (0 – 10) 3 (0 – 10) 2 (0 – 7) 0.17\nVAS on coughing 4 (0 – 10) 4 (0 – 10) 3 (0 – 8) 0.35\nVAS on movement 4 (0 – 10) 4 (0 – 10) 3 (0 – 8) 0.07\nVAS shoulder pain 0 (0 – 5) 0 (0 – 8) 0 (0 – 7) 0.73\n8 pm\nVAS abdominal 3 (0 – 9) 2 (0 – 10) 2.5 (0 – 8) 0.17\nVAS on coughing 4 (0 – 9) 3 (0 – 10) 3 (0 – 8) 0.79\nVAS on movement 4 (0 – 8) 3 (0 – 10) 2 (0 – 8) 0.04\nVAS shoulder pain 0 (0 – 8) 0 (0 – 7) 0 (0 – 5) 0.89\nDay 3\n8am\nVAS abdominal 3 (0 – 10) 2 (0 – 10) 2 (0 – 8) 0.11\nVAS on coughing 3 (0 – 8) 2.5 (0 – 10) 3 (0 – 8) 0.63\nVAS on movement 3 (0 – 10) 2.5 (0 – 9) 3 (0 – 8) 0.23\nVAS shoulder pain 0 (0 – 8) 0 (0 – 7) 0 (0 – 5) 0.81\n8 pm\nVAS abdominal 2 (0 – 9) 1.5 (0 – 6) 1 (0 – 6) 0.38\nVAS on coughing 2 (0 – 7) 2 (0 – 6) 2 (0 – 8) 0.83\nVAS on movement 2 (0 – 9) 2 (0 – 6) 2 (0 – 6) 0.37\nVAS shoulder pain 0 (0 – 8) 0 (0 – 4) 0 (0 – 2) 0.80\n\n4162 Surgical Endoscopy (2022) 36:4154–4170\n1 3\ndry gas was used. In a comparable setting, Herrmann et al. \nreported in their study significantly less shoulder tip pain \nat 6 h, when all VAS points were cumulated over 48 h: the \nactual VAS scores were very low in both groups (in the mean \nat 6 h 0.09 vs 0.45 in the control group), so that the clini-\ncal relevance might be reduced [30]. Other clinical studies \nValues are given as median (range)\nPACU  post-anesthesia care unit, VAS visual analogue scale\nTable 2  (continued) Group 1 “AIR” Group 2 “HUMI” Group 3 “HUMI +” p-value\nDay 4\n8am\nVAS abdominal 2 (0 – 10) 1.5 (0 – 8) 2 (0 – 7) 0.45\nVAS on coughing 3 (0 – 7) 2 (0 – 8) 2 (0 – 8) 0.29\nVAS on movement 2.5 (0 – 7) 2 (0 – 8) 2 (0 – 8) 0.15\nVAS shoulder pain 0 (0 – 4) 0 (0 – 4) 0 (0 – 5) 0.84\n8 pm\nVAS abdominal 2 (0 – 7) 1 (0 – 7) 2 (0 – 5) 0.26\nVAS on coughing 3 (0 – 7) 2 (0 – 7) 2.5 (0 – 7) 0.75\nVAS on movement 3 (0 – 7) 3 (0 – 7) 2.5 (1 – 6) 0.55\nVAS shoulder pain 0 (0 – 7) 0 (0 – 4) 0 (0 – 4) 0.32\nDay 5\n8am\nVAS abdominal 2 (0 – 5) 1 (0 – 6) 2 (0 – 6) 0.15\nVAS on coughing 2.5 (0 – 6) 2 (0 – 6) 3 (0 – 7) 0.87\nVAS on movement 2 (0 – 7) 2 (0 – 6) 2 (0 – 6) 0.24\nVAS shoulder pain 0 (0 – 4) 0 (0 – 3) 0 (0 – 6) 0.56\n8 pm\nVAS abdominal 2 (0 – 7) 1 (0 – 3) 2 (1 – 8) 0.08\nVAS on coughing 2.5 (0 – 8) 1.5 (0 – 3) 3 (0 – 7) 0.45\nVAS on movement 3 (0 – 8) 1.5 (0 – 3) 3 (1 – 8) 0.20\nVAS shoulder pain 0 (0 – 2) 0 (0 – 0) 0 (0 – 1) 0.10\nDay 6\n8am\nVAS abdominal 2 (0 – 9) 1 (0 – 5) 1.5 (0 – 3) 0.26\nVAS on coughing 2 (0 – 8) 2 (0 – 5) 2 (0 – 6) 0.96\nVAS on movement 2 (0 – 8) 1 (0 – 3) 1.5 (0 – 4) 0.55\nVAS shoulder pain 0 (0 – 2) 0 (0 – 0) 0 (0 – 0) 0.07\n8 pm\nVAS abdominal 2 (0 – 5) 1 (0 – 1) 1 (0 – 8) 0.40\nVAS on coughing 0 (0 – 7) 2 (0 – 2) 2 (0 – 5) 1\nVAS on movement 2 (0 – 5) 0 (0 – 2) 2 (0 – 8) 0.45\nVAS shoulder pain 0 (0 – 2) 0 (0 – 0) 0 (0 – 0) 0.37\nDay 7\n8am\nVAS abdominal 2 (0 – 4) 0.5 (0 – 2) 1 (0 – 4) 0.47\nVAS on coughing 0 (0 – 7) 0.5 (0 – 1) 1 (0 – 2) 0.87\nVAS on movement 2 (0 – 5) 0.5 (0 – 2) 1 (0 – 4) 0.52\nVAS shoulder pain 0 (0 – 2) 0 (0 – 0) 0 (0 – 0) 0.10\n8 pm\nVAS abdominal 1 (0 – 4) 0 (0 – 1) 2 (0 – 4) 0.46\nVAS on coughing 3 (0 – 7) 0 (0 – 3) 0 (0 – 1) 0.43\nVAS on movement 3 (0 – 5) 0 (0 – 2) 2 (0 – 4) 0.44\nVAS shoulder pain 0 (0 – 2) 0 (0 – 0) 0 (0 – 0) 0.37\n\n4163Surgical Endoscopy (2022) 36:4154–4170 \n1 3\ndemonstrate conflicting results [31, 32] or describe a reduc-\ntion in shoulder tip pain only [33]. In a recent meta-analysis \nwith a mixed patient population (surgical, gynecological), \nthere could be evidence for reduced pain in the first 8 h after \nsurgery and less morphine use; interestingly, the underlying \nstudies with clear benefits for humidified gas in this meta-\nanalysis were surgical interventions (bariatric and cholecys-\ntectomy), while the gynecological studies included did not \nshow benefits for humidified gas [17]. Otherwise, the lack of \na difference between group “HUMI” and “AIR” may justify \nusing warmed, humidified gas as standard instead of forced \nair warming, due to a physician’s choice or for possible eco-\nnomic reasons.\nConsidering that epidural anesthesia in some patients may \nhave influenced our results, we performed the exploratory \nanalysis to correct for this effect without major influence on \nthe results: in fact, group “HUMI +” had less pain in PACU, \nbut this effect did not extend through the next hours or days. \nEpidural anesthesia is a standard in a wide field of indica-\ntions, even in laparoscopic surgery, and yields impressive \nresults [34]. However, for simple hysterectomy, the tech-\nnique may be too invasive, whereas in patients with endo -\nmetriosis, it is a helpful tool to reduce pain in a predisposed \npatient population suffering from pain, often for years. In \nfact, it did not influence the results of our intervention.\nInsufflation of humidified gas in predisposed \npatient groups\nOur post hoc analysis revealed two important results. First, \npatients suffering from endometriosis showed higher pain \nscore levels than non-endometriosis patients nearly over \nFig. 2  A VAS pain score of the three intervention groups—abdomi-\nnal pain. “AIR” = red. “HUMI” = green. “HUMI +” = blue. (Filled \nsymbol: median; empty symbol: min and max). B VAS pain score \nof the three intervention groups—pain on coughing. “AIR” = red. \n“HUMI” = green. “HUMI +” = blue. (Filled symbol: median; empty \nsymbol: min and max). C VAS pain score of the three interven-\ntion groups—pain on movement. “AIR” = red. “HUMI” = green. \n“HUMI +” = blue. (Filled symbol: median; empty symbol: min and \nmax). D VAS pain score of the three intervention groups—shoulder \npain. “AIR” = red. “HUMI” = green. “HUMI +” = blue. (Filled sym-\nbol: median; empty symbol: min and max)\n\n4164 Surgical Endoscopy (2022) 36:4154–4170\n1 3\nthe whole period during our observation (Fig.  4A). How-\never, we detected significantly less pain in both intervention \ngroups compared to the control group if endometriosis was \npresent, which lasted for several days (Fig.  4B). This is a \nnovel finding, indicating that female patients suffering from \nendometriosis may especially profit from the use of humidi-\nfied and warm insufflation gas, while generally in higher \npain. This can have several possible explanations. First, \npatients with endometriosis may be suffering from chronic \npain, which often causes structural and functional changes \nin the nociceptive system. Endometriosis induces inflam-\nmation in the tissue surrounding it [35] and can be found \nin 70% of patients suffering from chronic pelvic pain [36]. \nAdditionally, the surgery characteristics may also influence \nthe results of the study. For instance, surgical treatment of \nendometriosis, which is, according to our clinic standards, \nperformed via excision of the affected areas, results in the \nstripping of peritoneum and exposure of relatively large sur-\nfaces of underlying tissue to the insufflation gas, possibly \nfacilitating tissue drying and other local reactions. This dif-\nfers from other gynecologic surgeries, like hysterectomy, \nmyomectomy, or ovarian cystectomy, where the exposed \nsurface can be smaller or covered by coagulation area or \nsurgical sutures.\nWhen grouping our patients according to prior or non-\nprior abdominal surgery, we measured a higher pain level \nin patients without pre-existent surgery (Fig.  5A), which \nmay be due to the fact, that in pre-operated patients with \na likelihood for adhesions in 40–63% of gynecological \nor obstetric patients, [37] pain relief by adhesiolysis may \nhave been beneficial per se [38, 39]. Nonetheless, the use \nof WHCD leads to a significant reduction of pain in the \npatient group facing higher pain levels. Therefore, patient \ngroups with the risk of higher postoperative pain (in our \nstudy endometriosis patients and those without prior sur -\ngery) may potentially benefit from using warm humidified \ninsufflation gas, which prevents the drying of the wound \nsurfaces during surgery that may contribute to intraoperative \npain [7]. In rodent experiments, the use of humidified gas \nprotected against both adhesions and the surface reaction of \nmesothelium and peritoneum was ameliorated compared to \ndry gas [11, 12]. In porcine models, the authors describe an \nincrease in peritoneal damage simply using dry gas; these \nstudies demonstrated further that HIF-1α, a string indicator \nfor tissue hypoxia but also a modulator in pain regulation, \nwas enhanced [15, 40]. Additionally, HIF-1α disturbances \nhave been revealed to be present in endometriosis formation \nand reaction [41]. We did not measure HIF-1α in tissue or \nabdominal fluid, etc. to proof this theory, but it may be of \ninterest for further studies investigating effects on abdominal \npain by insufflation gas.\nLimitations and strength\nOur study has several strengths and limitations that need to \nbe addressed. First, the study design had a clear randomi-\nzation, single blinding, a pre-defined surgical team, and a \nvariety of measures to assess “pain” in a well-defined homo-\ngeneous population.\nSince the study was designed to address heating capa-\nbilities and pain reduction, three groups were constructed, \nalthough for the research question, if humidified and warm \nFig. 3  A Maximum pain scores of the three intervention groups. \n“AIR” = dot. “HUMI” = triangle. “HUMI +” = square. B Estimated \ntreatment effect on pain score with significant less pain score in group \n“HUMI +” vs control group at arrival in PACU (Asterisk). “HUMI” \nvs “AIR” = dot. “HUMI +” vs “AIR” = triangle\n\n4165Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nTable 3  Secondary endpoints of the study\nGroup 1 “AIR” Group 2 “HUMI” Group 3 “HUMI +” p-value\nAnalgesic consumption\nOperation Day\nPiritramide (mg) 5.25 (3 – 24) [n = 24] 4.5 (3 – 22.5) [n = 31] 5.25 (1.5 – 22.5) [n = 26] 0.79\nMetamizole (g) 1 (0.75 – 3) [n = 23] 1 (1 – 4) [n = 24] 1 (1 – 4) [n = 23] 0.48\nParacetamol (g) 1 (1 – 3) [n = 21] 1 (1 – 2) [n = 18] 1 (1 – 2) [n = 17] 0.43\nIbuprofen (g) 0.6 (0.4 – 1–8) [n = 8] 0.9 (0.4 – 1.2) [n = 4] 0.4 (0.4 – 1.2) [n = 8] 0.22\nAnalgesic consumption\nDay 1\nPiritramide (mg) 15 (3.75 – 22.5) [n = 6] 7.5 (3.75 – 18.8) [n = 12] 7.5 (3.75 – 15) [n = 9] 0.14\nMetamizole (g) 2 (1 – 6) [n = 15] 2 (0.75 – 5) [n = 29] 2 (1 – 5) [n = 26] 0.95\nParacetamol (g) 1 (1 – 3) [n = 16] 1 (1 – 4) [n = 19] 2 (1 – 3) [n = 11] 0.45\nIbuprofen (g) 0.8 (0.4 – 2.0) [n = 11] 1.2 (0.6 – 2.4) [n = 9] 1.2 (0.8 – 3.0) [n = 11] 0.37\nAnalgesic consumption\nDay 2\nPiritramide (mg) 11.2 (3.75 – 18.8) [n = 2] 7.5 (7.5 – 7.5) [n = 2] 7.5 (7.5 – 15) [n = 3] 0.90\nMetamizole (g) 1 (0.5 – 4) [n = 17] 2 (1 – 4) [n = 18] 2.25 (0.5 – 4) [n = 16] 0.26\nParacetamol (g) 1 (1 – 3) [n = 5] 1 (1 – 3) [n = 14] 2 (1 – 3) [n = 7] 0.57\nIbuprofen (g) 1.7 (0.4 – 4.0) [n = 10] 0.8 (0.4 – 2.4) [n = 10] 1.2 (0.4 – 1.8) [n = 14] 0.20\nAnalgesic consumption\nDay 3\nPiritramide (mg) 15 (3.75 – 26.2) [n = 2] [n = 0] 22.5 (22.5 – 22.5) [n = 1]\nMetamizole (g) 2 (0.5 – 4) [n = 11] 2 (1 – 4) [n = 10] 2 (1 – 4) [n = 13] 0.80\nParacetamol (g) [n = 0] 2 (1 – 3) [n = 5] 1.5 (1 – 2) [n = 2]\nIbuprofen (g) 1.4 (0.4 – 2.8) [n = 12] 0.6 (0.4 – 2.4) [n = 7] 1.2 (0.4 – 1.8) [n = 7] 0.23\nAnalgesic consumption\nDay 4\nPiritramide (mg) 7.5 (7.5 – 7.5) [n = 1] 3.75 (3.75 – 3.75) [n = 1] 7.5 (7.5 – 7.5) [n = 1]\nMetamizole (g) 1.5 (1 – 4) [n = 5] 2 (1 – 4) [n = 7] 2 (0.5 – 5) [n = 12] 0.75\nParacetamol (g) [n = 0] 2 (2 – 2) [n = 3] 1 (1 – 1) [n = 1]\nIbuprofen (g) 1.4 (0.8 – 1.8) [n = 10] 1.2 (1.2 – 1.8) [n = 3] 1.2 (0.4 – 2.4) [n = 6] 0.10\nAnalgesic consumption\nDay 5\nPiritramide (mg) [n = 0] 3.75 (3.75 – 3.75) [n = 1] 3.75 (3.75 – 3.75) [n = 1]\nMetamizole (g) 1 (0.5 – 5) [n = 3] 3 (1 – 4) [n = 6] 2 (1 – 4) [n = 7] 0.74\nParacetamol (g) 1 (1 – 1) [n = 2] 2 (2 – 2) [n = 1] [n = 0]\nIbuprofen (g) 1.2 (0.4 – 1.8) [n = 9] 1.5 (1.2 – 1.8) [n = 2] 1.5 (0.8 – 2.4) [n = 4] 0.83\nAnalgesic consumption\nDay 6\nPiritramide (mg) [n = 0] [n = 0] [n = 0]\nMetamizole (g) 2 (1 – 3) [n = 2] 4 (2 – 4) [n = 3] 2 (2 – 4) [n = 3] 0.45\nParacetamol (g) 1 (1 – 1) [n = 1] [n = 0] 1 (1 – 1) [n = 1]\nIbuprofen (g) 1.2 (0.8 – 4.0) [n = 7] 1.5 (1.2 – 1.8) [n = 2] 1.2 (1.2 – 1.2) [n = 1] 0.63\nAnalgesic consumption\nDay 7\nPiritramide (mg) [n = 0] [n = 0] [n = 0]\nMetamizole (g) 3 (3 – 3) [n = 1] 4 (4 – 4) [n = 1] 2 (1 – 4) [n = 3]\nParacetamol (g) [n = 0] [n = 0] 1 (1 – 1) [n = 1]\nIbuprofen (g) 1.2 (0.8 – 1.6) [n = 3] 1.5 (1.2 – 1.8) [n = 2] 0.8 (0.8 – 0.8) [n = 1]\nEpidural anesthesia\nDuration (hours) 70 (31.5 – 145) 53.2 (5 – 118) 58.5 (4.5 – 123) 0.39\n\n4166 Surgical Endoscopy (2022) 36:4154–4170\n1 3\ninsufflation gas reduces postoperative pain, a two-sided \nmodel would have been sufficient. In our analysis, we \nremained in the group “HUMI”/ “AIR” and “HUMI +”/ \n“AIR” design; one model was calculated with both groups \npooled against group “AIR” without changing significance \nlevels and under consideration of statistical balancing. \nBecause we did not see any differences, we remained in the \nthree-group model to follow the investigation plan properly.\nThis study was powered to detect a difference in intra-\noperative core body temperature. As a limitation, we must \nmention that no power was calculated for questioning pain \nscore differences.\nThe unequal distribution of patients stratified by previous \nabdominal surgery is worth mentioning. While the endo-\nmetriosis/ non-endometriosis patients are nearly equally \ndistributed, there are 66% with previous abdominal surgery \nand only 1/3 without. Therefore, we must assume that the \nresults stratified by previous abdominal surgery are perhaps \nless meaningful.\nIt is of interest whether the results of this monocentric \nstudy can be extrapolated to other patient populations (e.g., \nurologic) or reproduced in other hospital settings.\nFurther studies on the pathogenetic mechanisms of the \nobserved differences, involving inflammatory pathways and \nHIF-1α, especially in the subgroup of patients with endome-\ntriosis, are needed.\nThe adverse events we recorded were overall mild and not \nrelated to the study and unlikely explainable simply by the \nuse of differently warm and humid insufflation gas.\nConclusion\nApplication of prewarmed and humidified insufflation gas \nduring laparoscopic surgery was not clinically relevant in \nreducing post-surgical pain in a mixed gynecological patient \npopulation. However, patients suffering from endometrio-\nsis or patients with expected high pain levels, in our study \npatients without a history of abdominal surgery, showed less \npain up to several days. Therefore, in predisposed patients \nthe use of preheated and humidified insufflation gas may be \nbeneficial.\nValues are given as median (range)\nTable 3  (continued)\nGroup 1 “AIR” Group 2 “HUMI” Group 3 “HUMI +” p-value\nFlow rate (ml/h) 4 (3 – 6) 4.73 (3.43 – 6) 5.17 (3.2 – 6) 0.22\nLength of stay\nIn PACU (mins) 88 (27 – 318) 95 (10 – 270) 90 (30 – 235) 0.96\nIn hospital (days) 4.5 (1 – 10) 4.5 (0.5 – 14) 4.75 (1 – 13.5) 0.94\n\n4167Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nTable 4  Estimated treatment \neffects on secondary \nendpoints with significant less \nconsumption of Ibuprofen in \ngroup “HUMI +” vs control \ngroup at day 2 (Asterisk)\n“HUMI” – “AIR” “HUMI +” – “AIR”\nEstimated effect p-value Estimated effect p-value\nOperation day\nPiritramide (mg)  − 0.997 ± 1.60 0.7479  − 1.525 ± 1.66 0.5589\nMetamizole (g) 0.3507 ± 0.340 0.4859 0.1735 ± 0.343 0.8192\nParacetamol (g)  − 0.174 ± 0.214 0.6246  − 0.117 ± 0.217 0.7984\nIbuprofen (g) 0.1479 ± 0.372 0.8780  − 0.2145 ± 0.302 0.6928\nDay 1\nPiritramide (mg) −6.221 ± 3.01 0.0767 −5.485 ± 3.16 0.1549\nMetamizole (g) −0.0527 ± 0.367 0.9778 0.0784 ± 0.374 0.9580\nParacetamol (g) 0.340 ± 0.226 0.2370 0.359 ± 0.261 0.2939\nIbuprofen (g) 0.0478 ± 0.276 0.9695 0.2236 ± 0.265 0.6060\nDay 2\nPiritramide (mg) −4.037 ± 6.09 0.7243 −2.403 ± 5.57 0.8607\nMetamizole (g) 0.5944 ± 0.387 0.2229 0.4153 ± 0.397 0.4763\nParacetamol (g) 0.106 ± 0.348 0.9219 0.344 ± 0.391 0.5829\nIbuprofen (g) −0.6162 ± 0.275 0.0508 −0.5871 ± 0.258 0.0471*\nDay 3\nPiritramide (mg) NA NA 4.537 ± 7.52 0.7616\nMetamizole (g) −0.0536 ± 0.481 0.9855 0.2940 ± 0.455 0.7341\nParacetamol (g) NA NA NA NA\nIbuprofen (g) -0.5914 ± 0.291 0.0828 -0.3248 ± 0.291 0.4349\nDay 4\nPiritramide (mg) −3.037 ± 8.49 0.8974 −1.764 ± 8.69 0.9603\nMetamizole (g) 0.7638 ± 0.631 0.3800 0.1301 ± 0.575 0.9522\nParacetamol (g) NA NA NA NA\nIbuprofen (g) −0.3667 ± 0.391 0.5458 −0.2056 ± 0.311 0.7245\nDay 5\nPiritramide (mg) NA NA NA NA\nMetamizole (g) 0.7954 ± 0.761 0.4774 0.0297 ± 0.738 0.9973\nParacetamol (g) 0.843 ± 0.816 0.4856 NA NA\nIbuprofen (g) 0.0509 ± 0.465 0.9859 0.1813 ± 0.355 0.8161\nDay 6\nPiritramide (mg) NA NA NA NA\nMetamizole (g) 1.4072 ± 0.952 0.2473 1.1877 ± 0.948 0.3569\nParacetamol (g) NA NA 0.000 ± 0.940 1.000\nIbuprofen (g) −0.0916 ± 0.475 0.9636 −0.1686 ± 0.588 0.9290\nDay 7\nPiritramide (mg) NA NA NA NA\nMetamizole (g) 0.2778 ± 1.432 0.9632 −0.8085 ± 1.184 0.7106\nParacetamol (g) NA NA NA NA\nIbuprofen (g) 0.2369 ± 0.534 0.8536 −0.2402 ± 0.636 0.8879\nEpidural anesthesia duration (hours) −23.4 ± 15.7 0.2534 −14.2 ± 16.7 0.6058\nLength of stay in PACU (mins) −1.810 ± 10.316 0.861 −2.930 ± 10.245 0.775\n\n4168 Surgical Endoscopy (2022) 36:4154–4170\n1 3\nSupplementary Information The online version contains supplemen-\ntary material available at https:// doi. org/ 10. 1007/ s00464- 021- 08742-1.\nAcknowledgements We would like to thank the Clinical Trial Center \nRWTH Aachen for randomization and study monitoring. We also thank \nFisher and Paykel Health Care Ltd., Auckland, New Zealand for finan-\ncial support. There was no influence on study design, data acquisition, \ndata analysis, interpretation, or publication whatsoever by this com-\npany. We gratefully acknowledge the theater staff for managing the \npatients according to the study conditions.\nFunding Open Access funding enabled and organized by Projekt \nDEAL. This study was supported by an unrestricted research grant \nform Fisher and Paykel Health Care Ltd., Auckland, New Zealand and \nfunded by Fisher and Paykel Health Care Ltd.\nDeclarations \nDisclosures Markus Breuer, Julia Wittenborn, Julia van Waesberghe, \nAna Kowark, Deborah Mathei, András Keszei, Svetlana Tchaikovski, \nMagdalena Zeppernick, Felix Zeppernick, Elmar Stickeler, Rolf Ros-\nsaint, Norbert Zoremba, Ivo Meinhold-Heerlein, and Christian Bruells \nhave no conflicts of interest or financial ties to disclose.\nEthical approval The study was approved by the Ethics Committee \nat the RWTH Aachen University Faculty of Medicine, Germany, in \nAugust 2015. The trial was registered under the name “Temperature \nand Pain in Laparoscopy” (TePaLa) with ClinicalTrials.gov on May \n17, 2016, trial number NCT02781194.\nFig. 4  A Maximum pain scores of the three intervention groups with \nstratification by endometriosis. “AIR” = dot. “HUMI” = triangle. \n“HUMI +” = square. B Estimated treatment effect on pain score with \nstratification by endometriosis. Significant less pain score in subjects \nsuffering from endometriosis (Asterisk). “HUMI” vs “AIR” = dot. \n“HUMI +” vs “AIR” = triangle\nFig. 5  A Maximum pain scores of the three intervention groups \nwith stratification by previous abdominal surgery. “AIR” = dot. \n“HUMI” = triangle. “HUMI +” = square. B Estimated treatment effect \non pain score with stratification by previous abdominal surgery. Sig-\nnificant less pain score in subjects, without previous abdominal sur -\ngery (Asterisk). “HUMI” vs “AIR” = dot. “HUMI +” vs “AIR” = tri-\nangle\n\n4169Surgical Endoscopy (2022) 36:4154–4170 \n1 3\nOpen Access This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article's Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article's Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. 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Kim BG, Yoo JY, Kim TH, Shin JH, Langenheim JF, Ferguson \nSD, Fazleabas AT, Young SL, Lessey BA, Jeong JW (2015) Aber-\nrant activation of signal transducer and activator of transcription-3 \n(STAT3) signaling in endometriosis. Hum Reprod 30(5):1069–\n1078. https:// doi. org/ 10. 1093/ humrep/ dev050\nPublisher's Note Springer Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}