The Effect And Related Mechanism Of Esketamine Combined With Type Ⅱ Thoracic Nerve Block On The Postoperative Recovery In Patients With Breast Cancer Under General Anesthesia

Part One:The effect of esketamine combined with type II thoracic nerve block on the postoperative recovery in non-elderly patients with breast cancer under general anesthesiaObjective:To evaluate the effect of esketamine combined with type II thoracic nerve block on the postoperative recovery in non-elderly patients with breast cancer under general anesthesia.Methods:A total of 136 non-elderly women（18～64 years old）under-going a modified radical mastectomy were randomly divided into control group（group C,n=68）and experimental group（group PE,n=68）.Sufentanil was mainly used for anesthesia induction and patient-controlled intravenous analgesia（PCIA）in group C.Esketamine was mainly used for anesthesia induction and PCIA in group PE.Ultrasound-guided Pecs II block was perfor-med after anesthesia induction and all other anesthetics were administered in the same way in the two groups.The MAP and HR were recorded at 0 min before anesthesia induction（T₀）,10 minutes after anesthesia induction（T₁）,during skin incision（T₂）,30 minutes after skin incision（T₃）,at the end of the surgery（T₄）,30 minutes（T₅）,6 hours（T₆）,12 hours（T₇）,and 24 hours after surgery（T₈）.Bispectral index（BIS）was recorded at T_0-4.Observer’s Assess-ment of Alertness/Sedation Scale（OAA/S）was recorded at T_4-8.Numerical Rating Scale（NRS）scores were recorded at T₅,T₆,T₇ and T₈.At T₀ and T₈,venous blood samples were collected and the serum inflammatory cytokines IL-10,IL-6 and IL-1?content were detected by multiple microsphere flow cytometry.The Hospital Anxiety and Depression Scale（HADS）was used to assess the patients’anxiety and depression,the Montreal Cognitive Assess-ment Scale（Mo CA）was used to assess the cognitive condition at one day before surgery and at discharge.The Assens Insomnia Scale（AIS）was used to assess the sleep situation at the 1th and 3th day after surgery.Anesthesia recovery time,postoperative PACU residence time,times of postoperative PCIA pressing and postoperative rescue analgesia within 24 h after surgery,the length of hospital stay after surgery,the patient satisfaction score and the patient 40-item quality of recovery（Qo R-40）score were recorded at dis-charge.The Functional Assessment of Cancer Therapy-Breast（FACT-B）was recorded at the 3th month after surgery.The occurrences of adverse reactions within 48 h after operation were recorded.Results:Compared with group C,the MAP and HR in the PE group were increased at T₁（P<0.05）,no statistically difference in MAP and HR at T₀,T_2-8（P>0.05）;the BIS was increased at T₁ and T₂（P<0.05）,no statistically differences were observed in BIS at T₀,T₃ and T₄（P>0.05）;no statistically differences in serum IL-10,IL-6,IL-1?content at T₀（P>0.05）,the IL-6 was decreased at T₈（P<0.05）,no statistically difference of IL-10 and IL-1?at T₈（P>0.05）;no statistically difference in HADS-A and HADS-D scores at 1 day before surgery（P>0.05）,the HADS-A,HADS-D scores,the incidences of depression and anxiety were decreased at discharge（P<0.05）;the AIS score was decreased on the 1th and 3th day after surgery（P<0.05）,the incidence of sleep disorder was decreased（P<0.05）;patient satisfaction score and the Qo R-40 score were increased at discharge（P<0.05）;postoperative incidences of nausea and vomiting were decreased（P<0.05）.No statistically differences were observed in OAA/S score,anesthesia recovery time,postoperative PACU residence time and the length of postoperative hospital stay between the two groups（P>0.05）;no statistically differences in the Mo CA scores and incidence of cognitive impairment between the two groups（P>0.05）;no statistically differences in NRS score and PCIA press times between the two groups（P>0.05）,no remedial analgesia was given after surgery in both two groups（P>0.05）;no statistically difference was observed in the FACT-B score at the 3th month after surgery（P>0.05）.Conclusions:Esketamine combined with type II thoracic nerve block were used in modified radical mastectomy under general anesthesia can avoid the decrease of BP and HR in the later period of anesthesia induction,dec-rease the incidences of postoperative nausea and vomiting,reduce posto-perative inflammatory response,relieve postoperative anxiety and depression,improve patient satisfaction and recovery quality,it is beneficial to early postoperative prognosis.Part Two The effect of esketamine combined with type II thoracic nerve block on the postoperative recovery in elderly patients with breast cancer under general anesthesiaObjective:To evaluate the effect of esketamine combined with type II nerve block on the postoperative recovery in elderly patients with breast cancer under general anesthesia.Methods:Seventy-six elderly female patients（≥65 years old）under-going a modified radical mastectomy were randomly divided into control group（group C,n=38）and experimental group（group E,n=38）.Both groups were given intravenous injection of sufentanil 0.3～0.4μg/kg,etomidate 0.2～0.3 mg/kg and rocuronium 0.5 mg/kg for induction of anesthesia.Ultrasound-guided Pecs II block was performed after anesthesia induction in the two groups.Propofol(5～7 mg·kg^-1·h^-1)and remifentanil(5～10μg·kg^-1·h^-1)were administered intravenously,and rocuronium bromide（0.15 mg/kg）was administered intermittently.Both groups received PCIA after surgery.Group C:sufentanil 1.5 ug/kg+azasetron 10 mg+0.9%sodium chloride injection to100 ml;Group E:esketamine 1 mg/kg+azasetron 10 mg+0.9%sodium chlo-ride injection to 100 ml.When the postoperative NRS≥4 points after pressur-ing analgesia pump at rest,tramadol 50 mg was intravenously injected for rescue analgesia.The MAP,HR and Sp O₂ were recorded at 0 min before anesthesia induction（T₀）and 12 h（T₁）,24 h（T₂）,and 48 h（T₃）after surgery.The NRS score and OAA/S were recorded at T₁,T₂,and T₃ after surgery.At T₀ and T₂,the intravenous blood samples were collected and serum levels of IL-6 and HMGB1 were measured by enzyme-linked immunosorbent assay.The AIS was used to assess sleep condition at the 1th and 3th after surgery.The Anxiety and depression conditions were assessed by the HADS,and the Mo CA was used to assess the cognitive condition at 1 day before surgery and at discharge.Early postoperative recovery was evaluated by Qo R-40 score at discharge and FACT-B score at the 3th month after surgery.Postoperative hospital stay and patient satisfaction score at discharge were recorded.The pressing times of PCIA,the requirement for rescue analgesia,the occurrence of adverse reactions within 48 h after operation were recorded.Results:Compared with group C,no statistically difference were obser-ved in IL-6 and HMGB1 in group E at T₀（P>0.05）,the serum contents of IL-6and HMGB1 were decreased in group E at T₂（P<0.05）;the AIS score was decreased at the 1th and 3th after surgery in group E（P<0.05）;no statistically difference in the HADS-A and HADS-D scores at 1 day before surgery（P>0.05）,the HADS-A scores,HADS-D score and the incidences of anxiety and depression were reduced at discharge in group E（P<0.05）;no statistically differences in Mo CA score at 1 day before surgery（P>0.05）and the Mo CA score was increased and the incidence of cognitive impairment was reduced at discharge in group E（P<0.05）;the patient satisfaction score and the Qo R-40score were increased at discharge in group E（P<0.05）;the dizziness,the number of nausea and vomiting within 48 h were decreased（P<0.05）.No statistically differences in MAP,HR,Sp O2,NRS score and OAA/S score at each time point in the two groups（P>0.05）.There were no statistically differ-ence in the pressing times of PCIA and the requirement of rescue analgesia after surgery in the two groups（P>0.05）.No statistically difference in posto-perative hospital stay and the FACT-B scores at the 3th month after surgery of the two groups（P>0.05）.Conclusions:The application of esketamine combined with ultrasou-nd guided pectoral nerve block type II in in elderly patients with breast cancer under general anesthesia can reduce postoperative inflammatory response,relieve postoperative anxiety and depression,improve sleep quality and posto-perative neurocognitive recovery,increase the patient satisfaction and early postoperative recovery quality.Part Three Effect of esketamine on cognitive dysfunction in aged rats after laparotomy exploration under sevoflurane anesthesia and the role of hippocampal necroptosis mechanismObjective:To investigate the effect of esketamine on cognition dysfun-ction in aged rats after laparotomy exploration under sevoflurane anesthesia and the role of hippocampal necroptosis mechanism.Methods:One hundred and twenty healthy aged male SD rats（aged 22months）were randomly divided into 4 groups（n=30 each）:Model group（group M）,Model+Esketamine group（group ME）,Control group（group C）,Control+Esketamine group（group CE）.The rats were performed exploratory laparotomy with sevoflurane anesthesia in group M and group ME,esketa-mine（10 mg/kg）was injected intraperitoneally at the end of operation and was given once a day for six days in group ME,while the same volume of0.9%sodium chloride was injected intraperitoneally at the end of operation and was given once a day for 6 days in group M.The same volume of 0.9%sodium chloride was injected intraperitoneally once a day for 6 days in group C.The rats were injected intraperitoneally esketamine（10 mg/kg）once a day for 6 days in group CE.Each group randomly selected ten rats and the spontaneous movement was evaluated by open field test at the 1th day after operation,the Morris water maze test was used for assessment the ability of memory and learning at the 1th,3th and 7th day after surgery.Ten rats were randomly selected from each group and sacrificed,the hippocampus tissues were colle-cted.The necroptosis rate and cytosolic calcium concentration of hippocampal neurons were tested by flow cytometry.Western blot was used to estimate the expression of necroptosis key protein MLKL,p-MLKL,RIPK1,p-RIPK1,RIPK3,p-RIPK3 proteins.Enzyme-linked immunosorbent assay was used for detecting the levels of IL-6,IL-1βand TNF-αof hippo-campus.Results:No statistical difference was found in total movement distance and total movement speed of the open field experiment among the groups at the 1th day after surgery（P>0.05）.Positioning navigation phase of Morris water maze test:at the 1th day after surgery,compared with group C,the escape latency was increased in group M and group ME（P<0.05）,and no statistical change was found in group CE（P>0.05）;the escape latency was significantly decreased in group CE compared to group M（P<0.05）,and no statistical differences was found in group ME compared to group M（P>0.05）;compared with group CE,the escape latency was increased in group ME（P<0.05）.Space exploration phase of morris water maze test:the platform was removed at the 7th day after operation,the times of crossing platform and the resting time in target zone were decreased in group ME and group M com-pared to group C（P<0.05）,no statistical differences was found in group CE（P>0.05）;the times of crossing platform and the resting time in target zone were increased in group CE and group ME compared to group M（P<0.05）;the times of crossing platform and the resting time in target zone were decreased in group ME compared to group CE（P<0.05）.The results of Flow cytometry:the hippocampal neuron necroptosis and cytosolic Ca²⁺concen-tration were increased in group M and group ME compare to group C（P<0.05）,no statistical change was observed in group CE（P>0.05）;compared with group M,the necrosis rate and cytosolic Ca²⁺concentration of hippo-campal neurons were decreased in group CE and group ME（P<0.05）;com-pared with group CE,the hippocampal neuron necroptosis and cytosolic Ca²⁺concentration were increased in group ME（P<0.05）.Western Blot results:Compared with group C,the expression of RIPK1,p-RIPK1,RIPK3,p-RIPK3,MLKL and p-MLKL were increased in group M and group ME（P<0.05）,and no statistical change was found in group CE（P>0.05）;compared with group M,the expression of RIPK1,p-RIPK1,RIPK3,p-RIPK3,MLKL and p-MLKL was decreased in group CE and group ME（P<0.05）;compared with group CE,the expression of RIPK1,p-RIPK1,RIPK3,p-RIPK3,MLKL and p-MLKL were increased in group ME（P<0.05）.ELISA results:Com-pared with group C,the levels of IL-6,IL-1βand TNF-αwere increased in group M and ME（P<0.05）,no statistical changes were observed in the levels of IL-6,IL-1βand TNF-αin group CE（P>0.05）;compared with group M,the levels of IL-6,IL-1βand TNF-αwere decreased in group CE and group ME（P<0.05）;Compared with group CE,the levels of IL-6,IL-1βand TNF-αwere increased in group ME（P<0.05）.Conclusions:Esketamine can improve the early neurocognitive recovery after laparotomy exploration under sevoflurane anesthesia in aged rats.The mechanism may be associated with reducing the necrosis rate and inflam-matory response in the hippocampus by inhibiting the RIPK1-RIPK3-MLKL signaling pathway.