Invest Clin 61(1): 60 - 72, 2020 https://doi.org/10.22209/IC.v61n1a06
Effect of anesthetic, analgesic and sedative agents on human cell phagocytosis. Review.
Jesús Mosquera1 e Ivan Pimienta2
1 Instituto de Investigaciones Clínicas Dr. Américo Negrette, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela.
2Universidad Regional Autónoma de Los Andes, Uniandes, Ambato, Ecuador.
Abstract. Along with preoperative stress, anesthetics per se are associated with decreased activity of the immune system. Phagocytosis is an important process where particles, such as dead cells and bacteria, are eliminated from the organism. This process is complex and involves cell chemotaxis, tissue infiltra- tion, several coordinated cellular events and the production of reactive oxygen and nitrogen species (ROS). Therefore, the aim of this review was to report the effects of anesthetic, analgesic and sedative agents on human cell phagocytosis. This review suggests that human phagocytosis processes are affected by main anesthetic, analgesic and sedatives agents that result in decreased chemotaxis, phagocytosis and ROS production. These effects may impair the anti-bacterial function of phagocytes. Clinical anesthesiologists should select the anesthetics and the anesthetic methods with careful consideration of the clinical situation and the immune status of patients, concerning long-term mortality, morbidity, and the optimal prognosis.
Efecto de los agentes anestésicos, analgésicos y sedativos sobre la fagocitosis celular humana.
Invest Clin 2020; 61 (1): 60-72
Received: 06-09-2019 Accepted: 23-01-2020
Anesthetics are a diverse group of drugs used in the management of pain. The admin- istration of anesthetics is necessary to pro- vide inhibition of individual pain pathways (local anesthesia) or to render a patient un- conscious so that surgical procedures can be carried out (general anesthesia) (1). Phago- cytosis is a process where cells surround and engulf particles such as dead cells and bacteria. This is important both, for single- cell organisms (to acquire nutrients) and as part of the immune system (to destroy for- eign invaders). This process is complex and involves several coordinated events such as membrane remodeling, receptor motion, cytoskeleton reorganization and intracellu- lar signaling (2). Before phagocytosis is ac- complished, the phagocyte and the particle
must adhere to each other. The mechanisms involved in this attachment depend on the chemical nature of the particle’s surface. The capacity of phagocytes to engulf mi- croorganisms plays an important role in the immune defense (3). However, drugs that might impair their engulfing capacity can in- duce immunosuppression (4). Patients that undergo surgical interventions are exposed to anesthetic and analgesic drugs during the procedure that, together with perioperative stress, may impair phagocytes function and expose to infections (4,5). Therefore, we con ducted this review to obtain information re- garding the effects of relevant anesthetic, analgesic and sedative agents on human cell phagocytosis. Multiple literature searches were performed from1973 through 2019 us- ing online databases from PubMed, Scielo and Bireme.
Isoflurane
With respect to this inhaled anesthet- ic agent, studies had shown controversial results. It has been reported to have no ef- fect on phagocytosis (opsonized E. Coli) of human neutrophils in patients undergoing elective interventional embolization of cere- bral arterio-venous malformations (6). Iso- fluorane did not alter phagocytosis of latex by human monocytes (7). In vitro exposure to isoflurane for 90 min does not significant- ly alter the phagocytic capacity (Escherichia coli) of neutrophils from women during preg- nancy (8). Isoflurane promoted phagocytosis (efferocytosis) of apoptotic cells by macro- phages, via upregulation of Mer surface ex- pression, through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane (9). In a gas concentration assay, chemilu- minescence, superoxide production, and hydrogen peroxide production induced by opsonized zymosan as a phagocytic stimulus were not altered by isoflurane (10). However, altered phagocytic function due to this drug has been reported. Decreased phagocytosis (opsonized and unopsonized Listeria mono- cytogenes) was reported using this drug in alveolar macrophages from bronchoalveolar lavage obtained during orthopedic surgery (11). Isoflurane exposure also decreased hu- man neutrophil phagocytosis (12).
Halothane
In general halothane induces alteration of phagocytic function of phagocytes. An- esthesia with halothane induced decreased chemotactic, phagocytic and bactericidal activity in patients with pathological injury- effected changes or due to varicose veins of extremities (13). Anesthesia with halothane caused a dose-related depressant effect on human neutrophil phagocytic index and a nitroblue-tetrazolium reduction test in pa- tients undergoing gynecological surgery (14). Anesthesia with halothane induced de-
creased release of oxygen-free radicals dur- ing the phagocytosis of zymosan A by human neutrophils (15). In an assay gas concentra- tion, chemiluminescence, superoxide pro- duction, and hydrogen peroxide production induced by opsonized zymosan as a phago- cytic stimulus, were diminished by halo- thane (10). However, in other studies halo- thane failed to alter the phagocytic function. In this regard, halothane did not inhibit hu- man neutrophil phagocytosis, degranulation and the enhanced non-mitochondrial respi- ration associated with phagocytosis function in vitro (16).
Sevoflurane
This drug does not alter neither phago- cytosis of human polymorphonuclear leu- cocytes in bronchoalveolar lavage from pa- tients under anesthesia (17) or phagocytosis (E Coli), and oxidative burst of circulating granulocytes and monocytes (18).
Desflurane
This drug does not alter phagocytosis of human polymorphonuclear leucocytes in broncoalveolar lavage from patients under anesthesia (17).
Enflurane
Enflurane causes significantly greater depression of human neutrophil phagocytic index and nitroblue tetrazolium reduction test in patients undergoing gynecological surgery (14) and induces decreased release of oxygen-free radicals during the phagocy- tosis of zymosan A and Bordetella pertussis by human neutrophils (15, 19).
Nitrous oxide
Nitrous oxide decreases neutrophil an- tibacterial capacity in vitro. Exposure of hu- man whole blood to nitrous oxide decreased the percentage of neutrophils showing phagocytosis, and the amount of ingested bacteria (20). Nitrous oxide also decreases release of oxygen-free radicals during serum- opsonized zymosan and Bordetella pertussis phagocytosis by human neutrophils (19).
Xenon
Phagocytosis (E Coli) and oxidative burst of granulocytes were reduced with xe-
non anesthesia, whereas monocytes were not affected (18). However, xenon preserved neu- trophil and monocyte antibacterial capacity in vitro. Exposure of human whole blood to xenon increased the percentage of neutro- phils showing phagocytosis, and the amount of ingested bacteria. Respiratory burst activ- ity in neutrophils and monocytes was not af- fected by xenon (20).
Methoxyflurane
No information was found.
Propofol
2
The intravenous anesthetic agent pro- pofol is used to induce and maintain anes- thesia during surgical or other invasive pro- cedures and to sedate critically ill patients (21, 22). Previous studies have shown that this drug has controversial effects regarding the phagocytic functions. This anesthetic drug acts via stimulation of the β -subunit
phagocytosis of human polymorphonuclear leucocytes in broncoalveolar lavage from patients under anesthesia (17) or from pa- tients undergoing coronary artery bypass grafting (32). No alteration of human neu- trophil phagocytosis (opsonized E. Coli) us- ing propofol, in patients undergoing elec- tive interventional embolization of cerebral arterio-venous malformations, has been re- ported (6). No alteration on phagocytosis (opsonized and unopsonized Listeria mono- cytogenes) was reported using this drug in alveolar macrophages from bronchoalveolar lavage obtained during orthopedic surgery (11). Propofol at the higher concentration failed to reduce both respiratory burst and phagocytosis (Staphylococcus aureus) of human neutrophils (33). Propofol exhibited no significant effects on human neutrophil oxidative burst and phagocytosis (E. Coli) in patients with severe brain injury requir- ing long-term sedation (34). Propofol, at
A
of the GABA
receptors inducing impair-
clinically relevant concentrations, reduces
A
2
ment of chemotaxis and phagocytosis (mi- crospheres) of circulating human monocytes and macrophages (23-25). Propofol inhibits phagocytosis (latex beads) via the GABA receptor and dysregulation of p130cas phos- phorylation in macrophages from patients undergoing general anesthesia (26). In vi- tro studies have shown that propofol inhibits human neutrophil chemotaxis, phagocyto- sis and reactive oxygen species (ROS) (O -, H O , OH) production, in a dose-dependent
chemotaxis but fail to reduce phagocytosis of human neutrophils (35). In addition, pro- pofol stimulated human microglial phagocy- tosis in vitro (36).
Ketamine
Controversial results regarding the ef- fect of ketamine have been reported. Clini- cally relevant concentrations of ketamine can suppress macrophage function of phagocy- tosis, its oxidative ability, and inflammatory cytokine production, possibly via reduction
2 2
manner (27). In vitro studies have shown
that propofol diminishes human neutrophil and monocyte phagocytosis (E Coli) and oxi- dative burst even in clinically concentrations (28). In vitro studies showed that propofol inhibited phagocytosis and killing of Staphy- lococcus aureus as well as Escherichia Coli (29). However, other studies showed that propofol failed to alter phagocytosis and as- sociated processes. In this regard, this drug did not alter the phagocytosis of Staphylo- coccus aureus by human monocytes (30) or phagocytosis of Candida albicans by human neutrophils (31). Propofol does not alter
of the mitochondrial membrane potential
(37). Ketamine significantly inhibited both phagocytosis (Staphylococcus aureus and Escherichia coli) and bactericidal activity by human neutrophils (38). In vitro studies have shown that ketamine diminishes hu- man monocyte phagocytosis (E Coli) at high concentrations (28). However, other studies showed no effect on the phagocytic function of phagocytes. In his regard, ketamine did not adversely affect phagocytic function of human neutrophils at relevant therapeutic concentrations (39). No depressed phago- cytosis and ROS production of human neu-
trophil was observed in vitro by the use of ketamine at clinically concentrations (40). Ketamine at a higher concentration fail to reduce both respiratory burst and phago- cytosis (Staphylococcus aureus) of human neutrophils (33).
Etomidate
In vitro studies have shown that this drug significantly inhibited both phagocyto- sis (Staphylococcus aureus and Escherichia coli) and bactericidal activity (41).
Thiopental
Thiopental at clinically relevant con- centrations reduced both chemotaxis and phagocytosis of human neutrophils (35) and at the higher concentration reduced both respiratory burst and phagocytosis (Staphy- lococcus aureus) of human neutrophils (33). In vitro studies showed that thiopental de- creased human neutrophil chemilumines- cence (respiratory burst) and phagocytosis (Staphylococcus aureus and Escherichia coli) at clinical drug concentrations in a dose-dependent fashion (42). According to this, Nishima et al (40) reported that thio- pental was capable of decreasing at clinically relevant concentrations chemotaxis, phago- cytosis, and reactive oxygen species (ROS) (O -, H O , OH) production of human neu-
2
Previous studies have shown that clinical doses of this drug has no effects on chemo- taxis, phagocytosis or superoxide anion (O -) production of human neutrophils, suggest- ing that this drug may be useful in patients with infection, sepsis, or systemic inflamma- tion (5). According to this, in vitro studies have shown that clinically relevant concen- trations of dexmedetomidine do not affect chemotaxis, phagocytosis, or superoxide production by human neutrophils (44). How- ever, decreased human neutrophil phagocy- tosis of E. Coli, associated with suppressed respiratory burst, nitric oxide (NO) pro- duction, and induced nitric oxide synthase (iNOS) activity induced by dexmedetomi- dine have been reported (45).
Clonidine
2
This is a α -adrenergic receptor agonist also used as adjuncts to anesthesia. Chemo- taxis, phagocytosis and further production of superoxide anion of human neutrophils, are not altered by the used of this drug (5) and in vitro studies had shown that clinically relevant concentrations of clonidine do not affect chemotaxis, phagocytosis, or superox- ide production by human neutrophils (44). However, this drug inhibits phagocytosis of cultured human trabecular meshwork cells
2 2 2
trophils. The impairment of phagocytic func-
tion (microspheres) has also been reported in human monocytes, mediated via stimula-
(isolated from the juxtacanalicular and cor-
neoscleral regions of the human eye) (46).
Xylazine
A
tion of GABA
receptors by thiopental (25).
This alpha2-agonist had no effects on
In addition, thiopental can also depress the phagocytosis of Staphylococcus aureus by human monocytes (43). In vitro studies have shown that thiopental diminishes human neutrophil and monocyte oxidative burst in- duced after phagocytosis (Staphylococcus aureus and Escherichia coli) at high concen- trations (28, 38).
Dexmedetomidine
2
Dexmedetomidine is a highly-selective α -adrenergic receptor agonist used for seda- tion of critically ill patients in an intensive care setting and as adjuncts to anesthesia.
2
chemotaxis, phagocytosis, or superoxide an- ion (O -) production of human neutrophils; the lack of effect of this drug has also been reported by in vitro studies (5, 44).
Methohexital
It has been reported that this barbitu- rate is capable of decreasing the phagocyto- sis of viable S. aureus by human monocytes (43). In vitro studies showed that metho- hexital inhibited granulocyte recruitment and phagocytosis activity (S. aureus) in a dose-dependent manner (47). However, other studies show that it failed to alter
the phagocitic function. In this regard, this drug did not influence human neutrophil chemiluminescence (respiratory burst) in a dose-dependent fashion (42). Methohexital exhibited no significant effects on human neutrophil oxidative burst and phagocytosis (E. Coli) in patients with severe brain injury requiring long-term sedation (34).
Pentobarbital
This drug did not influence human neutrophil chemiluminescence (respiratory burst) in a dose-dependent fashion (42).
Phenobarbital
In vitro studies showed that phenobar- bital decreased human neutrophil chemilu- minescence (respiratory burst) in a dose- dependent fashion (42).
Thiamylal
Subclinical doses of thiamylal caused enhancement of the human phagocytic ac- tivity of neutrophils, however, super-clinical doses of thiamylal inhibited phagocytic ac- tivity of these cells (39).
Amobarbital
No information was found.
Diazepam
This benzodiazepine did not alter phagocytic function (microspheres) in hu- man monocytes (25). In addition this drug in concentration-dependently doses increased chemotaxis and phagocytosis in isolated human neutrophils by Ca2+ -independent mechanisms (48). However, diazepam is in- hibitory in vitro for the phagocytic functions being its action mediated via specific recep- tors on immunocompetent cells (49).
Midazolam
At clinically concentrations this intra- venous anesthetic depress human neutrophil phagocytosis and further production of ROS (40). In vitro studies have shown that mid- azolam diminishes human neutrophil oxida- tive burst after phagocytosis (E Coli) at high concentrations (28), but failed to reduce both respiratory burst and phagocytosis of
S. aureus (33).
Flunitrazepam
In vitro studies showed that this drug significantly inhibited both phagocytosis (Staphylococcus aureus and Escherichia coli) and bactericidal activity (41).
Alprazolam
Alprazolam increases human neutro- phil phagocytosis of bacteria and further killing and monocyte phagocytosis without modifying antibacterial activity values (50).
Lorazepam
No information was found
Promethazine
2
2
In general this drug alters the produc- tion of ROS, necessary to destroy ingested bacteria. Promethazine predominantly af- fected the ability of macrophages to produce O - during phagocytosis (51). Promethazine also affected the ability of human neutro- phils to produce O - and hexose monophos- phate shunt activity during phagocytosis (opsonized zymosan) (52, 53).
Chlorpromazine
Chlorpromazine increases killing activi- ty against S. aureus phagocytosed by human monocyte-derived macrophages (54).
Acepromazine
No information was found.
Fentanyl
Fentanyl failed to inhibit receptor ex- pression, phagocytosis and reactive oxygen production by monocytes in clinically rele- vant as well as supraclinical concentrations (55). Intravenous injection of fentanyl did not alter human neutrophil phagocytic func- tion and superoxide anion generation (56, 57). In addition, in vitro studies showed that fentanyl did not influence phagocytosis as well as bactericidal activity in human neu- trophils (41). However, high-dose fentanyl anesthesia in patients undergoing coronary bypass surgery showed decreased phagocyto- sis of zymosan, S. aureus and E. coli by hu- man granulocytes (58).
Alfentanil
In vitro studies showed that alfentanyl did not influence phagocytosis as well as bactericidal activity in human neutrophils (41). However, this drug alters phagocytosis of latex by human monocytes (7).
Remifentanil
No information was found.
Sufentanil
No information was found.
Droperidol
This drug is used as a sedation ad- junct to general anesthesia. In vitro studies showed that droperidol caused a significant inhibition of phagocytosis as well as bacteri- cidal activity in human neutrophils (41).
Bupivacaine
In vitro studies showed that bupivacaine alters phagocytic functions. In this regard, this drug inhibited priming of LPS on human neutrophils (59). Bupivacaine in a time-de- pendent manner diminished phagocytosis, bacterial uptake, oxidative burst and CD11b expression by human neutrophils (43). Bupi- vacaine impairs surface receptor expression Fc gamma receptor III (CD16), complement receptor 1 (CD35) and complement recep- tor 3 (CD11b) and may thereby contribute to reduced phagocytic activity and oxidative burst (60). Other studies report different ef- fect of this drug. In vitro studies showed that bupivacaine did not alter the chemotaxis, phagocytosis and oxidative burst of human neutrophils at clinically doses (61, 62).
Lidocaine
Lidocaine inhibited adhesion, chemo- taxis, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils and macrophages (62, 63). Lido- caine also diminished phagocytosis, bacterial uptake, oxidative burst and CD11b expression in human neutrophils, in a time-dependent manner (30, 61). In vitro studies showed that
lidocaine inhibited priming of LPS on human neutrophils (59).
Procaine
Procaine inhibits adhesion, chemotaxis, phagocytosis, and the production of superox- ide anion and hydrogen peroxide by neutro- phils and macrophages (63). Procaine also inhibited the phagocytosis of latex particles by normal monocytes (64). In vitro studies showed that procaine inhibited priming of LPS on human neutrophils (59).
Tetracaine
In vitro studies showed that tetracaine inhibited priming of LPS on human neutro- phils (59), and inhibited adhesion, chemo- taxis, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils and macrophages (63).
Mepivacaine
Mepivacaine inhibits adhesion, chemo- taxis, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils and macrophages (63).
The accumulated evidence described above suggests that human phagocytosis processes seem to be more sensitive to the main anesthetic, analgesic and sedatives agents, which results in decreased chemo- taxis, phagocytosis and ROS production and leads to impairment of the anti-bacterial function by phagocytes (Table I). However, different results between those obtained from patients and those obtained from in vitro experiments, have been reported. Prob- ably direct information obtained from pa- tients before and after surgery, represents a closer view of real effect of anesthetic drugs. In addition, the attenuation of the preopera- tive stress responses, by a combination of sedative drugs with general anesthesia, can protect surgical patients from further altera- tion of phagocytosis processes during the preoperative period. This is very important in patients with risk of microorganism infec-
tions. Other situation to be analyzed is the combination of different drugs used during anesthesia and the final effect of that combi- nation and the preparation of drugs used for anesthesia (65). The negative consequences associated with preoperative immunosup- pression, such as an increased risk of post- operative infection, could be decreased by the optimal selection of anesthetics and an- esthetic techniques. Concerning the stress response induced by anesthesia, intravenous anesthesia may be superior to inhalation an- esthesia in reducing hypothalamic-pituitary adrenal axis activation (66). In the future, anesthetic protocols may be chosen not only for their anesthetic and analgesic effects, but also for their immunomodulatory ef- fects, considering the underlying conditions for which the patients need to be anesthe- tized (4, 67-69).
Neuraxial anesthesia provide several advantages over other anesthetic agents, in- cluding decreased risk of infection through
attenuation of the stress response and pres- ervation of immune function (70-73). De- spite these benefits, patients with altered immune status are often not considered can- didates for neuraxial techniques because of the risk of infection (74).
Despite these documented effects on human phagocytosis, the clinical importance of anesthesia-mediated changes in periopera- tive immunosupression remains uncertain. Currently, there are no clinical studies eval- uating the influence of choice of anesthesia and analgesia on the outcome after oncologic surgery or in immunocompromised patients.
In general, the drugs used during anes- thesia induce suppressed phagocytosis pro- cesses; therefore, the anesthetic protocols may be chosen not only for their anesthetic and analgesic effects, but also for their im- munomodulatory effects. There is evidence suggesting that the choice of anesthetic is important when considering the underlying condition of the particular patient.
EFFECT OF ANESTHETIC, ANALGESIC AND SEDATIVE AGENTS ON HUMAN PHAGOCYTOSIS PROCESSES
Agents
Effect on phagocytosis processes
References
Lieners et al., 1989 (10); Carrera et al., 1993 (7); Clark et al.,
Isoflurane ↓/ne
1993 (8); Kotani et al., 1998 (11); Heine et al., 2000 (6); Du et al.,
2017 (9); Koutsogiannaki et al., 2019 (12)
Halothane ↓/ne Nunn et al., 1979 (16); Barth et al., 1987 (15); Lieners et al., 1989
(10); Khan et al., 1995 (14); Ciepichał and Kübler, 1998 (13)
Sevoflurane ne Erol et al., 2009 (17); Fahlenkamp et al., 2014 (18) Desflurane ne Erol et al., 2009 (17)
Enflurane ↓ Perttilä et al., 1986 (19); Barth et al., 1987 (15); Khan et al., 1995
(14)
Nitrous oxide ↓ Perttilä et al., 1986 (19); De Rossi et al., 2002 (20) Xenon ↓/ne De Rossi et al., 2002 (20); Fahlenkamp et al., 2014 (18)
Ince et al., 1988 (24); Krumholz et al., 1994 (29); Skoutelis et al.,
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Heller et al., 1998 (28); Kotani et al., 1998 (11); Heine et al., 2000
Propofol ↓/ne
(6); Bali and Akabas, 2004 (23); Corcoran et al., 2006 (32); Huet-
temann et al., 2006 (34); Ploppa et al., 2008 (30); Shiratsuchi et
al ., 2009 (26); Erol et al., 2009 (17); Wheeler et al., 2011 (25); Yu
et al. 2011 (36); Bravo et al., 2019 (31)
Agents
Effect on phagocytosis processes
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Krumholz et al., 1995 (38, 41); Toyota et al., 1995 (39); Davinson
Ketamine ↓/ne
et al., 1995 (33); Heller et al., 1998 (28); Nishina et al., 1998 (40);
Chang et al., 2005 (37)
Etomidate ↓ Krumholz et al. 1995 (38, 41)
Salo and Perttilä et al., 1989 (19); Skoutelis et al., 1994 (35);
Thiopental ↓
Weiss et al., 1994 (42); Davinson et al., 1995 (33); Krumholz et al.
1995 (38, 41); Heller et al., 1998 (28); Nishina et al., 1998 (40);
Ploppa et al., 2008 (43); Wheeler et al., 2011 (25)
Dexmedetomidine ↓/ne Nishima et al., 1999 (44); Anderson et al., 2014 (5); Chen et al.,
2016 (45)
Clonidine ↓/ne Wang et al., 1994 (46); Nishima et al., 1999 (44); Anderson et al.,
2014 (5)
Xylazine ne Nishima et al., 1999 (44); Anderson et al., 2014 (5)
Methohexital ↓/ne Weiss et al., 1994 (42); Huettemann et al., 2006 (34); Ploppa et
al., 2006 (47); Ploppa et al., 2008 (30, 43)
Pentobarbital ne Weiss et al., 1994 (42)
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2011 (25)
Midazolam ↓/ne Davinson et al., 1995 (33); Heller et al., 1998 (28); Nishina et al.,
1998 (40)
Flunitrazepam ↓ Krumholz et al., 1995 (41) Alprazolam ↑ Covelli et al., 1993 (49)
Promethazine ↓ DeChatelet et al., 1973 (53); Trush and Van Dyke, 1978 (52); Tra-
ykov et al.,1997 (51)
Chlorpromazine ↑ Ordway et al. 2002 (54)
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2000 (57); Yeager et al., 2002 (56); Menzebach et al., 2004 (55)
Alfentanil ↓/ne Carrera et al., 1993 (7); Krumholz et al., 1995 (38) Droperidol ↓ Krumholz et al., 1995 (38)
Bupivacaine ↓/ne Welters et al., 2001 (60); Mikawa et al., 2003 (61); Jinnouchi et
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Lidocaine ↓ Mikawa et al., 2003 (61); Azuma and Ohura, 2004 (63); Jinnouchi
et al, 2005 (59); Ploppa et al., 2008 (30); Kawasaki et al., 2010 (62)
Procaine ↓ Jurjus et al., 1988 (64); Azuma and Ohura, 2004 (63); Jinnouchi
et al, 2005 (59)
Tetracaine ↓ Azuma and Ohura, 2004 (63); Jinnouchi et al., 2005 (59) Mepivacaine ↓ Azuma and Ohura, 2004 (63)
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