The Journal of EVIDENCE-BASED DENTAL PRACTICE USE OF LOCAL ANESTHETICS WITH A creek torveten VASOCONSTRICTOR AGENT DURING DENTAL TREATMENT IN HYPERTENSIVE AND CORONARY DISEASE PATIENTS. A SYSTEMATIC REVIEW MARIA SEMINARIO-AMEZ®, BEATRIZ GONZALEZ-NAVARRO®, RAUL AYUSO-MONTEROS, ENRIC JANE-SALAS4, AND JOSE LOPEZ-LOPEZ* DDS, Master Degre in Oral Macicing, Oral Surgery and inplantology, School of Dentistry, Univesity of Bacelons, Barcelons, Spain BAD, DDS, Master Degree in Oral Meceine, Oral Sugery and implantology, Assistant Professor of Ora Pathology, Schoo of Dentist, Univeraty of Bo (Oral Heath and Maststory Sytem Group (Balliige Clore Research nett) IDBELL, Univers of Barston Barcelona, Spa PHD, DDS, Master gros in Oral Rehabilitation, Asociste Profesor of Prosthodontics, Schl of Demy, Univer of atclons- Oral Heath and stator System Group @lliige Siomedieal Resewch estat) [IBELL Unversity of Batalons, Barcelona Spain “PND, MD, DDS. Agoregate Professor of Oral Pathlogy, School of Dent, Unersty af Barcelona - Oral Heath ond Mastcatory Systm Group Belltge Biomedical Research irsttute IDIBELL, Unversity of Barcelona, Saceono, Spain PHD, DDS, MD, Prfersrof Oral Pathology Schl of Det, Univers of arcana - Oral Heath an Mastcatory System Group (athitge Biomedical Resesich Institue) ABELL, UniertyofBoresion, Medical Surgel Ares and MasesI Director of Dentistry Hosp, Unversty of orceona,Baresina, Spain ABSTRACT ‘CORRESPONDING AUTHOR: Raul Ayuso Montero, Department of Cdontostomatology, Schoo! of Coronary disease and Hypertension are highly prevalent health problems workl> erie Pobellon cle Gobierno wide, with the latter being one ofthe most common diseases in patients ws- | aay Untersy Corpo Ciena iting dental clinics. Local anesthetics (LAs) with vasoconstrictor agents (VC) ae pitas Unwersiy Campus, CF known to be commonly used in dental practice, For the above-mentioned rea peated ut sons, dentists should know how to adapt and troat patients with these hazardous Background Ubregat, Barcelona, Spain. E-mail: raulayuso@ub.edu conditions Objective KEYWORDS The aim of ths study was to find outif the use of local anesthetic (LAs) in com- Hypertension, Coronary disease, bination with vasoconstrictor (VC) agents in dental treatment presents a riskin | Hemodynamics, patient with a known history of Hypertension and/or Coronary disease Vasoconstrctor-agonts, Dentistry Materials and methods This systematic review was conducted in accordance with The PRISMA guide- Source of Funding: Ths research did lines and registered on the PROSPERO database (CRD42020187367). The search not receive any specific grant from strategy was based on Mesh terms, Boolean operator AND, andthe PICOmedel, funding agencies inthe public, It was designed to identify all the randomized clinical trials (RCTs) published in commercial, or notforprofit sectors ‘the last 0 years, which assessed whether the use of LAA with VC agents in dental ‘treatment produces a significant increase/decrease in hemodynamics in patients vith known history of Hypertension and/ar Coronary disease. The Cochrane Col laboration’s tool was used to assess risk of bias of the included RCTs Conflict of Interest: None, Received 3 August 2020; revised 16 February 2021; accepted 28 March 2021 Results An initial electronic search resulted in 87 papers; however only RCTs met the | 1 Evid Base Dent Pract 2021: [101569] inclusion criteria. There was a total of 482 subjects (N=482), ofwhich 41Zhad a 1532-3382/83600 known history of Hypertension or Coronary disease ©2021 Ekovor ne Allrights reserved, dol: hetps://doi.org/10.1016/ eure vont 2001The Journal of EVIDENCE-BASED DENTAL PRACTICE Conclusions According to the literature reviewed, the use of 1 to 2 cartridges of local anestheties with 1:80,000, 1:100,000 or 1:200,000 epinephrine in patients with controlled Hyperten: sion and/ er Coronary disease is safe. Randomized clinical trials are essential in determining the safety or risks asso- ciated with the use of LAs with VC agents in patients with poorly controlled Hypertension and Coronary disease, INTRODUCTION ardiovascular diseases (CVDs) are the leading cause of cdeath globally Hypertension, a subgroup of CVDs, is considered one of the leading causes of premature death worldwide.’ This condition may increase the risk of heart at- tack, stroke, kidney failure and other diseases.” Hyperten: sion is defined as a blood pressure equal to or greater than 140mm Hg/0mm Hg. Conversely, the ideal blood pressure, in which the individual has the lowest cardiovascular risk, is 120mm Hg/ 80mm Hg Coronary disease refers to the re duction of heart blood vessels lumen’. Coronary disease and Hypertension are highly prevalent health problems workd- wide," withthe latter being one of the mast common dis eases in patients visiting dental clinics.°* This means that every health professional should know how to treat patients with these conditions to avoid situations which may jeopar. dize their health, and consequently their lfe."* Local anesthetics (LAs) with vasoconstrictor (VC) agents are widely used in dentistry, especialy in oral surgery” ‘The most commonly used VC agent is Epinephrine," because it provides many advantages such as reducing toxicity, increasing the anesthetic effect and improving hemostasis." Nonetheless, Felypressin is also used." Epinephrine isa catecholamine type vasoconstrictor which has a non-selective adrenergic profile. It causes the reduc: tion of peripheral blood-vessel diameter (a1 agonist), and stimulates 61 receptors, increasing heart rate (HR) and con sequently, blood pressure (BP). In 82 receptors, Epinephrine stimulates vasodilation in muscles and internal organs *'® ‘On the other hand, Felypressin is a synthetic analogue of the antidiuretic hormone, Vasopressin. It has been suggested as an alternative to epinephrine to decrease the systemic ad verse reactions because it is considered to have no direct effect on the myocardium. In that sense, the blood pressure increase is attributed to peripheral resistance." For the above reasons, the association of a local anesthetic (LA) with @ VC agent might result in adverse hemodynamic effects, thus making its use controversial in patients with a history of Hypertension (HTN) and/or Coronary disease.‘ Concerning patients, the psychological and emotional fac- tors must be taken into account. Anxiety or a stressful ex perience may generate an exaggerated endogenous cate- cholamine production, which also may lead into hemody: namic and metabolic disturbance," ‘The air of this study was to review the published literature in order to find out whether the use of LAs in combination with a VC agent in dental treatment presents a risk in pationt with a known history of Hypertension (HTN) andlor Coronary disease. MATERIALS AND METHODS. This systematic review was conducted in accordance with the PRISMA guidelines (Preferred Reporting ltems for Sys- ‘tematic Reviews and Meta-Analyses)” and registered on the PROSPERO database (CRD42070187369). To select the RCTS included, we used the PICO strategy.” as follows: Part: pants (P) were “Patients with known history of Hypertension and/or Coronary disease"; the intervention () was “use of LAs with @ VC agent”; the control (C) was “use of Ls with out a VC agent" or “healthy patients”; and the outeame (0) was "hemedynamic changes occurred when using LA with and without a VC agent" (Figure 1) Sources of Information A thorough electronic literature review was conducted on PubMed, Cochrane Library and Scielo databases in May 2020. The identification of studies was based on the follow- ing search strategy and it was not limited by language. Search Strategy ‘A detailed search based on Mesh torms was performed. It ‘wos structured with Boolean operator (AND) and designed to identify all randomized clinical trials (RCTs) published in the last 30 years, which assessed ifthe use of LAs with @ VC agent in dental procedures represents a risk in patients with Hypertension and/or Coronary disease The Mesh terms used were: "hypertension AND anesthe sia, local AND vasoconstrictor agents AND hemodynam- ies AND tooth extraction’, “coronary disease AND anes thesia, local AND vasoconstrictor agents AND hemodynam- ies AND tooth extraction", “cardiovascular diseases AND anesthesia, local AND vasoconstrictor agents AND hemo- dynamics AND tooth extraction”, "hypertension AND anes- ‘thesia, lacal AND vasoconstrictor agents AND tooth extrac tion", "coronary disease AND anesthesia, local AND vaso- constrictor agents AND tooth extraction", “cardiovascular discases AND anesthesia, local AND vasoconstrictor agents AND tooth extraction", "hypertension AND anesthesia, lo- cal AND vasoconstrictor agents AND hemodynamics AND surgery, oral’, "coronary disease AND anesthesia, local AND vasoconstrictor agents AND hemodynamics AND surgery, oral’, "cardiovascular diseases AND anesthesia, local AND vasoconstrictor agents AND hemodynamics AND surgery, oral’, "hypertension AND anesthesia, local AND hemody- namics AND dentistry", "coronary disease AND anesthesia,Fig, 1. Article selection process and inclusion criteria used in this systematic review. The Journal of EVIDENCE-BASED DENTAL PRACTICE Articles identified on Pubmed database, with Mesh therms and Boolean operator “AND” (0=306) Articles excluded Articles sereened (40) 2 Alter cmoving (Published inthe last “Non-RC desien : iuplicates 30 years) 8 (n=87) (0-57) = Out of topic Full-text articles assessed for eligibility (n=17) RCTs included (a=9) Selection criteria and Pico strategy. Studies: RCT design Pa lisease or Hypertension snts: Coronary: Intervention group: Use of LA with VC agent Control group: Healthy patients /use of LA without VC agent ‘Outcomes: Changes in SBP, DBP; HR. Full-text articles exeluded with reasons (n-8) Non-Aecomplishment of PICO strategy Use of other drugs (analgesics, sedation) Patients with congenic Disease or Syndromes Healthy patients in intervention group RCT: Randomized clinical trial; LA: Local anesthetics; VC: Vasoconstrictor; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: Heart rateThe Journal of EVIDENCE-BASED DENTAL PRACTICE ‘Table 1. RCTs included. Demographic data and systemic condition of participants. Hypertensive or Participants eevaene Ta aa Conta yup oe Medial, Addons te sashes Meo age £50. oN Gg yesine youn RuteaeN Sey ~SCSCT SS oa soteePaiMs SLI wD rae, eeakhor BomoALeta{t3} Hsiye oo Th = ee eo = 5 Novos RS.ota7) S87 88s Th one eee mo etal. [12] CoulayeM©, —-SDIETI7ys «33D — etal. [9] Comodo VG eal 58798 BCD : mo i Se bsye RoienoveM, HSE «ERT ee etal 8) DM, dlabetes melts ns, non speifed: SD, standard deviation; Yes, years local AND hemodynamics AND dentistry”, “cardiovascular diseases AND anesthesia, local AND hemodynamics AND dentistry". Process of Data Collection ‘The search was conducted by two reviewers (MSA and BGN) to avoid bias. Disagreements were evaluated and resolved in consensus meetings with JLL, RAM and EJS. Selection Criteria Study eligibility was structured and based on the PICO strat- egy (Participants, Intervention, Control and Outcomes) .” Studies were selected according to the inclusion/exclusion criteria outlined in Figure 1 Descriptive literature reviews, case reports, series of clinical reports, and studies that included congenital heart disease patients; as well as studies that evaluated the action of other rugs on patients’ hemedynamies, were excluded (Figure 1) Data Extraction Data extracted from each study were analyzed and sorted by two independent examiners (MSA and BGN). The following characteristics were obtained: author, year of publication, number of patients in intervention group and control group, patient’ sex, mean age, systemic condition, treatment per formed, monitoring appliance and period, local anesthetics and vasoconstrictor agents used; as well as doses and num- bor of cartridges. We also obtained data from the results of the papers lke significant differences on hemodynamic pa rameters between the intervention and control groups. Data wore collected using a standardized form, considering only information available inthe papers. The details of each study ate presentedin Tables 1-3, Na meta-analysis was performed due to heterogeneity of data Analysis of the Quality of Included Studies We used The Cochrane Collaboration’stool for assessing isk of bias in randomized clinical trials It covers six domains of bias: selection bias, performance bias, detection bias, attri- tion bias, reporting bias, and other bias. MSA and RAM in- dependently reviewed each RCT included and determinedit ‘there was a high, low or unclear risk of bias for each domain, Disagreements were arbitrated and resolved by discussion, with BGN, EJS and ILL. ‘The innovative approach of this systematic review, focused fon patients with a known history of Hypertension and/orCoronary disease, is that it may contribute to a scientific literature-based practice, and that itis based onlyinrandom- ized clinical tials, presenting a high level of scientific vi- dence RESULTS Search and Selection Process After removing the duplicate records, an electronic search resulted in 87 papers. However only 57 were publishedin the last 30 years. A total of 40 papers were discarded for being off topic or had a non-RCT design. Of the resulting 17 arti- cles, only 9met the inclusion criteria based on PICO strategy (Figure 1) Analysis of the Quality of Studies The Cochrane Collaboration’s tool for assessing risk of bias of Randomized clinical trials wes used.” As explained in Table 4, all the authors had a low risk of bias on “Attrition bias" and "Reporting bias” domains. In our point of view, ‘we considered the “selection bias” and “reporting bias” do- mains as “very important domains". In that sense, only Abu Mostafa N, et al and Torres-Lagares D, eta.” had alow risk of bias in both. Conversely, the Performance bias”, "Detec: tion bias” and "Other bias” were the domains with the worst profiles, which means a “high risk of bias". In this review, wo determined "Other bias” when the authors performed “dit ferent kinds of treatments” or when “different persons per- formed the treatments” on subjects included in the study groups. These aspects may lead to different emotional re sponses, thus inereasing risk of bias, Sample Size and Characteristics A total of 482 subjects (N = 482) were studied. Of those sub- jects, 412 had history of Hypertension and/or Coronary dis ease. The mean age’s weighted average was 58,73+9,88 years, without considering Abu-Mostafa N, et al and Uzeda MJ, et al which did not provide this data. The male/female ratio was 2.81.6. Eight studies included only rmedically-controlled Hypertensive and Coronary disease pa- tients." In the case of Conrado VC, et al." it was not specified, but they focused on chronic coronary artery dis- ease patients (confined by previous coronary angiograph), and with stable angina on exertion. Additionally, they re- ported the exclusion of patients with unstable angina; acute ‘myocardial infarction (occurring < 3 months}; imminent ind cation of cardiac surgery or angioplasty; heart diseases as- sociated with coronary disease; heart failure; recent stroke (< 3 months); severe Hypertension (SBP >0= 180mmHg and DBP >o=110mmlHg) and uncontrolled Diabetes Mell ‘us. Regarding exclusion criteria, the most common reasons ‘were: pregnancy and breastfeeding,” #-blockers medica tion, severe heart diseases***"" and uncontrolled systemic diseases or other medical disorders.*””""""® Nonetheless, The Journal of EVIDENCE-BASED DENTAL PRACTICE Neves RS, et al’ and Santos- Paul MA, etal.” also included patients diagnosed with Diabetes Mellitus (DM). According to the treatment performed, most ofthe studies wore related to oral surgery, especially tooth extraction.” "" However, Torres-Lagares D, et a.” and Bronzo AL, et a." performed periodontal treatment, and Neves RS, et al.’ single restora- tive procedures (Table 2) Local Anesthetics and Vasoconstrictor Agents Two hundred and thirteen patients underwent dental treatment with the use of a LAs with epinephrine"? The concentrations administered wore: &Lido- caine + 1:100,000 epinephrine. 2%Lidocaine + 1:80,000 epinephrine” — 4%Articaine-+ 1:100,000 epinephrine and 4%Articaine+1:200,000 epinephrine.” 2%Mepi- vacaine-+1:100,000 epinephrine."""? 3% Lido- caine + 1:100,000 epinephrine.’ Concerning Felypressin, 86 patients were treated with this VC agent. The concentration administered was: 3% Prilocaine + 0.03 IU Felypressin.*"" On the other hand, there wore 264 patients treated without a VC agent. Thus, 3% Mepivacaine, "2 29 Lidocaine,” 4% Prilocaine'” and 3% Lidocaine” were used (Table 2) Doses of LAs (with or without VC agent) ranged from 1.8ml to SAml, equaling to 1 to 3 cartridges.” It is important to highlight that Torres-Legares D, et al'” and Bronzo AL, et al.” administered different LAs to the same patients, OF course, after wash-out periods of 1 week and 10 min, respectively, Intervention and Control Groups The studies included similar “intervention groups"; but dif ferent “control groups”. Seven studies included only “Pa- tients with history of Hypertension and/or Coronary disease” and compared the hemodynamic changes occurred when using LAwith VC agents, with the hemodynamic changes oc- curred when using 2 LA plain." In the case of Uzeda Mj, et al’ they compared the hemodynamic changes when using LAs with VC agents in Hypertensive and/or Coronary disease patients with the hemodynamic changes when used in healthy pationts. While, Zivotié-Vanovié M, et al.” sepa- rated the examined patients into two groups, “cardiovascu- lar disease patients (CV)" and “healthy patients (H)*; then, those patients were randomly assigned to two subgroups: In the Group A(°CVa" and "Ha") the LA contained Epinephrine 1 100,000; and in Group B ("CVb" and “Hb") the LA was plain Lidocaine, This allowed for two “control groups It should be highlighted that there were 2 studies which not only compared the use of a LA with a VC agent with the use of plain LA; but also, used another LA solution and/or another VC agent.*"? For example, Abu Mostafa N, et al had a total of N=45 Hypertensive/ Coronary disease pa- tients which were randomly allocated into 3 groups of 15 Patients to compared the use of 2% Lidocaine + 1:80,000 Month 2021The Journal of EVIDENCE-BASED DENTAL PRACTICE J202h 3 ayoedeuou su aes9u8 130) 7 ‘ho voLvaR mp ‘SnoIB RIED DD 2 foonouit auuydaud 20% isle su aureopn xe ou ONE —_voRDeR¥e Wool % ° 16 zi ‘Wonouenanionz wer 1 ouresenday set vorsesxe Wood, @ ° 1 Se DAepEHIED kaye) aues09n sez vorsesxe yoo o ° nce OW ome oupaen re19ps a a oor ‘aser6 annpacaid wut) auieopmn xz angesoise: Bus ze ° Et hte sysenon wers-e us suuysouds 00 01:1 + eue>0P ou ou Sz vomenw@ oo. ° ° ee wepezn ger usseicieg ny wourean lye foveous xy ‘200+ eURD0IN4 Ke ou yewepoueg ul u ° 3 onp'0o1:t + eue20p9 upg eue20pn xz ou 92 soo se ° se ugg auuydauids lupey twpgyussaideg ny gage + 2ueoA isle ouerendanxe B00 + ouD0IN4 XE 52 vowrenx0 yoo. st s Sh sh "Neyesonrney eBe DA OWI WOBRDAIOVT IANO eUNHIOUES WMV weugeos DDD OD/DIDAVT 5) eunydoudy = WeUREOHL MED roy Ny _2OKRO HM Ne MN ee ‘950g /SonNRE=uE EO] Toes edno1D [possosse sosop so3>ujsuesosen pue sano4soue [2207 ‘pouioysed wouneen jeuep ‘uenesoje sdnei5 ‘PaPA;U $194 Z a14eL x 5Epinephrine/3.6ml, 3% Mepivacaine/3.6mil, and 3% Prilo caine +0.03 IU Felypressin/3.6m\, respectively, As well 25, Torres Lagares D, et al” which had a total of N=10 pa- tients who underwent periodontal treatment of the 4 ses sions using a different LA and VC agent in every session with @ washout period of 1 week. The LAs and VC agents Used were as follows: 4% Articaine 1:100,000/3.6 nl, 4% Art- caine 1:200,000/3.4ml, 3% Mepivacaine/3.6 ml, 2% Mepiva- caine + Epinephrine :100,000/3 6 Hemodynamics Hemodynamic parameters were recorded with conventional or digital sphygmomanometer and pulse-oximeter and with Holter ECG.”* Conrado VC, et al." also used bio- chemical markers to determine the ischemic risk. Uzoda MU, et al’ did not specify which device they used. The RCTs in- cluded, reported whether a statistically significant increase cor decrease in Systolic blood pressure (SBF], Diastolic blood pressure (DBP) and Heart rate (HR) was found when compar- ing the intervention group with the control group. Accord- ing to this, there were authors who did not find any statis- tically significant difference in SBP, DBP or HR between the groups,’ and others who found it (Table 3 ).°#21 No adverse effects were reported in RCTs included in this review"; and surprisingly all the authors defined the use of two?!" or three’ cartridges of LAs with VC agent (1:80,000, 1: 100,000 oF 1:200,000 Epinephrine and 0.031 Fe- Iypressin) in controlled Hypertensive and Coronary disease patients as safe." DISCUSSION The use of LAs with VC agents -mainly Epinephrine: in pa: tients with a known history of Hypertension and/or Coronary disease pationts, is controversial” The mandatory reason is Epinephrine’s adrenergic profile." Even though a cartridge of LA with 1:100,000 epinephrine corresponds 10 a dose of 0.018mg of epinephrine, which is very low in comparison with those administered for anaphylaxis or heart attacks (0.5 to 1 mg) *"" doubt remains when treating cardiovasculartisk patients. As mentioned in the introduc: tion, Epinephrine offers meny advantages such as reducing toxicity, increasing the anesthetic effect and improving hemostasis, thus being a useful tool for intra-operative bleeding control" However, it must be teken into consideration that this hemostatic effect has been associ ated with delayed wound healing, an increase in the risk of infection, and determine harmful effects on sof tissue flaps, due to decreased blood flow.” Liu W, et al.'® produced @ systematic review which included 101 studies (RCTs, non RCTs, case-control studies, case reports, case series, and cross-sectional studies published between 1967 and 2010) that focused on adverse drug reactions (ADRs) associated with the use of LAs. They found that ADRs related to LAs The Journal of EVIDENCE-BASED DENTAL PRACTICE vith epinephrine are 2.16 times higher than plain LAs (which suggests the need to be cautious when using a VC agent), They also explained that usually adrenergic reactions are misdiagnosed as allergic reactions, and how psychological stress due to the LA injection could be a contributory factor to develop a sympathetic activation that is correlated with stress hormones and metabolites blood levels increase. For this reason, many authors have studied whether the use of local anesthetics with a vasoconstrictor agent can signifi cantly modify hemodynamic parameters." In that sense, we conducted this systematic review. Among RCTS included, we found that 4 studies did not observe any statis- tically significant difference when comparing SBP, DBP and HRbetween the groups after the injaction of 1 to 3cartridges of LA with or without VC agent.” In the ease of the authors who found them, they mentioned that those statis- tical differences had no clinical repercussion and attributed these differences to fear and anxiety experiences.° #2"? Despite the absence of clinical repercussions, itis important to discuss the results reported by Abu-MostafaN, etl. who found that the mean SBP increased.after LA injection and de- creased after extraction in the three groups of patients. They also highlighted that in the Mepivacaine plain group it was significantly higher than in the Lidocaine with Epinephrine group (p= 0.037 ANOVA). They also reported that the mean DBP of both Epinephrine and Felypressin groups decreased after injection and after extraction. In contrast, the meen DBP ofthe Mepivacaine plain group incteased afte injection and decreased after extraction but was still higher than pre- injection measurement, The mean HR also increased after injection and after extraction in all the groups; but the differ tence in HR and in DBP wore not significant among the three groups. Uzeda MJ, et al® reported a significant difference in BP between the groups in the waiting room (SBP and DBP) and at the moment of surgical drapes placement (SBP) with lower values in the normotensive group. They also found @ statistically sigificant difference in HR at “10 minutes after A injection", with lower values in the Hypertensive group, Respecting VC agents, epinephrine is the most com monly used. There are, of course, other options like Fo- Iypressin®="»2"2 and Clonidine.” They are however not Used routinely Felypressin constrcts venous outflow, so it is less vasoconstrictive than epinephrine. For that reason, it may cause less hemodynamic disturbance, and a smaller hemostatic effect. Kyosaka Yet al conducted a RCT where 2types of LA with VC agents were compared, They assessed the action of 2% lidocaine with 1:80,000 adrenaline (L+AD) and 3% prilocaine with 0.03 IU/mL felypressin (P-+ FP) on BP and HR in older adults with systemic diseases who un- derwent dental extraction (n=22, aged over 65 years). Sur- prisingly, they found that (P+FP) administration increased the SBP and DBP. They also found that (L-+ AD) administra- tion increased HR and decreased the DBP. They attributed vont 2001The Journal of EVIDENCE-BASED DENTAL PRACTICE (@Bed sou vo paras} vagy) Susomuow aunsse.d Pooja ALcxeinquie pe eHoH) (earjdw0> 210m sy 2 2 jun) aunpanoidsog “et jlUop ay yo| woned ‘ayn jun eainseue jo Buuuibeg aut {wo4) ainpano.y ou NNN ‘hysesBopiesonals sno4-$2 ersoysoue a1ojaq au 1) uyaseg 29 1e32 'SysaAON, ‘enpe2cic e2\6ins 40 pus ‘uonseluy seye 9, aueweoed ou 1 1 1 su sadeip jeaGins eye Woos Buniem gz [oe rmepezn (uourelu oye (1) yead (ize1g oyned os ‘107 souy fenpacoid fe>1Upa1 XG I9POU -WiXic) Bun) Buyers exSuiBqns uonoolu ou oN 1 1 snap suauioyioe0 parewoiny ‘wiuonuaneul asd) soy 1 leu e12 Twowog ainpaooid oye (ongoa-vav eyo.) yp vonselu y1 942 ‘anpedoid ou GN GN GN srawouewieUBAyds anewouny Biojeq g aunpesoid aicisq yy OL ye 38 ‘yu neg souLes asing pue [royuoyy aunssaig Poors Woy @NOUNO] —_"‘voUDeAXe Joye ¢ "vouselu W1 Joye ou oN ON 1 ssiewouewoushyds 3uense3 (uonsalu aioyeq) sey /eUsq Sp ere 'NeISON-NEY BH daa das. 2neq spoveg povodos GN /1/ as weeu pue BuuOWON Ne 280k powny sio0yo osionpy ‘einssoid pooja ui sobuey> {uesyubls Ajeonsness payoda: spayo asioape pue saBueyp a1weukpoway ‘pas ao;kap pue spotiad Buuoyuous /pSPN>U S194 a4eL Vokene 21, Number XXThe Journal of EVIDENCE-BASED DENTAL PRACTICE sinssaid pooyg 2yoishs gg s2ouauyp ou Qasr ‘811 ney yt omssand poor ajouEp gg ‘asap 'gfanseed pOOIG I 1 Joye,g Zu ‘vouoeaxe sye 713) poued Burejay pue ‘uogsesixa jeep Buunp uonsolu: “ON ON sowuow 953 pu adooseieg ‘yi 6uunp poued ainpooo: Zit [ah 38 W9PoUe-sHONZ onsen jewuep Joye sy pz osty ‘Buurans zaye pue (1 uuoden pue ano) ou NNN ue Jouvou 993 ue 181/0H, vs [Lu 1832 “Sn opeHeD (veder “ZOLLLOEN tang sues Ove lepow @sseurls jo pe} 20}U0U ‘aursserd ou GN GN GN. 00IG HEP a;oMRDaYe ansEnUl-UON ‘hs6uns asojoq woos Bunien gE lel 1833 ‘OW amour quoune@n jo uonejdusco Pua usune0n jeep Jo 989 queuneay uomelul eye ug 2+ 1 Buia vowel ayy povad Iysn ‘rosauin 241 eopoHN ou a ' 1 lauony Umiauopoaejne zoe wen OL zi) 7839 ‘qssve6y-ssu0) BH daa aS e2n9q spoued GN / 1/0102 weey pue paviodes saye osonpy Ne 9 joK (penunv0>)¢ age vont 2001The Journal of EVIDENCE-BASED DENTAL PRACTICE Table 4, Risk of bias evaluation using The Cochrane Collaboration tool.” Authors Allecstion Concealment Blinding of pasticipants and ‘personnel g 2 wv re gia af cog e a g "2 AbuMostafaN, et a [5] Santos-Paul MA, et al [10] Bronzo AL, et [13] Uzede MI, et ol [6] Neves RS, et al 7] Tones. Lagares D, et al [12] Oguntewe MO, et al P] Conrado VC, et al [11] © (O1S | OOO] SO | @ | Renton sequence generation eeeeeeeee eeeeoeeeoee Zivotié-Vanovie M, et al [8] Legend/meaning: @ Low risk of bias ‘@ Unclear risk of bias @ High risk of bias, this variation to increased peripheral vascular resistance pro duced by P+ FP). On the other hand, Gazal G. mentioned thatparilocaine has asmaller vasodilator effect than lidocaine, thus overcoming the weakness of felypressin as vasoconstric- tor and promoting a long-lasting anesthetic effect. In that sense, he recommended its use as an alternative for cardio: vascular patients in dental treatment. Clonidine is an a2adrenoceptor agonist that is being in creasingly used together with LA for spinal or epidural anal- gosia.” Clonidine might have hemodynamic advantagos compared with epinephrine as @ vasoconstrictor because of its central hypotensive effect.” Nevertheless, its main dis advantage is its shelf ite 6-8 hes), and it must be mixed with the LA immediately before application." ‘Asmentioned before, dental treatments contribute to stress and anxiety due to pain and/or fear. This experience may generate an exaggerated endogenous catecholamine pro duction (which has not been assessed nor demonstrated) £5:00152) and consequently a hemodynamic distur- bance." "!% This fact is also supported by Bronzo AL, et al who introduced an “anesthetic simulation” session as part of their study methodology and found that dur-ing the simulation, both SBP and DAP increased signif cantly (e<0.05) compared to the other steps of the session (rest, assessment of oral health, and subgingival scaling) They also made a complementary analysis, and found that SBP increased significantly during anesthesia and subgingi- val scaling only in patients with highest trit anxiety. How- ever, no significant ciference was observed in DBP (p>0.05). We must emphasize that none of the authors who mention the possibilty of endogenous catecholamines increase, as sessed nor demonstrated it. For this reason, we consider it just a speculation. Regarding the studies which also assessed ST-segment a: {eration (myocardial ischemia), Neves RS, et al.’ reported no evidence of myocardial ischemia neither at the baseline pe- riod nor during the procedure. Although 10 patients experi- enced ischemic episodes, and 6 of them belonged to the non-epinephrine group, all of them occurred at least two hours after dental procedure had been completed, so they ‘wore attributed to the heart disease itself. Additionally, they did not find any statistically significant difference between ‘the two groups, which agreed with Conrado VC, et al!" How- ever, they reported three patients inthe epinephrine group who had mild ST-segment ischemic depression (1.0mm) in the initial period of anesthetic action, but the simultaneous occurrence of any other alteration considered as detectors of myocardial ischemia (let ventricular hypocontractility and elevation of myonecrosis markers) was not observed. ‘As an interesting quote, one RCT excluded patients med icated with Beblockers’ and other studies also mentioned and endorsed this contraindication." """" Bader, et al“ per formed a systematic review that should be mentioned due 1o its contribution to understand the interaction between epinephrine (the most used vasoconstictor agent) and non- solective B-blockos (fis-line antinyportensive medication) It is well known that beta receptors increase heart rate and contraction force (B- receptors}, but also produce vasodila- tion (8-2 receptors) Thereby, when a non-selective B-blocker interacts with epinephrine, the epinephrine-vasodilation ac tion is eliminated, while the alfa-receptor activity (vasocon- striction) stay intact, thus contributing to a hypertensive cri- ‘Another characteristic to be highlighted is the lack of studies focusedon patients with severe cardiovascular diseases such 2s pootly-controlled hypertension, unstable angina, conges- tive heart failure, and acute myocardial infarction (occurring <= 1 year). Infact, these conditions were also exclusion criteria in most of the studies."”"" That is why the use of LA with 2 VC agent could be contraindicated in these kinds of pa- tients, until the literature demonstrates the opposite. Never- ‘theless, in imminent cases, motorization and postoperative follow-ups are necessary." Another important aspect to consider isthe correct administration ofthe local anesthetic, The Journal of EVIDENCE-BASED DENTAL PRACTICE which must avoid intravascular injection to guarantee mini- mum systemic side effects.” Limitations The principal limitation was that the RCTs included in this Systematic review mentioned that they included patients di- agnosed with Coronary disease and/or Hypertension, but they did not clearly define nor specify what “Coronary dis- ease” mean. Only Neves RS, et a.’ described it as patients vith clinical symptoms of stable engina and on drug therapy, positive exercise testing, and angiographically proven coro- nary stenosis > 70% in at least one major artery, Conrado VC, etal’ also mentioned that they considered patients with sta- ble angina on exertion. When talking about Hypertension, theyall considered a blood pressure equal to or greater than 140mm Ha/90mm Hg." CONCLUSION According to the literature reviewed, epinephrine isthe most commonly used VC agent in dental treatment. The use of 1 to2 cartridges of LA with 1:80,000, 1:100,000 or 1:200,000 of epinephvine in pationts with controlled Hypertension and/or Coronary disease is safe. However, all the RCTs reviewed in cluded only controlled patients, which makes not possible to apply this conclusion to patients with poorly controlled Hypertension and/or Coronary disease or patients with se- vere cardiovascular diseases. Randomized clinical trials with low risk of bias are needed to determine the safety or risky profile ofthe use of LAs with VC agents in poory-controlled Hypertensive and Coronary disease patients. ETHICAL APPROVAL Not required. PATIENT CONSENT Not required. AUTHOR CONTRIBUTION Maria Seminario-Amez, Beatriz Gonzélez-Navarro and Jose Lopez-Loper. Systematic review and data extraction: Maria Seminario- ‘Amez and Beatriz Gonzélez-Navare. Methodology: Raul Ayuso-Montero, Enric Jané-Salas and Jose Lopez. Lopez. Formal analysis: Maria Seminario-Amez and Raul Ayuso-Montere Writing original drat: Month 2021“The Journal of EVIDENCE-BASED DENTAL PRACTICE Maria Seminario-Amez, Beatriz Gonzélez-Navarro and Raul ‘Ayuso-Montero Writing, review and editing: Enric Jané-Salas and Jose Lope?-Loper. All co-authors have been read, revised critically, and ap: proved this manuscript and its submitted form. 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