Review Article The Impact of Intravenous Lidocaine on ICP in ...Review Article The Impact of...

Review ArticleThe Impact of Intravenous Lidocaine on ICP inNeurological Illness: A Systematic Review

F. A. Zeiler,1 N. Sader,2 and C. J. Kazina1

1Section of Neurosurgery, Department of Surgery, University of Manitoba, GB1-820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R92University of Manitoba, GB1-820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R9

Correspondence should be addressed to F. A. Zeiler; [email protected]

Received 30 May 2015; Revised 17 August 2015; Accepted 25 August 2015

Academic Editor: Robert Boots

Copyright © 2015 F. A. Zeiler et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. The goal of our study was to perform a systematic review of the literature to determine the effect that intravenous (IV)lidocaine had on ICP in patients with neurological illness. Methods. All articles are from MEDLINE, BIOSIS, EMBASE, GlobalHealth, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to March 2015). The strength ofevidence was adjudicated using both the Oxford and GRADE methodology. Results. Ten original articles were considered for thefinal review. There were 189 patients studied. Seven studies focused on prophylactic pretreatment with IV lidocaine to determineif there would be an attenuation of ICP spikes during stimulation, with 4 displaying an attenuation of ICP. Three studies focusedon a therapeutic administration of IV lidocaine in order to determine ICP reduction effects. All therapeutic studies displayed areduction in ICP. Conclusions. We cannot make a strong definitive recommendation on the effectiveness of IV lidocaine on theattenuation of ICP spikes during stimulation. There currently exists both Oxford 2b and GRADE B literature to support and refutethe attenuation of ICP spikes with IV lidocaine during stimulation.There currently exists Oxford 2b, GRADEB evidence to supportICP reduction with lidocaine when used as a therapeutic agent.

1. Introduction

Numerous medical therapies have been utilized in the treat-ment of elevated intracranial pressure (ICP) [1].Themajorityof ICP therapies are directed at reducing cerebral bloodvolume, attenuation of edema, cerebrospinal fluid (CSF)diversion, and decreasing metabolic demands of the neuraltissue, with the goal of maintaining adequate cerebral bloodflow (CBF) and cellular preservation.

Specific concerns of ICP elevations occur during the peri-intubation period, due to the significant stimulation thatoccurs during definitive airway management. Lidocaine use,both intravenous (IV) and laryngotracheal (LT), has beenreported to blunt the ICP elevations during intubation [2].Though one would assume that the ICP mediated effects oflidocaine stem from its local anesthetic effect, there are otherproposed mechanisms of ICP reduction via the IV route.Lidocaine injected IV has been shown in models to inducecerebral vasoconstriction leading to a decrease in cerebralblood volume and thus ICP [2, 3]. Furthermore, IV lidocaineleads to sodium channel inhibition and thus a reduction in

cerebral activity and metabolic demands [3, 4], as well asexcitotoxicity [5], leading to a potential ICP reduction effect.

To date few studies have documented the ICP effect of IVlidocaine in humanswith neurological illness [6–16].The goalof our study is to perform a systematic review of the literatureon the use of intravenous lidocaine and its effects on ICP inpatients with neurological illness.

2. Methods

A systematic review using the methodology outlined inthe Cochrane Handbook for Systematic Reviewers [17] wasconducted. The data was reported following the PreferredReporting Items for Systematic Reviews and Meta-Analyses(PRISMA) [18]. The review question and search strategywere decided upon by the primary author (F. A. Zeiler) andsupervisor (C. J. Kazina).

2.1. Search Question, Population, and Inclusion and ExclusionCriteria. The question posed for systematic review was thefollowing: What is the effect of IV lidocaine on ICP in

Hindawi Publishing CorporationCritical Care Research and PracticeVolume 2015, Article ID 485802, 12 pageshttp://dx.doi.org/10.1155/2015/485802

2 Critical Care Research and Practice

patients with neurological illness? We posed this broadquestion so as to include all eligible studies with objective ICPdocumentation during IV lidocaine administration, since wesuspected the literature to be scarce.

All studies, prospective and retrospective, were included.Studies of any language were included, with relevantmanuscripts translated in order to ensure that they metthe predefined inclusion/exclusion criteria. The reason foran all-inclusive search was based on the small number ofstudies of any type identified by the primary author duringa preliminary search of MEDLINE.

The primary outcome measure was documented effectof IV lidocaine on ICP. Secondary outcome measures werepatient outcomes and adverse effects of lidocaine therapy.

Inclusion criteria were all studies including human sub-jects with neurological illness, prospective or retrospectivestudies of any size, any age category, any language, the use ofIV lidocaine, and documentation of ICP response. Exclusioncriteria were animal studies, those studies not documentingthe ICP response, and the use of LT lidocaine only.

2.2. Search Strategy. MEDLINE, BIOSIS, EMBASE, GlobalHealth, SCOPUS, and Cochrane Library from inceptionto March 2015 were searched using individualized searchstrategies for each database. The search strategy for MED-LINE can be seen in Appendix A of the supplementarymaterial (see Supplementary Material available online athttp://dx.doi.org/10.1155/2015/485802), with a similar searchstrategy utilized for the other databases. In addition, theWorld Health Organization’s International Clinical Tri-als Registry Platform and https://clinicaltrials.gov/ weresearched looking for studies planned or underway.

In addition, meeting proceedings for the last 5 yearslooking for ongoing and unpublished work based on lido-caine therapy in neurological patientswere examined by handsearching the published proceedings for individual meet-ings. Both electronic and paper publications were searchedwhen available. The meeting proceedings of the followingprofessional societies were searched: Canadian Neurologi-cal Sciences Federation (CNSF), American Association ofNeurological Surgeons (AANS), Congress of NeurologicalSurgeons (CNS), European Neurosurgical Society (ENSS),World Federation of Neurological Surgeons (WFNS), Amer-ican Neurology Association (ANA), American Academy ofNeurology (AAN), European Federation of NeurologicalScience (EFNS),World Congress of Neurology (WCN), Soci-ety of Critical Care Medicine (SCCM), Neurocritical CareSociety (NCS), World Federation of Societies of Intensiveand Critical Care Medicine (WFSICCM), American Societyfor Anesthesiologists (ASA), World Federation of Societiesof Anesthesiologist (WFSA), Australian Society of Anesthe-siologists, International Anesthesia Research Society (IARS),Society of Neurosurgical Anesthesiology and Critical Care(SNACC), Society for Neuroscience in Anesthesiology andCritical Care, and the Japanese Society of Neuroanesthesiaand Critical Care (JSNCC).

Finally, reference lists of any review articles or systematicreviews on IV lidocaine, or ICP control, in neurologically illpatients were reviewed for relevant studies.

2.3. Study Selection. Utilizing two reviewers (F. A. Zeilerand N. Sader), a two-step review of all articles returnedby our search strategies was performed. First, the reviewersindependently screened all titles and abstracts of the returnedarticles to decide if they met the inclusion criteria. Second,full text of the chosen articles was then assessed to confirm ifthey met the inclusion criteria and that the primary outcomeof ICP response was reported in the study. Any discrepanciesbetween the two reviewers were resolved by discussion and athird party (C. J. Kazina) if necessary.

2.4. Data Collection. Data was extracted from the selectedarticles and stored in an electronic database. Data fieldsincluded patient demographics, type of study (prospectiveor retrospective), number of patients, dose of lidocaine,duration of therapy, effect on ICP, adverse effects, and patientoutcome.

2.5. Quality of Evidence Assessment. Assessment of the levelof evidence for each included study was conducted by twoindependent reviewers (F. A. Zeiler andC. J. Kazina), utilizingthe Oxford criteria [19] and the Grading of RecommendationAssessment Development and Education (GRADE) criteria[20–25] for level of evidence. We elected on utilizing twodifferent systems to grade level of evidence given the factthat these two systems are amongst the most commonly usedsystems. We believe this would allow a larger audience tofollow our systematic approach in the setting of unfamiliaritywith a particular grading system.

TheOxford criteria consist of a 5-level grading system forliterature. Level 1 is split into subcategories 1a, 1b, and 1cwhichrepresent a systematic review of randomized control trials(RCT) with homogeneity, individual RCTwith narrow confi-dence interval, and all or none studies, respectively. Oxfordlevel 2 is split into 2a, 2b, and 2c representing systematicreview of cohort studies with homogeneity of data, individualcohort study or low quality RCT, and outcomes research,respectively. Oxford level 3 is split into 3a and 3b representingsystematic review of case-control studies with homogeneityof data and individual case-control study, respectively.Oxfordlevel 4 represents case-series and poor cohort studies. Finally,Oxford level 5 represents expert opinion.

The GRADE level of evidence is split into 4 levels: A,B, C, and D. GRADE level A represents high evidencewith multiple high quality studies having consistent results.GRADE level B represents moderate evidence with one highquality study, or multiple low quality studies. GRADE level Cevidence represents low evidence with one or more studieswith severe limitations. Finally, GRADE level D representsvery low evidence based on either expert opinion or fewstudies with severe limitations.

Any discrepancies between the grading of the two review-ers were resolved via discussion and a third reviewer whenrequired.

2.6. Statistical Analysis. A meta-analysis was not performedin this study due to the heterogeneity of data and study designwithin the articles identified.

Critical Care Research and Practice 3

Total number of articles fromdatabase and other sources

470

Articles from database search

466

Articles from search of other sources

4

Articles after duplicate removal

414

Articles after application of inclusion/exclusion criteria to

title and abstract (1stscreening):

39

Articles after application of inclusion/exclusion criteria to full text (2nd screening):11 articles (10 original articles, with 1 companion pub.)

Duplicates removed 56

375 removed because of thefollowing:(i) 49 non-English studies that

were nonrelevant(ii) 22 animal studies

(iii) 304 nonrelevant

29 removed because of thefollowing:

(i) 11 review articles(ii) 3 LT lidocaine only

(iii) 1 no mention of IV lidocaine effect on ICP after treatment

(iv) 1 animal study(v) 13 nonrelevant

1 added from reference sections

Figure 1: Flow diagram of search results.

3. Results

The results of the search strategy across all databases andother sources are summarized in Figure 1. Overall a totalof 470 articles were identified, with 466 from the databasesearch and 4 from the search of published meeting pro-ceedings. A total of 56 were removed due to duplicationof reference, leaving 414 to review. By applying the inclu-sion/exclusion criteria to the title and abstract of these arti-cles, we identified 39 articles that fit these criteria. An addi-tional 1 article was added from reference sections of pertinentreview articles, leaving a total of 40 fullmanuscripts to review.Of the 40 identified, 36 were from the database search and4 were from published meeting proceedings. Applying theinclusion/exclusion criteria to the full text documents, only11 articles were eligible for inclusion in the systematic review,with 8 fromdatabase and 3 frommeeting proceeding sources.The 29 articles thatwere excludedwere done so because eitherthey did not report details around IV lidocaine administra-tion, there was no documentation of ICP, they were reviewarticles, or they were nonrelevant basic science articles.

Of the 11 articles identified, one article was a companionabstract publication [9] to a formal manuscript publication[8]. The data from this companion abstract [9] was includedin the tables for completeness only and was not included inthe data synthesis in order to prevent duplication of patient

data. Thus, 10 original articles were included in the datareview and data analysis. Two of the manuscripts were non-English papers requiring translation [13, 14], with one beingFrench [14] and the other Italian [13].

Of the 10 original articles included in the review [6–8, 10–16], all were prospective studies. There were 4 prospectiveRCT [7, 10, 11, 14], 2 prospective nonrandomized trials [6, 12],and 4 prospective cohort studies [8, 13, 15, 16].

Four of the articles [8, 13, 15, 16] focused on achievingthe ICP response to IV lidocaine in severe traumatic braininjury (TBI) patient populations, while 3 articles describedmalignant elective brain tumor patients [6, 7, 11], and 1 studymentioned hydrocephalus patients with elevated ICP10. Twostudies failed to detail the patient populations and statedthey were “post-operative neurosurgical patients” or “electiveoperative neurosurgical patients” and also failed to indicate ifthe patients had elevated ICP prior to lidocaine administra-tion [12, 14]. The ICP was recorded via cranial monitoring inall but 1 study, which utilized lumbar cisternal pressure [14].

Overall, there were 189 patients across the 10 stud-ies included in the review, with 133 given IV lidocaineand 56 serving as controls. The control patients wereadministered the following: esmolol (11), LT lidocaine(11), thiopental (10), placebo (10), steroid/glycerin (7), andsteroids/glycerin/nitroglycerin (7).


There were 54 severe TBI patients, 62 elective tumorpatients, and 30 hydrocephalus patients undergoing ven-triculoperitoneal shunt (VPS) placement, and 43 patientswere listed as “post-operative neurosurgical patients” [12] or“elective operative neurosurgical patients” [14].

The average age across all studies was 34.6 to 55 years.Five studies failed to document patient age [8, 10–12, 15].Study demographics and patient characteristics can be seenin Table 1, while treatment characteristics and effect on ICPand adverse events are reported in Table 2.

3.1. IV Lidocaine Treatment Characteristics. Within the 10studies identified [6–8, 10–16], 4 were prospective RCT [7, 10,11, 14]. The first study [7] compared IV lidocaine (𝑛 = 10)versus saline placebo (𝑛 = 10) pretreatment, in elective tumorpatients undergoing surgery, to determine the effect on ICPcontrol during laryngoscopy. The dose of lidocaine used wasa single 1.5mg/kg IV bolus. The second study [10] compared3 different IV lidocaine doses, in patients with hydrocephalusand elevated ICP, in order to determine the effect on ICPonce the patient was under a general anesthetic. The doses oflidocaine studied were 1mg/kg IV (𝑛 = 10), 1.5mg/kg IV (𝑛 =10), and 2mg/kg IV (𝑛 = 10). The third study [11] comparedIV lidocaine (𝑛 = 11) to LT lidocaine (𝑛 = 11), in electivetumor patients, in order to determine the effect on ICPduringlaryngoscopy. The doses of lidocaine used were 1.5mg/kgIV bolus and 4mL of 4% lidocaine instilled directly. Thefourth study [14] compared pretreatment with IV lidocaine(𝑛 = 10) versus IV esmolol (𝑛 = 10), in elective operativeneurosurgical patients, in order to determine the effect onICP (measured via lumbar drain) during laryngoscopy. Thedoses of the medication used were lidocaine 1.5mg/kg IVsingle dose and esmolol 1.5mg/kg IV single dose.

There were 2 prospective nonrandomized studies [6,12]. The first study [6] compared IV lidocaine (𝑛 = 10)versus thiopental (𝑛 = 10), in elective tumor operationswith sustained ICP elevations after induction, in order todetermine the impact on ICP control. The doses of medi-cation studied were lidocaine 1.5mg/kg IV single dose andthiopental 3mg/kg IV single dose. The second study [12]compared steroids/glycerin/IV lidocaine (𝑛 = 7) versussteroids/glycerin (𝑛 = 7) and steroids/glycerin/nitroglycerin(𝑛 = 7), in postoperative neurosurgical patients, inorder to determine the impact on ICP control. All patientsreceived dexamethasone 5–10mg three times daily andglycerin 200 gm/day. The doses of lidocaine and nitroglyc-erin were 1.5–3mg/kg/min IV continuous infusion and 3–7mcg/kg/min continuous infusion, respectively. The dura-tion of the continuous infusions was not specified.

Four prospective cohort studies [8, 13, 15, 16] evaluatedthe effects of IV lidocaine on ICP control. The first study [8]prospectively followed 10 severe TBI patients with refractoryICP issues.This study documented the effects of pretreatmentwith 1.5mg/kg single bolus IV lidocaine and saline boluses inevery patient, in order to determine the impact on ICP duringsuctioning. The second study [13] prospectively followed 20severe TBI patients with refractory ICP and compared theeffect of no lidocaine, IV lidocaine, and LT lidocaine beforetreatment on ICP during suctioning in all patients.The doses

of lidocaine used were 1.5mg/kg IV single dose and 2 mLof 5% lidocaine instilled directly via the endotracheal tube.The third study [15] prospectively followed 15 severe TBIpatients with refractory ICP and compared the effects ofa variety of pretreatments (saline, fentanyl, thiopental, IVlidocaine/succinylcholine, and LT lidocaine) on ICP controlduring suctioning. The dose of lidocaine used was 1.5mg/kgIV single bolus and LT 1.5mg/kg instilled directly. Thefinal study [16] prospectively followed 9 severe TBI patientsto determine the effects of pretreatment with IV and LTlidocaine impacted ICP control during suctioning. Both IVand LT were administered in all patients during separateperiods. The dose of lidocaine used was 1.5mg/kg IV singledose and 2 mL of 4% lidocaine single direct instillation.The lidocaine was administered at different intervals prior tosuctioning: 1, 3, 5, 10, and 15 minutes.

Seven studies evaluated IV lidocaine in a prophylacticmanner prior to stimulation [7, 8, 11, 13–16], in order todetermine the drugs ability to attenuate ICP elevations.Threestudies evaluated IV lidocaine in a therapeutic manner, inorder to determine the potential ICP reduction effects of thedrug [6, 10, 12].The lidocaine treatment characteristics can beseen in Table 2.

3.2. ICP Response

3.2.1. Pretreatment Regimens. Among the 4 RCT [7, 10, 11, 14]manuscripts identified, 3 studies focused on pretreatmentwith IV lidocaine prior to laryngoscopy or suctioning [7, 11,14]. The first study [7], comparing lidocaine to placebo, dis-played an attenuation of ICP elevation favoring IV lidocaine.The lidocaine group displayed a max mean ICP elevationof 6mmHg, versus 16mmHg in the placebo group. Thesecond study [11] comparing IV versus LT lidocaine displayeda significant reduction in baseline ICP in the IV group andattenuation of ICP elevation during laryngoscopy in the IVgroup.The LT lidocaine group displayed no effect on ICP.Thethird study [14] compared IV lidocaine versus esmolol andfailed to display a difference in either group on ICP control.Both lidocaine and esmolol pretreatment failed to attenuateICP elevations with intubation.

Within the 4 prospective cohort studies identified [8, 13,15, 16], all focused on pretreatment with IV lidocaine priorto endotracheal suctioning. Two displayed a suppression ofICP elevations with IV lidocaine [8, 16], while the other 2failed to demonstrate an attenuation of this response with IVlidocaine [13, 15]. However, one study which failed to displayan attenuation of ICP during suctioning, did show a baselinereduction in ICP by 4–6mmHg prior to stimulation [15].

3.2.2. Therapeutic Regimens. One RCT study was identifiedwhich studied the therapeutic effect of IV lidocaine on ICP[10]. This study compared different doses of lidocaine inhydrocephalus patients and displayed a significant reductionin ICP from baseline in all groups studied. The study alsodisplayed a dose-dependent ICP reduction effect with thelowest dose (1.0mg/kg) and the highest dose (2mg/kg)displaying a 17.5% and 37.5% reduction, respectively.


Table1:Stud

ycharacteris

ticsa

ndpatie

ntdemograph

ics.

Reference

Num

bero

fpatients

Stud

ytype

Article

locatio

nMeanage(years)

Patie

ntcharacteris

tics

Prim

aryandsecond

arygoalof

study

Bedford

etal.[6]

20Lidocaine(𝑛=10)

Thiopental(𝑛=10)

Prospective

nonrando

mized

ManuscriptLidocaine=

51.1±4.4

Thiopental=47.5±5.0

Braintumorsu

ndergoingele

ctiver

esectio

nhaving

susta

ined

ICPele

vatio

nsfor>

30sec

after

indu

ction

Anesthetic:

thiopental,n

itrou

soxide/O2,

andmorph

ine

Prim

ary:to

determ

inethe

effecto

fIV

lidocaine

versus

thiopentalon

ICP

controlfor

sustainedICPele

vatio

nsSecond

ary:no

nesta

ted

Bedford

etal.[7]

20Lidocaine(𝑛=10)

Placebo(𝑛=10)

Prospective

rand

omized

controltria

l

Meetin

gabstr

act

Lidocaine=

49±6

Placebo=55±6

Braintumorsu

ndergoingele

ctiver

esectio

nAn

esthetic:

thiopental,n

itrou

soxide/O2,

andmorph

ine

Prim

ary:to

determ

inethe

effecto

fIV

lidocaine

versus

salin

e(atindu

ction)

onICPdu

ringlaryngoscopy

Second

ary:no

nesta

ted

Don

egan

and

Bedford

[8]

10Prospective

coho

rtManuscript

Unk

nown

Severe

TBIw

ithICP>20

mmHgdu

ring

suctioning

Concurrent

ICPtherapy:hyperventilation

(pCO2goal30

mmHg),m

annitol,

dexamethasone,and

pentob

arbital(𝑛=5)

Prim

ary:to

determ

inethe

effecto

fIV

lidocaine

versus

salin

eonICPdu

ring

suctioning

Second

ary:no

tstated

∗Don

egan

etal.[9]

9Prospective

coho

rtMeetin

gabstr

act

Unk

nown

Severe

TBIw

ithICP>20

mmHgdu

ring

suctioning

Concurrent

ICPtherapy:hyperventilation

(pCO2goal30

mmHg),m

annitol,

dexamethasone,and

pentob

arbital(𝑛=5)

Prim

ary:to

determ

inethe

effecto

fIV

lidocaine

versus

salin

eonICPdu

ring

suctioning

Second

ary:no

tstated

Grover

etal.[10]

30Prospective

rand

omized

trial

Manuscript

Age>5years

Clinicallyraise

dICPandun

dergoing

VPS

surgery

Anesthetic:

thiopentalindu

ctionwith

suxametho

nium

NMBA

Maintenance

with

66%nitro

usoxide/oxygen

mix,pancuronium

,and

morph

ine

Prim

ary:to

determ

inethe

effecto

fdifferent

IVlid

ocaine

doseso

nICP

Second

ary:no

tstated

Ham

illetal.[11]

22LT

Lidocaine(𝑛=11)

IVLidocaine(𝑛=11)

Prospective

rand

omized

trial

Manuscript

Unk

nown

Braintumorsu

ndergoingele

ctiver

esectio

nAn

esthetic:

thiopental,succinylch

oline,and

50%nitro

usoxide/oxygen

mix

Prim

ary:to

determ

inee

ffectof

LTversus

IVlid

ocaine

onICPdu

ringlaryngoscopy

Second

ary:HRandMABP

Hira

yama

etal.[12]

21patie

nts

Steroid/gly

cerin

(𝑛=7)

Steroid/gly

cerin

/lidocaine(𝑛=7)

Steroid/gly

cerin

/nitroglyc

erin

(𝑛=7)

Prospective

nonrando

mized

Meetin

gabstr

act

Unk

nown

“Postoperativ

e”neurosurgery

patie

nts

Concurrent

ICPtherapy:dexamethasone

5–10mgTID,glycerin

200g

m/day

Prim

ary:to

determ

inethe

effectsof

IVlid

ocaine

versus

nitro

glycerin

onICP

Second

ary:no

tstated


Table1:Con

tinued.

Reference

Num

bero

fpatients

Stud

ytype

Article

locatio

nMeanage(years)

Patie

ntcharacteris

tics

Prim

aryandsecond

arygoalof

study

Mon

tarry

etal.[13]

20Prospective

coho

rtManuscript

32

Severe

TBI

Concurrent

ICPtherapy:

thiopental,m

aintainednegativ

efluid

balance,pC

O2goal28

mmHg

Prim

ary:to

determ

inethe

effectsof

IVversus

LTlid

ocaine

onICPcontrol

durin

gendo

trachealsuctioning

Second

ary:cerebralperfusionpressure

Samaha

etal.[14]

22Esmolol(𝑛=11)

Lidocaine(𝑛=11)

Prospective

rand

omized

trial

Manuscript

Esmolol:50±13

Lidocaine:47±16

Electiv

eneurosurgicalpatie

nts(tumors

andaneurysm

clipp

ings)

∗ICPmeasuredviaLD

Anesthetic:

thiopentalindu

ction,

sevoflu

rane,

maintenance,pCO2goal33–35m

mHg

Prim

ary:to

determ

inethe

effecto

fesmololversus

lidocaine

IVbo

lus(130s

ecbefore

intubatio

n)on

lumbarc

istern

pressuresd

uringlaryngoscopy

(ICP

measuredbefore,during,and2and5m

inaft

erintubatio

n)Second

ary:MABP

,CPP

White

etal.[15]

15Prospective

coho

rtManuscript

Unk

nown

Severe

TBIw

ithele

vatio

nsof

ICP>

20mmHgdu

ringor

immediatelyaft

ersuctioning

Concurrent

ICPtherapy:sedatio

nwith

diazepam

andmorph

ine,hyperventilation

(pCO225–30m

mHg)

Prim

ary:to

determ

inethe

effectsof

different

pretreatment(salin

e,fentanyl,

thiopental,lidocaine,and

succinylcholine)on

ICPdu

ring

suctioning

Second

ary:MABP

Yano

etal.

[16]

9Prospective

coho

rtManuscript

34.6(range:16to

71)

Severe

TBI

Concurrent

ICPtherapy:no

tspecific,

hyperventilated

topC

O2goalof

25to

30mmHg

Prim

ary:to

determ

inethe

effecto

fIVand

LTlid

ocaine

onICPdu

ringsuctioning

Second

ary:no

tstated

𝑛=nu

mbero

fpatients,HR=heartrate,MABP

=meanarteria

lblood

pressure,ICP

=intracranialpressure,C

PP=cerebralperfusionpressure,C

SF=cerebrospinalfl

uid,

mmHg=millim

eterso

fmercury,IV=

intra

veno

us,LT=laryngotracheal,TB

I=traumaticbraininjury,L

D=lumbard

rain,and

sec=second

.∗Don

egan

andBe

dford[8]a

ndDon

egan

etal.[9]

arecompanion

publications,w

ithDon

egan

etal.[9]

representin

gthem

eetin

gabstr

actp

ublishedpriortothefullm

anuscript[8].Th

edatafrom

Don

egan

etal.[9]

isno

tincludedin

thes

ynthesisof

dataandison

lyinclu

dedin

thetablesfor

completeness.


Table2:Lido

cainetreatmentcharacteristicsa

ndICPrespon

se.

Reference

Lido

cained

ose

Meandu

ratio

nof

lidocaine

administratio

n(days)

ICPrespon

seOther

prim

ary/second

ary

outcom

es

Adverse

effectsto

lidocaine

Con

clusio

ns

Bedford

etal.[6]

1.5mg/kg

IVbo

lusx

1(𝑛=10)

Thiopentaldose(𝑛=10)=

3mg/kg

IVx1

Sing

lebo

lus

dose

Lidocaine:decrease

inmeanICP

from

28mmHgto

13mmHg,with

nadirreached

atam

ean66±10sec

Thiopental:decreaseinmeanICP

from

33mmHgto

14mmHg,with

anadirreached

atam

ean48±9s

ec

MeanMABP

decrease

of26

mm

Hgwith

thiopental

NoMABP

changesw

ithlid

ocaine

Non

edescrib

ed

Lido

cainea

ndthiopental

aree

quallyan

effectin

redu

ctionof

ICPviaI

Vbo

lus,with

lidocaine

preserving

syste

mic

hemod

ynam

ics

Bedford

etal.[7]

1.5mg/kg

IVbo

lusx

1(𝑛=10)

Salin

e(𝑛=10)=

samev

olum

eSing

lebo

lus

dose

Pretreatmentw

ithIV

lidocaine

ledto

amaxim

ummeanICPincrease

of6m

mHgand4m

mHgat30

and

60sec

Salin

eplacebo

meanincrease

inICP

of16mmHgand13mmHgat30

and

60sec

MABP

increase

was

less

with

lidocaine

compared

toplacebo

Non

edescrib

ed

IVlid

ocaine

durin

glaryngoscopy

leadstoan

attenu

ationofICPele

vatio

ncomparedto

salin

e.

Don

egan

and

Bedford

[8]

1.5mg/kg

IVbo

lusx

1Salin

ewas

givenin

thesam

evolum

eas

lidocaine

Patientsreceiv

edboth

therapies

Sing

lebo

lus

dose

Lido

cainep

resuctionledto

amean

increase

inICPof

3.4±6.2m

mHg

and1.8±2.6m

mHgin

thoseo

nand

offbarbitu

ratesd

uringsuctioning

Salin

eplacebo

presuctio

nledto

ameanincrease

inICP19±4.7m

mHg

and5.7±3.2m

mHgin

thoseo

nand

offbarbitu

ratesd

uringsuctioning

Nosig

nificantd

ifference

inMABP

changes

durin

gsuctioning

Non

edescrib

ed

Lido

cainep

resuctioning

leadstoan

attenu

ationof

ICPele

vatio

nscomparedto

salin

e

∗Don

egan

etal.[9]

1.5mg/kg

IVbo

lusx

1Salin

ewas

givenin

thesam

evolum

eas

lidocaine

Patientsreceiv

edboth

therapies

Sing

lebo

lus

dose

Lido

cainep

retre

atmentled

toa

significantatte

nuationin

ICP

elevationwith

suctioning

Not

stated

Non

edescrib

ed

Lido

cainep

resuctioning

leadstoan

attenu

ationof

ICPele

vatio

nscomparedto

salin

e

Grover

etal.[10]

Threeg

roup

s:Group

1(𝑛=10):1m

g/kg

IVbo

lusx

1Group

2(𝑛=10):1.5

mg/kg

bolusx

1Group

3(𝑛=10):2m

g/kg

bolusx

1

Sing

lebo

lus

dose

Allgrou

psdisplayedas

ignificant

decrease

inICPwith

in2m

inof

lidocaine

administratio

nGroup

3display

eda3

7.5%redu

ction

inmeanICP,andGroup

1disp

layeda

17.5%

meanredu

ction

Group

3was

theo

nly

grou

pto

display

significantd

ropin

SBP

SBP

decreased

with

2mg/kg

IVbo

lus

dose

IVlid

ocaine

bolusleads

tosig

nificantreductio

nsin

ICPHighlid

ocaine

dosin

gmay

lead

todrop

sinSB

P

Ham

illetal.[11]

LT(𝑛=11):4m

L4%

lidocaine

endo

tracheal

IV(𝑛=11):1.5

mg/kg

IVbo

lusx

1Sing

ledo

se

IVlid

ocaine

ledto

asignificant

decrease

inbaselin

eICP

with

noele

vatio

nsdu

ringlaryngoscopy

LTlid

ocaine

failedto

decrease

ICP

andallp

atientsh

adas

ignificant

elevationin

ICPdu

ringintubatio

n

Sign

ificant

HRand

MABP

increase

inLT

grou

p

Non

edescrib

ed

IVlid

ocaine

ledto

decrease

inbaselin

eICP

and

attenu

ated

ICPele

vatio

nsdu

ringlaryngoscopy


Table2:Con

tinued.

Reference

Lido

cained

ose

Meandu

ratio

nof

lidocaine

administratio

n(days)

ICPrespon

seOther

prim

ary/second

ary

outcom

es

Adverse

effectsto

lidocaine

Con

clusio

ns

Hira

yama

etal.[12]

Allhaddexamethasone

andglycerin,

with𝑛=7thistherapyin

isolatio

n.Lido

caine(𝑛=7):10%lid

ocaine

continuo

usinfusio

nat1.5

–3mg/min

Nitroglycerin

e(𝑛=7):

3–7m

cg/kg/min

Con

tinuo

usinfusio

n

Thea

ddition

oflid

ocaine

toglycerin

therapyledto

areductio

nin

ICP

spikes,w

itham

eanredu

ctionin

ICP

of8.9m

mHgover

24ho

urs

Thea

ddition

ofnitro

glycerin

toglycerin

ledto

ameanredu

ctionof

ICPof

7.4mmHgover

24ho

urs

Not

stated

Non

edescrib

ed

Both

IVlid

ocaine

and

nitro

glycerin

inthe

presence

ofglycerin

therapylead

toICP

redu

ctions

at24

hours

Mon

tarry

etal.[13]

Allpatie

ntsu

nderwentsuctio

ning

with

outlidocaine,thenwith

IV,and

finallywith

LTLidocaineIV:

1.5mg/kg

of2%

lidocaine

bolusx

1Lidocaine

LT:5%

lidocaine

Sing

ledo

se

NodifferenceintheICP

over

6min

forn

olid

ocaine,ore

ither

ofthe

lidocaine

routes,duringsuctioning

.10

patie

ntsh

addo

cumentedICP>

20mmHgandhadthes

ame

lidocaine

treatment

LidocaineIVled

toamild

redu

ction

inICPover6m

inby

approx.2

mmHg

LTlid

ocaine

didnoth

avea

nysig

nificanteffectcomparedtobaselin

e

NodifferenceinCP

PNot

describ

ed

Lido

caineIVor

LTdidno

tlead

toas

uppressio

nof

ICP

durin

gsuctioning

Lido

caineIVbo

lusd

uring

acuteICP

elevations

may

lead

tomild

redu

ctionin

ICP.

Samaha

etal.[14]

Lidocaine:1.5

mg/kg

IVx1

Esmolol:1.5mg/kg

IVx1

Sing

ledo

se

Postintubatio

nICProse

significantly

inbo

thgrou

psEsmolol:increased

from

11±

6mmHgto

17±10mmHg

Lidocaine:increasedfro

m10±

6mmHgto

16±9m

mHg

Sign

ificant

decrease

inCP

Pin

both

grou

psdu

ringintubatio

nEsmololdecreasedfro

ma

meanof92

to62

mmHg

Lidocained

ecreased

from

ameanof96

to68

mmHg

Afterintubatio

nCP

Pincreasedto99±

23mmHga

nd99±

17mmHginthee

smolol

andlid

ocaine

groups

Not

describ

ed

Both

lidocaine

andesmolol

failedto

attenu

atethe

elevatio

nin

CPPandICP

after

intubatio

n

White

etal.[15]

Everypatie

ntreceived

alltreatments

durin

gindividu

alsuctioning

episo

des

Salin

e=2m

LFentanyl=1m

cg/kg

Thiopental=3m

g/kg

Lido

caine=

1.5mg/kg

+succinylcholine=

1.5mg/kg

Lido

caineL

Talon

e=1.5

mg/kg

Sing

lebo

lus

dose

Lido

caine/succinylcholineIVand

thiopentallead

toam

eandecrease

inICPby

4–6m

mHgbu

thad

noeffect

ontheICP

durin

gsuctioning

LTlid

ocaine

hadmoree

ffectat

attenu

atingcoug

handICPele

vatio

nsdu

ringsuctioning

.How

ever,during

instillationitinitiated

coug

hing

and

ledto

ICPspikes

Fentanylhadno

effecto

nICP

MABP

notaffected

byanyregimen

Non

edescrib

ed

Lido

caineIVleadstoICP

redu

ctionbu

tnot

attenu

ationof

coug

hmediatedICPspikes

LTlid

ocaine

may

besuperio

rinpreventin

gcoug

hing

related

ICPspikes


Table2:Con

tinued.

Reference

Lido

cained

ose

Meandu

ratio

nof

lidocaine

administratio

n(days)

ICPrespon

seOther

prim

ary/second

ary

outcom

es

Adverse

effectsto

lidocaine

Con

clusio

ns

Yano

etal.

[16]

1.5mg/kg

IVbo

lusd

osea

tthe

follo

wingintervalsp

riorto

suctioning

:1,3,5,10,and15min

LTlid

ocaine

=2m

Lof

4%lid

ocaine

acrossthes

ameintervals

Sing

lebo

lus

doses

Neither

IVof

LTlid

ocaine

lowered

baselin

eICP

,but

both

supp

ressed

ICPele

vatio

nswith

suctioning

LTlid

ocaine

ledto

alow

erpeak

ICP

comparedto

IV

Not

stated

Non

edescrib

ed

Both

IVandLT

lidocaine

supp

ressICPele

vatio

nsdu

ringsuctioning

𝑁=nu

mbero

fpatients,mg=milligram,m

cg=microgram

,mL=milliliters,w

t=weight,kg

=kilogram

,hr=

hour,m

in=minute,HR=heartrate,MABP

=meanarteria

lblood

pressure,ICP

=intracranial

pressure,C

PP=cerebralperfusionpressure,C

SF=cerebrospinalfluid,mmHg=

millim

eterso

fmercury,IV=intravenou

s,LT

=laryngotracheal,T

BI=traumaticbraininjury,LD=lumbard

rain,and

sec=

second

.∗Don

egan

andBe

dford[8]and

Don

egan

etal.[9]

arec

ompanion

publications,w

ithDon

egan

etal.[9]

representin

gthem

eetin

gabstr

actp

ublishedpriortothefullm

anuscript[8].Th

edatafrom

Don

egan

etal.[9]

isno

tincludedin

thes

ynthesisof

dataandison

lyinclu

dedin

thetables

forc

ompleteness.


Table 3: Oxford and GRADE level of evidence.

Reference Study type Oxford level of evidence GRADE level of evidenceBedford et al. [6] Prospective nonrandomized 2b BBedford et al. [7] Prospective randomized trial 2b BDonegan and Bedford [8] Prospective cohort 2b C∗Donegan et al. [9] Prospective cohort 2b CGrover et al. [10] Prospective randomized trial 2b BHamill et al. [11] Prospective randomized trial 2b BHirayama et al. [12] Prospective nonrandomized 2b CMontarry et al. [13] Prospective cohort 2b CSamaha et al. [14] Prospective randomized trial 2b BWhite et al. [15] Prospective cohort 2b CYano et al. [16] Prospective cohort 2b C∗Donegan and Bedford [8] and Donegan et al. [9] are companion publications, with Donegan et al. [9] representing the meeting abstract published prior tothe full manuscript [8]. The data from Donegan et al. [9] is not included in the synthesis of data and is only included in the tables for completeness.

Two nonrandomized trials studied the therapeutic effectof ICP lidocaine on ICP [6, 12]. The first displayed a meandecrease in ICP of 15mmHg, with a mean time to nadir of66 ± 10 seconds [6]. This was equivalent to the thiopentalcomparison group. The second trial studied IV lidocaine(with steroids and glycerine) versus steroids/glycerine andsteroids/glycerin/nitroglycerin [12]. The lidocaine group dis-played a mean ICP reduction of 8.9mmHg over 24 hoursof continuous infusion. The nitroglycerine group displayedsimilar results.

3.3. Adverse Effects of Lidocaine Therapy. Two studiesrecorded adverse events related to IV lidocaine therapy [10,14]. The first displayed a dose related decrease in systolicblood pressure, with this effect documented at a dose of2mg/kg [10].The second study displayed a trend to significantreductions in cerebral perfusion pressure during lidocaineadministration [14].

The remaining studies included in the review [6–8, 11–13, 15, 16] failed to document any events or clearly state that“there were no adverse events.”

3.4. FunctionalOutcome. Patient functional outcomewas notreported in any study, as the focus of the manuscripts was todetermine the ICP effects of lidocaine.

3.5. Level of Evidence. Based on two independent reviewers(F. A. Zeiler and C. J. Kazina), there were a total of 10studies reviewed. The question “What is the effect of IVlidocaine on ICP in patients with neurological illness?” wasevaluated based on the Oxford and GRADE criteria for levelof evidence.

3.5.1. Oxford Level of Evidence: Pretreatment Regimens. Fourstudies were Oxford level 2b [7, 8, 11, 16] evidence supportingan attenuation of ICP elevation with IV lidocaine pretreat-ment prior to stimulation.Three studies were Oxford level 2b[13–15] evidence against the attenuation of ICP elevation withIV lidocaine pretreatment.

3.5.2. Oxford Level of Evidence: Therapeutic Regimens. Threestudies were Oxford level 2b [6, 10, 12] evidence supporting adecrease in ICP when IV lidocaine is utilized in a therapeuticmanner.

3.5.3. GRADE Level of Evidence: Pretreatment Regimens. Twostudies were GRADE B [7, 11] and 2 were GRADE C [8, 16]evidence supporting an attenuation of ICP elevation with IVlidocaine pretreatment prior to stimulation. One study wasGRADEB [14] and twowereGRADEC [13, 15] evidence. Onestudy was GRADE level B [10] and 2 were GRADE level C[5, 7] evidence against the attenuation of ICP elevation withIV lidocaine pretreatment.

3.5.4. GRADE Level of Evidence: Therapeutic Regimens. Twostudies were GRADE B [6, 10] and 1 was GRADE C [12]evidence supporting a decrease in ICP when IV lidocaine isutilized in a therapeutic manner.

A summary of all levels of evidence for individual articlescan be seen in Table 3.

4. Discussion

Some important aspects of IV lidocaine therapy in theneurological population have been emphasized during thisreview. First, there lacks convincing evidence to suggest thatIV lidocaine, when utilized as a pretreatment for stimulation(laryngoscopy/suctioning), has any impact on the attenuationof ICP spikes. There exists evidence to both support andrefute this. Second, there exists evidence, though limited,to suggest an ICP reduction effect of IV lidocaine whenused as a therapeutic measure. This ICP reduction effect wasdisplayed in both patients with and without elevated ICP.However, there lacks objective evidence to suggest that eithera reduction in cerebral metabolism, or cerebral vasoconstric-tion, are mechanisms leading to this ICP reduction. Third,comments on the ICP reduction effect of IV lidocaine whenutilized therapeutically can only be made for bolus dosingalone. Only 1 study was identified using continuous infusions


of lidocaine. Fourth, hypotension seems common with IVlidocaine therapy when utilized in both a pretreatmentand therapeutic fashion. This hypotensive effect seems dosedependent [10]. Finally, patient outcome secondary to IVlidocaine therapy cannot be made at this time.

Several important limitations exist to this study. First,there were a small number of studies, making the con-clusions of this review difficult to generalize to all neuro-logical patients. Furthermore, the 43 patients had unclearneuropathology identified within the studies thus making ithard to determine if there was a pathology specific benefitto lidocaine therapy. Third, the use of other ICP directedmedical therapies during lidocaine administration makesinterpreting the data on ICP response difficult. The majorityof the studies did not detail the other therapies that werebeing administered. Fourth, given the absence of outcomedata reported, we cannot make any comments on the impactof IV lidocaine on functional outcome. Fifth, the degree oftherapies applied to the TBI, hydrocephalus, and brain tumorpatient populations were likely dramatically different. A fulloutline of ICP therapies was not present in the majorityof studies, and this suspected variation between separatepathologies limits our ability to generalize the results forall patients with neurological illness. Finally, there is likelya significant publication bias with only those studies withpositive results making it to publication within the literature.

Through this review, the ICP response to IV lidocainehas been thoroughly outlined. The current literature doesnot strongly support a “protective effect” of IV lidocaineduring laryngoscopy/suctioning.Thepotential ICP reductioneffect of IV lidocaine when used as a therapeutic measureseems to exist, though the exact mechanism is unclear.Further prospective trials need to be conducted to confirmthe efficacy of IV lidocaine in both the pretreatment andtherapeutic settings.

Future study should focus on the severe TBI popula-tion with lidocaine use both as a bolus dose based ICPreduction agent and in the context of a continuous infusion.The potential benefit of bolus based regimens could beassessed via comparing IV lidocaine bolus to either sedationbolus or hypertonic/hyperosmotic solutions bolus. Similarly,the continuous infusion dosing regimen for ICP reductioncould be assessed in a prospective randomized fashion withimplementation during crisis. One could also foresee thepotential for early implementation of continuous IV lidocaineas a prophylactic measure for ICP reduction, in an attemptto reduce the sedation and hypertonic/hyperosmotic agentrequirements.

Final Recommendations. Overall, we cannot make a strongdefinitive recommendation on the effectiveness of pretreat-ment IV lidocaine for the attenuation of ICP elevationsduring stimulation.There isOxford 2b,GRADEB level of evi-dence supporting both the attenuation of ICP increases, andno impact on ICP control, with pretreatment IV lidocaine.

Therapeutic use of IV lidocaine for ICP reduction cur-rently displays Oxford 2b, GRADE B evidence supportingICP reduction with lidocaine administration.

5. Conclusions

There lacks strong literature to support the effectivenessof pretreatment IV lidocaine for the attenuation of ICPelevations during stimulation. There is Oxford 2b, GRADEB level of evidence supporting both the attenuation of ICPincreases, and no impact on ICP control, with pretreat-ment IV lidocaine. Therapeutic use of IV lidocaine for ICPreduction currently displays Oxford 2b, GRADE B evidencesupporting ICP reduction with lidocaine administration.

Conflict of Interests

The authors have no conflict of interests.

Authors’ Contribution

F. A. Zeiler contributed in the study design, data acquisition,data analysis, and paper composition. N. Sader contributedin data acquisition and data analysis. C. J. Kazina contributedin data analysis and paper composition.

References

[1] N. Stocchetti and A. I. R. Maas, “Traumatic intracranial hyper-tension,”The New England Journal of Medicine, vol. 370, no. 22,pp. 2121–2130, 2014.

[2] J. J. Brucia, D. C. Owen, and E. B. Rudy, “The effects of lidocaineon intracranial hypertension,” The Journal of NeuroscienceNursing, vol. 24, no. 4, pp. 205–214, 1992.

[3] P. Scheinberg, H. W. Jayne, L. I. Blackburn, and M. Rich,“Studies of cerebral circulatory functions following intravenousadministration of procaine hydrochloride,” Archives of Neurol-ogy and Psychiatry, vol. 68, no. 6, pp. 815–818, 1952.

[4] T. Sakabe, T. Maekawa, T. Ishikawa, and H. Takeshita, “Theeffects of lidocaine on canine cerebral metabolism and circu-lation related to the electroencephalogram,”Anesthesiology, vol.40, no. 5, pp. 433–441, 1974.

[5] T.-Y. Lin, C.-Y. Chung, C.-W. Lu, S.-K. Huang, J.-S. Shieh, andS.-J. Wang, “Local anesthetics inhibit glutamate release from ratcerebral cortex synaptosomes,” Synapse, vol. 67, no. 9, pp. 568–579, 2013.

[6] R. F. Bedford, J. A. Persing, L. Pobereskin, and A. Butler,“Lidocaine or thiopental for rapid control of intracranial hyper-tension?” Anesthesia and Analgesia, vol. 59, no. 6, pp. 435–437,1980.

[7] R. F. Bedford, H. R. Winn, G. Tyson, T. S. Park, and J. A. Jane,“Lidocaine prevents increased ICP after endotracheal intuba-tion,” in Intracranial Pressure IV, K. Shulman, A. Marmarou, J.D. Miller, D. P. Becker, G. M. Hochwald, and M. Brock, Eds., p.595, Springer, Berlin, Germany, 1980.

[8] M. F. Donegan and R. F. Bedford, “Intravenously administeredlidocaine prevents intracranial hypertension during endotra-cheal suctioning,” Anesthesiology, vol. 52, no. 6, pp. 516–518,1980.

[9] M. Donegan, R. F. Bedford, and R. Dacey, “IV lidocaine forprevention of intracranial hypertension,”Anesthesiology, vol. 51,no. 3, article S201, 1979.

[10] V. K. Grover, G. M. S. R. Reddy, V. K. Kak, and S. Singh,“Intracranial pressure changeswith different doses of lignocaine


under general anaesthesia,” Neurology India, vol. 47, no. 2, pp.118–121, 1999.

[11] J. F. Hamill, R. F. Bedford, D. C. Weaver, and A. R. Colo-han, “Lidocaine before endotracheal intubation: intravenous orlaryngotracheal?” Anesthesiology, vol. 55, no. 5, pp. 578–581,1981.

[12] A. Hirayama, S. Yamasaki, and K. Miyata, “A pilot study onpostoperative ICP control by glycerin combined with lidocaineor nitroglycerin,” in Intracranial Pressure VIII, C. J. J. Avezaat, J.H. M. van Eijndhoven, A. I. R. Maas, and J. T. J. Tans, Eds., pp.609–611, Springer, Berlin, Germany, 1993.

[13] M. Montarry, J. F. Poussel, F. Artru, and R. Chacornac, “Lido-caine protection of the pressure of cerebral perfusion in trachealstimulation,” Minerva Anestesiologica, vol. 51, no. 7-8, pp. 405–410, 1985.

[14] T. Samaha, P. Ravussin, C. Claquin, and C. Ecoffey, “Preventionde l’augmentation de la pression arterielle et de la pres-sion intracranienne lors de l’intubation endotracheale enneurochirurgie: esmolol versus lidocaıne,” Annales Francaisesd’Anesthesie et de Reanimation, vol. 15, no. 1, pp. 36–40, 1996.

[15] P. F. White, R. M. Schlobohm, L. H. Pitts, and J. M. Lindauer, “Arandomized study of drugs for preventing increases in intracra-nial pressure during endotracheal suctioning,” Anesthesiology,vol. 57, no. 3, pp. 242–244, 1982.

[16] M. Yano, H. Nishiyama, H. Yokota, K. Kato, Y. Yamamoto, andT. Otsuka, “Effect of lidocaine on ICP response to endotrachealsuctioning,” Anesthesiology, vol. 64, no. 5, pp. 651–653, 1986.

[17] J. P. T. Higgins and S. Green, Eds., Cochrane Handbookfor Systematic Reviews of Interventions Version 5.1.0, 2013,http://handbook.cochrane.org.

[18] D. Moher, A. Liberati, J. Tetzlaff, and D. G. Altman, “Preferredreporting items for systematic reviews and meta-analysis: thePRISMA statement,” Annals of Internal Medicine, vol. 151, no. 4,pp. 264–269, 2009.

[19] B. Phillips, C. Ball, D. Sackett, S. Straus, B. Haynes, and M.Dawes, “Oxford Centre for Evidence-Based Medicine Levels ofEvidence,” 2009, http://www.cebm.net/?o=1025.

[20] G. H. Guyatt, A. D. Oxman, G. E. Vist et al., “GRADE: anemerging consensus on rating quality of evidence and strengthof recommendations,” British Medical Journal, vol. 336, no.7650, pp. 924–926, 2008.

[21] G. H. Guyatt, A. D. Oxman, R. Kunz, G. E. Vist, Y. Falck-Ytter,andH. J. Schunemann, “Rating quality of evidence and strengthof recommendations: what is ‘quality of evidence’ and why is itimportant to clinicians?” British Medical Journal, vol. 336, no.7651, pp. 995–998, 2008.

[22] H. J. Schunemann, A. D. Oxman, J. Brozek et al., “GRADE:Grading quality of evidence and strength of recommendationsfor diagnostic tests and strategies,” British Medical Journal, vol.336, no. 7653, pp. 1106–1110, 2008.

[23] G. H. Guyatt, A. D. Oxman, R. Kunz et al., “Rating quality ofevidence and strength of recommendations: incorporating con-siderations of resources use into grading recommendations,”The British Medical Journal, vol. 336, no. 7654, pp. 1170–1173,2008.

[24] G. H. Guyatt, A. D. Oxman, R. Kunz et al., “Rating qualityof evidence and strength of recommendations: going fromevidence to recommendations,”TheBritishMedical Journal, vol.336, no. 7652, pp. 1049–1051, 2008.

[25] R. Jaeschke, G. H. Guyatt, P. Dellinger et al., “Use of GRADEgrid to reach decisions on clinical practice guidelines whenconsensus is elusive,” BMJ, vol. 337, article a744, 2008.

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Review Article The Impact of Intravenous Lidocaine on ICP in ...Review Article The Impact of...

Documents

Transcript of Review Article The Impact of Intravenous Lidocaine on ICP in ...Review Article The Impact of...