efficacy of ketamine in anesthetic dosage for the ... · with crps have concomitant peripheral...
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Efficacy of Ketamine in Anesthetic Dosage for the Treatment ofRefractory Complex Regional Pain Syndrome: An Open-LabelPhase II Study
Ralph-Thomas Kiefer, MD,* Peter Rohr, MD,† Annette Ploppa, MD,* Hans-Jürgen Dieterich, MD,*John Grothusen, PhD,§ Sandra Koffler, PhD,¶ Karl-Heinz Altemeyer, MD,† Klaus Unertl, MD,* andRobert J. Schwartzman, MD§
*Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany; †Departmentof Anesthesiology, Intensive Care and Emergency Medicine and Pain Therapy, Klinikum Saarbrücken, Teaching HospitalUniversity of the Saarland, Saarbrücken, Germany; Departments of §Neurology, ¶Psychiatry, Drexel University College ofMedicine, Hahneman University Hospital, Philadelphia, PA, USA
A B S T R A C T
Objective. Advanced complex regional pain syndrome (CRPS) remains very difficult to treat. Whilesubanesthetic low-dose ketamine has shown promise in early localized CRPS, its use in advancedCRPS has not been as effective. Since ketamine’s analgesic potency and duration of effect inneuropathic pain are directly dose-dependant, we investigated the efficacy of ketamine in anestheticdosage in refractory CRPS patients that had failed available standard therapies.
Methods. Twenty ASA I-III patients suffering from refractory CRPS received ketamine in anestheticdosage over 5 days. Outcome criteria were pain relief, effect on the movement disorder, quality oflife, and ability to work at baseline and up to 6 months following treatment.
Results. Significant pain relief was observed at 1, 3, and 6 months following treatment(93.5 � 11.1%, 89.4 � 17.0%, 79.3 � 25.3%; P < 0.001). Complete remission from CRPS wasobserved at 1 month in all patients, at 3 months in 17, and at 6 months in 16 patients. If relapseoccurred, significant pain relief was still attained at 3 and 6 months (59.0 � 14.7%, P < 0.004;50.2 � 10.6%, P < 0.002). Quality of life, the associated movement disorder, and the ability to worksignificantly improved in the majority of patients at 3 and 6 months.
Conclusions. This open-label trial suggests benefit in pain reduction, associated CRPS symp-toms, improved quality of life and ability to work following anesthetic ketamine in previouslyrefractory CRPS patients. However, a randomized controlled trial will be necessary to prove itsefficacy.
Key Words. Complex Regional Pain Syndrome; Ketamine; NMDA-Receptor; Reflex SympatheticDystrophy; Pain Therapy; Quality of Life
Introduction
The understanding of the pathophysiology ofmechanisms underlying complex regional
pain syndrome (CRPS) has vastly progressed inthe recent years [1]. Recent evidence has beenpresented that suggests focal small-fiber axonaldegeneration and alteration of the cutaneous
Reprint requests to: Robert J. Schwartzman, MD, Depart-ment of Neurology, Drexel Universtity, College of Medi-cine, Hahneman University Hospital, Broad and VineStreets, Mail Stop 423, Philadelphia, PA 19102-1192,USA. Tel: 215-762-7090; Fax: 215-762-3161; E-mail:[email protected].
Financial Disclosure: The study was financed by depart-mental resources.
PAIN MEDICINEVolume * • Number * • 2007
© American Academy of Pain Medicine 1526-2375/07/$15.00/** **–** doi:10.1111/j.1526-4637.2007.00402.x
innervation by small-diameter afferent and post-ganglionic sympathetic efferent fibers are impor-tant for its induction and maintenance [2,3].Caveats of this hypothesiz have been raised byJanig and Baron [4], who propose that patientswith CRPS have concomitant peripheral changesin the microenvironment at the site of injury thatinduce peripheral afferent sensitization, neuro-genic inflammation, and sympathetic afferent cou-pling in addition to functional reorganization ofthe somatosensory, motor, and autonomic circuitsin the central nervous system (CNS) [5–7].
There is general agreement that the pain inCRPS is disproportionate to the extent of theprimary triggering injury that does not respect aroot or nerve territory. Characteristic symptomsinclude severe unrelenting burning and deep pain,associated with mechano- and thermal allodynia,hyperalgesia, and hyperpathia. Swelling, auto-nomic dysregulation, a movement disorder,atrophy, and dystrophy are associated to varyingdegrees [8]. The syndrome may progress withtime, and signs and symptoms may spread to sitesthat were not primarily affected. In some patients,it is generalized [9,10]. Current standard therapyconsists of a variety physical, psychological, behav-ioral, pharmacological and interventional treat-ments [11–13]. Unfortunately, a subgroup ofCRPS patients remains refractory to all standardtherapy. For these refractory patients, no effectivetreatment exists [8].
Ketamine, the currently most potent clinicallyavailable N-methyl-D-aspartate (NMDA)-antagonist, has a well-established role in thetreatment of acute and chronic pain [14,15]. Itsmain action is through inhibition of NMDA-receptors, which are thought to play a crucial rolein the generation and maintenance of chronicpain [16,17]. In addition to its acute analgesiceffects, systemic ketamine modulates correlates ofcentral sensitization in chronic pain states on along-term basis. Wind-up and punctuate hyperal-gesia were shown to be significantly reduced upto 7 days after surgery [18]. Ketamine adminis-tered at higher intraoperative dosage for majorabdominal surgery reduced the area of woundhyperalgesia and significantly prevented the ini-tiation and maintenance of chronic pain [19,20].Possible mechanisms are that these effects aremediated through NMDA-receptor inhibition,which may be critical for central sensitization,and anti-inflammatory modulation of the immunesystem [17,21]. Proinflammatory cytokines areinvolved in the processes of peripheral and central
sensitization and are inhibited by ketamine [22].In the management of chronic pain, the use ofketamine at higher dosages has been limited bypsychotropic side effects. The incidence andseverity of ketamine side effects are dose-dependent as are its analgesic potency and dura-tion of action [15].
Several series and case reports have docu-mented reduction of pain intensity, allodynia andassociated CRPS signs of autonomic dysregulationand motor dysfunction following the admini-stration of subanesthetic systemic, epidural, andtopical ketamine [23–26]. A recent case report andlarger series demonstrated long-term pain relieffrom subanesthetic ketamine infusions, particu-larly in early and well localized CRPS [27,28].However, in a subgroup of refractory CRPS withspreading disease, subanesthetic continuous S(+)-ketamine infusions were ineffective [29].
This suggested that ketamine in anestheticdosages might be effective in this refractory CRPSsubgroup. Excellent clinical results were obtainedwith anesthetic doses of ketamine administered ona compassionate care basis to several refractoryCRPS patients (unpublished). Based on thislimited clinical experience, a standardized treat-ment regime was developed, and utilized in thepresent trial. The therapeutic efficacy of ketaminein anesthetic dosage was studied in a Phase II studyin 20 refractory CRPS-patients, who sufferedeither longstanding or rapidly progressive diseasethat had failed standard therapy. The primaryoutcome parameter was acute and long-term reliefof pain. Other measures included effects on themovement disorder, quality of life, social integra-tion, and the ability to work at 6 months followingtreatment.
Methods
PatientsThe human investigation committees in Tübingenand Saarbrücken, Germany, approved the study.Patients were recruited in the pain clinics of theDepartment of Neurology of Drexel UniversityCollege of Medicine (Philadelphia, PA) and painclinics of the Teaching Hospital University ofthe Saarland (Saarbrücken, Germany). Informedconsent emphasized the experimental nature ofthis treatment. Special emphasis was placed on therisks associated with the intensive care componentof this treatment which includes respiratory andurinary tract infections and other infectious
Kiefer et al.2
complications such as systemic inflammatoryresponse syndrome and sepsis. Organ failure(single or multi-organ failure), cardiovascularcomplications as well as the associated high mor-bidity and mortality rates of all of these seriouscomplications were stressed. All patients gave theirinformed written consent.
Inclusion CriteriaAll patients fulfilled the 1993 IASP–CRPS diag-nostic criteria, the 1999 modified research diag-nostic CRPS criteria, and the proposed modifiedresearch diagnostic criteria of the 2005 Budapestconference in at least one limb [30–32]. Otherassociated CRPS factors [1–4] were noted tovarying degrees in contiguous areas of the extrem-ity, the face or in a mirror distribution. Clusteranalysis placed all patients in subgroup; and [3] aflorid CRPS syndrome [32].
The average daily pain intensity had to be 7points or greater on a numerical rating scale(Numeric Rating Scale [NRS] endpoints 0: nopain, 10: worse pain imaginable) over a period of atleast 6 months while on standard therapy. TheCRPS symptomatology had to be either long-standing and spreading, or rapidly progressive.Standard conventional nonmedical (physicaltherapy, psychological approaches), or pharmaco-logical and interventional treatment modalitieshad to have failed. Failure of therapy was definedas: 1) no benefit from treatment, or 2) no lastingpain relief (>2 months). The designation “refrac-tory” included documented failure of: 1) nonmedi-cal; 2) pharmacological mono-, or combinedtherapy with nonsteroidal antiinflammatory drugs,tricyclic antidepressants, anticonvulsants, low orhigh potency opioids; 3) at least three inter-ventional procedures, including selective nerveblocks, epidural analgesia, brachial plexus blocks,sympathetic ganglion blocks, intravenous regionalsympathetic blocks, spinal cord stimulation, surgi-cal sympathectomy, or intrathecal drug deliverysystems; and 4) unchanged or progressing state ofdisease despite these efforts.
Inclusion was limited to ASA I-III patients(ASA: American Society of AnesthesiologistsPhysical Status Classification), which apart fromtheir pain-related disability, did not suffer fromclinically relevant systemic disease. Patients thatpresented with a history of significant cardiovas-cular, pulmonary, renal disease or mental disorderswere excluded. Further exclusion criteria includedknown contraindications to ketamine use (severearterial hypertension, hyperthyroidism, ischemic
heart disease or heart failure), as well as allergies toketamine or midazolam. All patients during thecourse of their treatments were evaluated by apsychiatrist for counseling and support and 9underwent detailed neuropsychological testingprior to and following treatment [33]. All patientshad difficulty falling and staying asleep but thisfeature of their illness was not studied systemati-cally. Patients with a history of substance or drugabuse, or a suspected somatoform pain disorderwere excluded. The inclusion criteria were evalu-ated by three physicians, a neurologist (RJS), andtwo anesthesiologists (RTK, PR).
Ketamine Treatment ProtocolAnesthesia was induced by bolus injection of ket-amine (1–1.5 mg/kg) and midazolam (2.5–7.5 mg).Tracheal intubation was facilitated by vecuronium(0.1 mg/kg). Treatment was maintained by infu-sions of ketamine over 5 days, starting at 3 mg/kg/h, followed by gradual daily titration up toa final dose of 7 mg/kg/h. Midazolam wasco-administered and adjusted as clinically required(0.15–0.4 mg/kg/h) to obtain a stable level of deepsedation (Ramsay-Score 4–5), and to attenuateketamine-specific side effects, i.e., agitation [34].The first three patients were not intubated andspontaneous ventilation was allowed. The re-maining 17 patients were electively intubated,to limit the risk of aspiration. These 17 patientswere mechanically ventilated. After 5 days,infusions were slowly tapered, first by reducingthe ketamine dosage by 20% every four hours,followed by gradual reduction of midazolam in thesame manner. Patients were then weanedfrom mechanical ventilation and extubated onceadequate spontaneous ventilation, sufficient gasexchange, and the appropriate level of conscious-ness together with intact protective reflexes wasattained.
Ketamine and Norketamine Plasma ConcentrationsBlood samples were drawn into prefabricatedEDTA-tubes (S-Monovette®, Sarstedt AG & Co.,Nürnbrecht, Germany) from all patients everyeight hours to determine ketamine and norket-amine (the primary ketamine metabolite) plasmaconcentrations during anesthesia and for 3 daysfollowing treatment. Blood samples were centri-fuged and plasma aliquots stored until analysis at-80°C. Ketamine and norketamine plasma con-centrations were analyzed by simultaneous high-pressure liquid chromatography (HPLC) [35].
Efficacy of Ketamine in Anesthetic Dosage 3
Standardized Additional DrugsDeep Venous Thrombosis and Ulcer ProphylaxisAll patients received intravenous unfractionatedlow-dose heparin 7.500–15.000 I.E./day (Liq-uemin®, Roche, Germany) under regular aPTTmonitoring, and the proton pump inhibitor pan-toprazole 40 mg/day (Pantozol®, Altana Pharma,Germany).
ClonidineClonidine (Catapresan®, Boehringer Ingelheim,Germany) was administered intravenously (0.20–0.85 mg/kg/h) to control cardiovascular stimula-tion and the psychomimetic and potentialneurotoxic side effects of ketamine. It was dosed asclinically required (0.20–0.85 mg/kg/h) to controltachycardia and hypertension. The coadministra-tion of clonidine at a minimum dose of 0.15 mg/kg/h was maintained throughout the intensive caretreatment.
Alimentation and Glycemic ControlAlimentationThe first three unintubated patients receivedfull parenteral nutrition (25 kcal/kg/day) witha ternary mixture of aminoacids (40 g/L), glucose(160 g/L), and fat (40 g/L), containing1040 kcal/L glucose-fat calories (Oliclinomel®
4.0% GF-E Baxter, Germany). Intubated patientsreceived full enteral nutrition (25 kcal/kg/day) vianasogastral tube (Nutrison Standard®, NutrisoneMultifibre®, Pfrimmer Nutrica, Germany, con-taining 1.000 kcal/L, proteins 40 g/L, carbohy-drates 123 g/L, fat 39 g/L).
Glycemic ControlIntensified insulin-therapy (Actrapid®, NovoNordisk A/S, Denmark) was applied, and insulindosed as clinically needed to maintain normogly-cemia (blood glucose concentrations: 90–150 mg/dL) [36].
Patient SafetyMonitoringContinuous standard intensive care monitoring(arterial blood pressure monitoring, ECG andST-segment analysis, core temperature, pulseoximetry, capnometry, central venous pressure)was performed in all patients. All patients hadbladder catheterization.
Blood Gas Analysis and Blood ChemistryBlood gas analysis was routinely performed every8 hours and additionally when clinically warrantedto adjust mechanical ventilation, insulin therapy,
acid-base balance, and electrolytes. Detailed bloodtests were performed before the treatment, dailyduring treatment, and for the first 2 weeksthereafter. Laboratory evaluation included cellcounts, electrolytes, coagulation parameters, liverenzymes, C-reactive protein (CRP), creatinephosphokinase (CPK), and CKMB-isoenzymeactivity.
Screening for Infectious ComplicationsWhen admitted patients were screened with pha-ryngeal, nose and rectal swabs for the presence ofmultiresistant pathogens (methycillin resistantS. aureus [MRSA]; vancomycin resistant entero-cocci [VRE]). During the treatment screeningincluded continuous monitoring of core bodytemperature, and laboratory parameters (daily leu-kocyte count, CRP), urine status, and trachealsecretion and urine cultures on the first day oftreatment and when respiratory or urinary tractinfection was suspected clinically. In the presenceof fever blood cultures were collected.
Outcome CriteriaThe patients’ progress during the study, the timesand nature of assessments at baseline, 1 week, 1, 3,and 6 months after treatment are summarized in aflow chart shown in Figure 1.
Pain Assessment and Degree of Pain ReliefThe degree of a patient’s subjective pain intensi-ties was rated by a numeric scale (NRS, endpoints:0—no pain, 10—worst pain imaginable) at base-line and at follow-up examinations. The degreeof pain relief following treatment was calculatedas: percent pain relief = (NRSbaseline - NRSfollow up)/NRSbaseline ¥ 100.
Movement DisorderData were obtained at baseline and 1, 3, and 6months after treatment for both upper and lowerextremities.
Upper Extremity Motor EvaluationAssessment of active range of motion was based onnorms described by Kendall et al. [37]. Arm move-ment was quantified by utilizing a combination ofthe performance of specific motor tasks (placinga book in a shelf above shoulder level, abilityto comb one’s hair, putting on a sweater, tying anapron) in addition to the results of the range ofmotion evaluation. Hand movement assessmentcombined grip function (gripping and holding acup) and pinch grip ability (gripping, holding anduse of a key, pencil and writing). Based on the
Kiefer et al.4
observed range of movement combined with per-formance in the described functional tasks, themovement disorder was quantified utilizing a4-point rating scale: 0: normal movement; 1: mod-erate disability (moderately reduced active rangeof motion, muscular strength, initiation, andcompletion of motor tasks); 2: severe disability(severely restricted active range of motion, weak-ness, poor initiation, and completion of motortasks); 3: total disability (only residual movement,severe weakness, and inability to perform motortasks).
Lower Extremity Motor EvaluationThe assessment of motor function of the lowerextremity was based on the ability to walk and wasscored on a 4-point rating scale: 0: normal move-ment (unimpaired walking); 1: moderate disabi-
lity (inability to walk 500 meters); 2: severe disabi-lity (inability to walk 200 meters); 3: total disability(ability to walk <50 meters or inability to walk).
Quality of LifeThe assessments to estimate disease-relatedimpairments in activities of daily living, socialintegration, and the ability to work represent rec-ognized aspects of quality of life. The assessmentswere performed at baseline and at 3, and 6 monthsfollowing therapy.
Activities of Daily LivingPatients were asked to rate their performance oftypical activities of daily living. The representativetasks of everyday life were based on selected keyitems contained in valid questionnaires, such asthe West Haven-Yale Multidimensional Pain
Figure 1 Flow chart summarizingpatients’ progress through the study.The left side of the diagram shows thetiming of the assessment of patientsand the investigated treatment withanesthetic ketamine. The right side ofthe diagram shows he investigatedoutcome parameters at the differentassessment times throughout thestudy. CRPS = complex regional painsyndrome; ICU = intensive care unit.
Patient Screening
Neuropsychological Screening
Ketamine Treatment (Day 1)
End of Ketamine Treatment (Day 5)
Discharge ICU (Days 8-10)
Peripheral Ward (Days 8-14)
Followup: 1 Week (Day 12) (N=20)
Followup: 1 Month (N=20)
Followup: 3 Months (N=20)
Hospital Discharge (Days 10-16)
Followup: 6 Months (N=20)
• Patient Characteristics/Medical History
• CRPS-Specific Medical History
MedicationTherapeutic interventions
• Pain Intensities
• CRPS-Related Disabilities:
Motor dysfunctionActivities of daily livingSocial integrityAbility to work
• Pain Intensities
• Degree of Pain Relief
• CRPS-Related Disabilities:
Motor dysfunctionActivities of dailylivingSocial integrityAbility to work
• Pain Intensities
• Degreeof Pain Relief
• Ketamine Side Effects
• Documentation of Complications
• Continuous ICU-Monitoring
• Screening for Infectious Complications
• Ketamine Plasma Levels
• Ketamine Side Effects
• Documention of Complications
• Pain Intensities
• Degree of Pain Relief
Recruitment/Inclusion (N=20)
Baseline (N=20)
Efficacy of Ketamine in Anesthetic Dosage 5
Inventory (WHYMPI) and the Stanford HealthAssessment Questionnaire (HAQ) [38,39].Patients were instructed to rate their abilityto independently perform the following tasks:self-care (preparing meals and eating [cuttingfood], drinking, dressing, washing, drying, andcombing), and household activities (house clean-ing, grocery shopping, washing dishes, and gar-dening). The degree of impairment was ratedusing a 4-point numeric scale: 0: no impairment(all tasks can be performed independently), 1:moderate impairment (tasks can be accomplishedbut with difficulty), 2: severe impairment (<50% ofactivities can be performed independently); 3: totalimpairment (majority of tasks cannot be per-formed; dependent on the help of others).
Social IntegrationPatients were queried in regard to their abilityto function socially and rated their overall im-pairment. Representative activities were chosenfrom the aforementioned validated questionnaires(WHYMPI, HAQ). Patients were asked to ratetheir ability to perform recreational activities (pur-suing hobbies, playing sports, taking trips, seeingfriends/relatives, reading, going out), culturalactivities (attending concerts, movies, theatre).The degree of impairment was rated using a4-point numeric rating scale: 0: no impairment, 1:moderate impairment (all activities can be per-formed, but with difficulty), 2: severe impairment(<50% of activities can be performed indepen-dently), 3: total impairment (majority of activitiescannot be performed and the patient is dependenton the help of others).
Ability to WorkThe ability to work was rated on a 4-point scale: 0:no impairment, 1: moderate impairment (able towork more than 4 h/day but less than 8 h/day), 2:severe disability (able to work up to 4 h/day), 3:total impairment (able to work only 2 h/day ortotally unable to work).
Side Effects of TreatmentKetamine-Specific Side EffectsPsychotomimetic side effects: the occurrence,duration, and severity of ketamine-specific psy-chotomimetic side effects were documentedfollowing treatment. These included: anxiety, hal-lucinations, restlessness, difficulty in concentra-tion, disruption of sleep, dizziness, dysphoria,euphoria, and disorientation.
Other Adverse Treatment EffectsThese included all potential adverse effects asso-ciated with the intensive care nature of the treat-ment, such as respiratory, urinary tract or systemicinfection, and cardiovascular and pulmonary com-plications. The occurrence of these complications,their treatment and resolution were documented.
StatisticsData were analyzed using the statistical softwarepackage JMP IN (Version 5.1.2, SAS Institute,Cary, NC). The Kolmogorov-Smirnov test wasused to assess normality. Nonparametric pairedt-tests on ranks were used to analyze differencesbetween baseline and those obtained during andfollowing therapy for not normally distributeddata. Normally distributed data were analyzed bypaired t-tests. Alpha was set at 0.05. For multiplecomparisons the alpha correction of Bonferroniwas performed.
Results
Patient DemographicsTwenty ASA-Class I–III patients were enrolledand completed the study (18 female and two male;mean age 30.4 � 10.4 years, range: 14–48 years).The mean duration of CRPS was 49.4 � 25.0months (range: 6–84 months). All patients sufferedfrom severe or spreading CRPS. Two had rapidcontiguous spread affecting the entire extremity,two suffered from mirror spread, and 16 had gen-eralized CRPS. All patients had been unresponsiveto multiple conventional treatments and had failedstandard pharmacological therapy and numerousinvasive procedures (Tables 1–4).
Pain Intensities and Pain reliefPain IntensitiesPain intensities were analyzed for the entiregroup, as well as for the subgroup of patients withrecurring initiating or maintaining pain (nocicep-tive or neuropathic, but without associated CRPSsigns or symptoms) and the subgroup with relaps-ing CRPS (neuropathic pain and associated CRPSsigns and symptoms).
At baseline, pain intensity of the entire group(N = 20), and of the subgroups with later recurringpain, and relapsing CRPS were NRS 8.9 � 0.3,8.8 � 0.2, and 9.2 � 0.2 (mean � SD), respec-tively, and no statistically significant differencesbetween the groups were detected.
Kiefer et al.6
Tab
le1
Cha
ract
eriz
atio
nof
CR
PS
-sta
tus
atba
selin
e:pa
tient
s’ag
e,ge
nder
,Am
eric
anS
ocie
tyof
Ane
sthe
siol
ogis
tsP
hysi
calS
tatu
sC
lass
ifica
tion
(AS
A-C
lass
),an
dC
RP
S-r
elat
edch
arac
teris
tics
atba
selin
e:tr
igge
ring
inju
ries,
site
sof
prim
ary
CR
PS
man
ifest
atio
n,du
ratio
nof
dise
ase
(mon
ths)
,th
ety
peof
spre
ad,
the
stat
usof
dise
ase
spre
adat
base
line,
and
the
pain
inte
nsity
atba
selin
e(N
RS
:0:
nopa
in,
to10
:w
orst
pain
imag
inab
le)
Pat
ient
No.
Age
(Yea
rs)
Gen
der
AS
A-C
lass
Trig
gerin
gIn
jury
/CR
PS
Man
ifest
atio
nC
RP
SD
urat
ion
(Mon
ths)
Type
ofS
prea
dS
tatu
sof
Spr
ead
Bas
elin
e
Pai
nIn
tens
ity(N
RS
:0–
10)
Bas
elin
e
116
fI
Spr
ain
inju
ry/r
ight
wris
tan
dha
nd8
Con
tiguo
usE
ntire
right
arm
92
26f
IB
rach
ialp
lexu
str
actio
nin
jury
/rig
htsh
ould
er12
Mirr
orS
houl
ders
and
arm
sbi
late
rally
93
25m
IIH
odgk
in’s
dise
ase,
com
pres
sion
ofbr
achi
alpl
exib
yly
mph
oma/
shou
lder
s24
Mirr
orS
houl
ders
and
arm
sbi
late
rally
9
446
fII
Bra
chia
lple
xus
trac
tion
inju
ry/r
ight
arm
60C
ontig
uous
,M
irror
Left
arm
9.5
529
fII
Ele
ctric
alsh
ock/
right
arm
30C
ontig
uous
Rig
htar
m,
shou
lder
,fa
ce8.
56
46f
IIIC
rush
inju
ryrig
htan
kle
and
foot
,op
erat
ive
oste
osyn
thes
is/
right
foot
72C
ontig
uous
Rig
htar
m,
right
face
8.5
728
fIII
Trau
ma
tolo
wer
back
/rig
htle
g60
Con
tiguo
us,
Mirr
orLe
ftle
g,rig
htar
m,
right
face
9.5
842
fII
Cru
ciat
elig
amen
tte
ar,
tibia
lim
pres
sion
frac
ture
/rig
htkn
ee30
Con
tiguo
usR
ight
leg
8.5
922
fII
Tend
onru
ptur
edi
git
IV,
oper
ativ
ere
pair/
right
hand
72C
ontig
uous
Rig
htfa
ce,
right
leg
910
19f
IIF
ract
ure
met
atar
sal-V
/rig
htfo
ot60
Mirr
or,
Con
tiguo
usLe
ftle
g,rig
htfa
ce9
1120
fII
Trau
ma
torig
htsh
ould
eran
dlo
wer
back
/rig
htar
m36
Mirr
or,
Con
tiguo
usLe
ftar
m,
right
face
912
35f
IIITr
aum
ato
right
shou
lder
and
low
erba
ck/r
ight
arm
72M
irror
Left
shou
lder
,le
ftar
m9
1338
fIII
Cru
shin
jury
digi
t-III
right
hand
,in
fect
ion
and
ampu
tatio
n/rig
htha
nd24
Mirr
or,
Con
tiguo
usR
ight
face
,rig
htle
g9
1419
mII
Spr
ain
inju
ryw
rist/r
ight
hand
84M
irror
,C
ontig
uous
Left
arm
,rig
htfa
ce,
right
leg
915
36f
IIP
ara-
veno
usi.v
.-lin
e/le
ftha
nd,
left
fore
arm
60C
ontig
uous
Left
arm
,le
ftfa
ce9
1625
fII
Arn
old
Chi
arir
epai
rop
erat
ion/
left
shou
lder
,ar
m25
Con
tiguo
usLe
ftfa
ce,
left
leg
917
48f
IIE
xten
sion
/dis
tens
ion
trau
ma/
right
hand
72M
irror
Rig
htle
g,rig
htfa
ce8.
518
41f
IIC
arac
cide
nt,
whi
plas
hin
jury
/rig
htar
m84
Con
tiguo
usR
ight
arm
,rig
htfa
ce,
left
uppe
rle
g9
1914
fIII
Bro
wn
recl
use
spid
erbi
tein
ner
right
thig
h/rig
htth
igh
and
leg
7M
irror
,C
ontig
uous
Left
face
,le
ftar
m9.
5
2033
fII
Tibi
alto
rsio
nfr
actu
re,
oste
osyn
thet
icop
erat
ion/
left
low
erle
g63
Mirr
or,
Con
tiguo
usR
ight
low
erle
g9
CR
PS
=co
mpl
exre
gion
alpa
insy
ndro
me;
NR
S=
Num
eric
Rat
ing
Sca
le.
Efficacy of Ketamine in Anesthetic Dosage 7
Following ketamine treatment, a significantreduction of pain intensity was observed at 1 weekand 1 month for the entire group (NRS 0.5 � 0.8,and 0.6 � 1.0), and the subgroup with recurringpain (1.4 � 0.7, and 1.7 � 1.1, N = 7) (P < 0.001).At 3 months, pain intensity was significantly(P < 0.001) reduced compared with baseline in theentire group (NRS 0.9 � 1.6) and the subgroupwith recurring pain (2.0 � 0.9, N = 4). Threepatients had a CRPS relapse, but had significantlyreduced pain compared with baseline (NRS3.8 � 1.4, P < 0.004). Pain intensity at 6 monthswas significantly reduced for the entire group ofpatients (2.0 � 2.4, P < 0.001), the subgroups withrecurring pain (3.6 � 2.0, P < 0.001, N = 6), andthose with a CRPS relapse (4.6 � 1.1, P < 0.002,N = 4). The results are summarized in Figure 2.
Pain ReliefThe calculated percentage of pain relief was sig-nificant following ketamine treatment at 1 week(mean � SD: 94.5% � 8.9, and at 1, 3, and 6months (93.5% � 11.1, 89.4% � 17.0, 79.3% �25.3) in the entire group of patients (P < 0.001).Analyses for the subgroup with recurring painshowed significant pain relief at 1 week (84.4% �8.22, N = 7, P < 0.001), and 1, 3, and 6 months(81.4% � 11.5, 77.8% � 10.1, and 64.32% �23.8, N = 7, 4, and 6, P < 0.001 in all), respectively.
Pain relief in the subgroup of CRPS patientwith relapse was maintained at 3, and 6 months(59% � 14.7, N = 3, P < 0.004, and 50.21% �10.6, N = 4, P < 0.002). Figure 2 summarizes theresults.
Movement DisorderUpper ExtremityFor statistical analyses, the separately assessedscores the impairment of movement in the armand hand of each side of the body was added to atotal score for hands and arms. Thus, the minimalsum score was 0 (normal bilateral movement) andmaximal 6 (total bilateral impairment). All patients(N = 20) showed impaired movement in the upperextremities.
At baseline a sum score of 3.2 � 1.2(mean � SD) for movement in the arms, and3.7 � 1.2 for movement in the hands was docu-mented (N = 20). At 1, 3, and 6 months, a sig-nificant (P < 0.001) reduction of the sum scorewas noted for the movement impairment in thearms (1.4 � 0.83, 0.5 � 0.8, and 0.4 � 0.8),and hands (1.6 � 0.8, 0.5 � 0.9, and 0.5 � 0.8),respectively.
Lower ExtremityStatistical analyses of scores for decreased move-ment in the lower extremities were based on thedirect scores of the aforementioned 4-point-basednumeric rating scale. Of the entire group, onlythose with a movement disorder in the lowerextremity were included for statistical analyses. Atbaseline, patients with movement disorder of thelower extremity (N = 15) had a score of 2.3 � 0.7(mean � SD). Following treatment, their im-pairment was significantly reduced at 1, 3, and 6months (1.3 � 0.9, 0.6 � 0.7, and 0.6 � 0.6;N = 15, P < 0.001). Figure 3 summarizes theresults.
Table 2 Demographics: summarizes statistic data of patients’ demographics for the entire group of patients, and theanalyzed subgroups: recurring pain (all patients with recurring pain, either neuropathic, nociceptive, or both at one of thefollow-ups), CRPS-relapse (all patients with a CRPS-relapse), and results of the statistical comparison of differencesbetween the entire group and the subgroups (exact p-values)
N
Entire GroupSubgroup: Recurring Painfrom Initial Injury Subgroup: CRPS-Relaspse
20 9 4
Age (years) (Mean � SD) 30.4 � 10.7 30.7 � 8.2 33.7 � 11.9Range (min–max) 34 (14–38) 23 (19–42) 26 (20–46)P Value 0.95 0.58
Weight (kg) (Mean � SD) 68.4 � 18.7 68.6 � 15.9 68.7 � 31.6Range (min–max) 67.3 (48.5–115.8) 49 (48.5–97.5) 66.0 (49.8–115.8)P Value 0.99 0.98
Height (cm) (Mean � SD) 167.6 � 10.7 168.9 � 12.6 168.0 � 12.6Range (min–max) 42.0 (152–194) 42.0 (152–194) 29.0 (154–183)P Value 0.78 0.95
Duration of CRPS (months) (Mean � SD) 49.4 � 25.6 49.7 � 22.8 60.0 � 19.6Range (min–max) 78 (6–84) 60 (24–84) 48 (36–84)P Value 1.0 0.59
CRPS = complex regional pain syndrome.
Kiefer et al.8
Tab
le3
Fai
led
phys
ioth
erap
yan
dph
arm
acot
hera
py:
sum
mar
izes
the
indi
vidu
alpa
tient
s’fa
iled
phys
ioth
erap
eutic
and
phar
mac
othe
rape
utic
appr
oach
esat
base
line
Pat
ient
No.
Phy
siot
hera
py
Pha
rmac
othe
rapy
Topi
calP
harm
ca
NS
AID
Ant
idep
ress
ants
Ant
icon
vuls
ants
Spa
smol
ytic
sS
odiu
m-C
hann
el-B
lock
erLo
w-P
oten
tO
pioi
dsH
igh-
Pot
ent
Opi
oids
Lido
cain
eD
MS
O
1+
++
++
2+
++
++
++
+3
++
++
++
4+
++
++
++
++
5+
++
++
++
+6
++
++
++
++
7+
++
++
++
8+
++
++
++
++
9+
++
++
10+
++
++
+11
++
++
++
12+
++
++
+13
++
++
++
14+
++
++
+15
++
++
++
16+
++
++
17+
++
++
++
+18
++
++
++
19+
++
++
+20
++
++
++
++
The
“+”
indi
cate
s,w
hich
trea
tmen
tsha
vebe
enpe
rfor
med
and
faile
d,de
fined
asbe
ing
with
out
prim
ary
effe
ct,
orno
last
ing
(>2
mon
ths)
onpa
inre
lief.
NS
AID
=no
nste
roid
alan
ti-in
flam
mat
ory
drug
s;D
MS
O=
dim
ethy
lsul
foxi
dco
ntai
ning
oint
men
t;IV
RS
B=
intr
aven
ous
regi
onal
sym
path
etic
bloc
kade
.
Efficacy of Ketamine in Anesthetic Dosage 9
Tab
le4
Fai
led
Inte
rven
tiona
lthe
rapi
es:
sum
mar
izes
for
the
indi
vidu
alpa
tient
s’fa
iled
inte
rven
tiona
ltre
atm
ents
atba
selin
e
Pat
ient
No.
Trig
ger-
Poi
nt-
Infil
trat
ions
Ner
ve-B
lock
sS
ympa
thet
icB
lock
s
i.v.
Lido
cain
e
Spi
nal
Cor
dS
timul
atio
nIn
trat
heca
lS
yste
ms
Sel
ectiv
eN
erve
Blo
cks
Bra
chia
lP
lexu
sB
lock
IVR
SB
Intr
aple
ural
Blo
ck
Ste
llate
Gan
glio
nB
lock
sC
ervi
cal
Epi
dura
lT
hora
cic
Epi
dura
lLu
mba
rE
pidu
ral
Lum
bar
Sym
path
etic
Cha
inB
lock
12
21
32
23
33
24
>8>4
22
>4>3
35
>10
>2>3
36
>4>4
24
24
+7
>6>4
22
++
8>8
21
19
>4>5
22
2>6
210
5>6
2>3
12
+11
>4>5
22
>62
112
>6>6
2>4
>41
2+
13>8
>83
>51
11
114
>8>8
21
>62
11
15>6
>82
>61
32
+16
>4>6
2>4
117
>10
>82
>8>3
218
>6>4
22
119
31
11
20>8
>11
23
22
++
The
perf
orm
edin
terv
entio
ns,w
hich
had
faile
d,ar
ein
dica
ted
bya
num
ber,
indi
catin
gth
efr
eque
ncy
offa
iled
inte
rven
tions
,or
bya
“+.”
Fai
lure
was
defin
edas
bein
gw
ithou
tprim
ary
effe
cton
pain
,or
nola
stin
gef
fect
(>2
mon
ths)
onpa
inre
lief.
IVR
SB
=in
trav
enou
sre
gion
alsy
mpa
thet
icbl
ocka
de.
Kiefer et al.10
Quality of LifeActivities of Daily LivingAt baseline, the ability to independently accom-plish activities of daily living was rated as severelyimpaired by seven, and as totally impaired by 13patients, with a mean score of 2.35 � 0.4(mean � SD) for the entire group. At 3 months,the impairment was rated as severe by one, asmoderate by 12, and as not impaired by seven
patients, with a mean score of 0.7 � 0.6, and asignificant difference compared with baseline(P < 0.001). At 6 months, there was a significantdifference in the ability to perform activities ofdaily living compared with baseline. One patientrated total impairment, three severe impairment,six moderate impairment, and 10 patients noimpairment for a mean score of 0.7 � 0.9(P < 0.001). Results are shown in Figure 4.
-2
0
2
4
6
8
10
baseline
follow-up times
NR
S:
0-1
0 [
po
ints
]
entire group recurring pain CRPS - relapses
* **
*
+#
** *
*
(A)
0
20
40
60
80
100
120
1 week
follow-up times
pain
relie
f
entire group recurring pain CRPS - relapses[ % ]
* ** *
+
#
****
(B)
1 week 1 month 3 months 6 months1 month 3 months 6 months
Figure 2 The pain intensities (A) and the degree of pain relief (B) before and following the treatment. Part (A) shows the painintensities (NRS: 0–10, data presented as mean � SD) of the entire treatment group (N = 20) for baseline, at 1 week, and1, 3, and 6 months following treatment and significant differences compared with baseline (*P < 0.001), and the results of thesubgroup analyses for patients with recurring pain (N = 7 at 1 week, and 1 month, N = 4 at 3, and N = 6 at 6 months) andsignificant differences compared with baseline, as well as results for the subgroup with relapsing CRPS (N = 3 at 3 months,N = 4 at 6 months) and significant differences compared with baseline (+P < 0.004; #P < 0.0029). Part (B) summarizes thepercentage of pain relief following the treatment. Data are presented as means � SD for the entire group and the subgroupswith recurring pain, and relapsing pain, respectively. Significant degrees in the percentage of pain relief are indicated(*P < 0.001; +P < 0.004; #P < 0.002). NRS = Numeric Rating Scale; CRPS = complex regional pain syndrome.
0
1
2
3
4
5
6
baseline
follow-up times
mo
ve
me
nt
dis
ab
ilit
y s
co
re [
po
ints
]
arms hands
0
0,5
1
1,5
2
2,5
3
follow-up times
mo
ve
me
nt
dis
ab
ilit
y s
co
re [
po
ints
]
∗
∗
∗ ∗
∗ ∗
1 month 3 months 6 months baseline 1 month 3 months 6 months
(A) Upper Extremity (B) Lower Extremity
Figure 3 The changes for the movement disability score (4-point rating scale: 0: normal movement, 3: total impairment) ofthe different assessment times. Data are presented as means � SD for baseline, and the follow-ups at 1, 3, and 6 months.(A) Upper extremity: data show the results of a sum-score (movement disability scores of both body sides were added, thusa minimal score of 0 (normal bilateral movement), and 6 (total impaired bilateral movement) for impairment of movement inarms and hands, and significant differences compared with baseline (*P < 0.001). (B) Lower extremity: results and significantdifferences in the movement disability score for the lower extremity at baseline and the follow up assessments (P < 0.001).
Efficacy of Ketamine in Anesthetic Dosage 11
Social IntegrationThe impairment in social integration prior totreatment was rated as complete by 11 patients andsevere by nine. Their mean impairment score was2.5 � 0.5. At 3 months, their impairment wasrated as severe by one, as moderate by 10, and ninewere unimpaired. Their mean score of 0.6 � 0.6,was significantly improved compared with theirpretreatment baseline (P < 0.001). At 6 months,there was significant improvement in the groupwith one patient rating total impairment, twosevere impairment, six moderate impairment,and 11 patients no impairment (mean score of0.6 � 0.8 (P < 0.001). Results are shown inFigure 4.
Ability to WorkThe impairment in the ability to work prior totreatment was rated as complete by 11, severe by 5,and as moderate by four patients (mean impairmentscore of 2.3 � 0.8). At 3 months, the impairment inability to work was rated as complete and severe byone patient in each category, as moderate by eight,and as not impaired by 10 patients (mean score of0.6 � 0.8), which was significantly improved com-pared with their baseline (P < 0.001). At 6 months,
there was significant improvement in the abilityto work as only two patients in the cohort wereunable to work, four had moderate impair-ment, and 14 patients had no impairment (meanscore of 0.5 � 0.9) (P < 0.001). Results are shownin Figure 4 and Table 5.
Ketamine and Norketamine Plasma ConcentrationsHigh-pressure liquid chromatography analysis ofketamine and norketamine plasma levels was in 18patients. The sampling and analysis of two patientswas incomplete, because of initial technical diffi-culties and therefore were not included in theanalyses. Figure 5 summarizes the plasma concen-trations for ketamine and norketamine.
Side Effects
Ketamine-Specific Side EffectsPsychotropic Ketamine Side EffectsPsychotropic side effects that included anxiety,dysphoria, nightmares, and difficulties with sleepwere observed in the majority of patients uponemergence from ketamine anesthesia. The inten-sity of these ketamine-specific side effects was
Figure 4 The results for the assess-ments of quality of life: the impairmentin activities of daily living, the impair-ment in social integration, and theability to work. Patients rated theirimpairment on a 4-point rating scale (0:no impairment, 3: total impairment).Part (A) shows the absolute number(N) of patients in each category ofimpairment at baseline and the follow-ups, and significant differences com-pared with baseline (*P < 0.001). (B)Severity of impairment: the impairmentscores for the entire group for impair-ment of activities of daily living, socialintegration, and the ability to work atbaseline, 3, and 6 months and signifi-cant differences compared with base-line (*P < 0.001).
0
2
4
6
8
10
12
14
16
activities of
daily living
social
integrity
ability to
work
activities of
daily living
social
integrity
ability to
work
activities of
daily living
social
integrity
ability to
work
baseline 3 months 6 months
disability domain / follow-up time
nu
mb
er
of
pa
tie
nts
No Impairment Moderate Impairment Severe Impairment Total Impairment
**
[ N ]
(A)
0
0,5
1
1,5
2
2,5
3
3,5
baseline 3 months 6 months
follow-up times
dis
ab
ilit
y s
co
re
activities of daily living social integrity ability to work
* **
* * *
[points]
(B)
Kiefer et al.12
Tab
le5
Indi
vidu
alou
tcom
efo
llow
ing
anes
thet
icke
tam
ine:
the
indi
vidu
alpa
tient
s’ou
tcom
efo
r:pa
inre
spon
se(d
ata
show
nfo
rth
efo
llow
-ups
at1,
3,an
6m
onth
s),
mov
emen
tdi
sord
er(d
ata
show
nfo
rba
selin
e,3,
6m
onth
s;nu
mbe
rsgi
ven
indi
cate
:su
msc
ore
mov
emen
tdi
sabi
lity
inth
ear
ms
(0:
bila
tera
lnor
mal
mov
emen
t–6:
bila
tera
lto
tali
mpa
irmen
t)/s
umsc
ore
mov
emen
tdis
abili
tyin
the
hand
s(0
:bila
tera
lnor
mal
mov
emen
t–6:
bila
tera
ltot
alim
pairm
ent)
/mov
emen
tdis
abili
tysc
ore
for
the
low
erex
trem
ities
(0:
norm
alw
alki
ng–3
:to
tali
mpa
irmen
t),
and
the
impa
irmen
tin
the
asse
ssed
aspe
cts
ofqu
ality
oflif
e:ev
ery
day
activ
ities
,so
cial
life
activ
ities
,an
dw
orki
ngca
paci
ty
Pat
ient
No.
Pai
nM
ovem
ent
Dis
orde
rsA
ctiv
ities
ofD
aily
Livi
ngS
ocia
lInt
egra
tion
Abi
lity
toW
ork
1M
onth
3M
onth
6M
onth
Bas
elin
e3
Mon
ths
6M
onth
sB
asel
ine
3M
onth
s6
Mon
ths
Bas
elin
e3
Mon
ths
6M
onth
sB
asel
ine
3M
onth
s6
Mon
ths
1F
RF
RF
R3/
3/0
0/0/
00/
0/0
TI
NI
NI
TI
NI
NI
TI
NI
NI
2F
RF
RF
R4/
5/0
0/0/
00/
0/0
SI
NI
NI
SI
NI
NI
SI
NI
NI
3R
PF
RF
R4/
4/0
0/0/
00/
0/0
SI
MI
NI
SI
MI
NI
SI
NI
NI
4R
PC
RP
SC
RP
S4/
5/2
2/2/
12/
2/1
SI
MI
SI
TI
MI
SI
TI
MI
TI
5F
RF
RR
P2/
3/0
1/0/
01/
1/0
SI
MI
SI
SI
NI
SI
TI
MI
NI
6F
RF
RF
R5/
5/3
0/0/
00/
0/0
TI
MI
MI
TI
MI
NI
TI
MI
NI
7R
PC
RP
SC
RP
S4/
5/3
2/3/
32/
3/3
TI
SI
TI
TI
SI
TI
TI
TI
TI
8F
RF
RR
P2/
4/2
0/0/
10/
0/1
SI
MI
MI
SI
MI
MI
MI
NI
NI
9F
RF
RF
R2/
3/1
0/0/
00/
0/0
SI
NI
NI
SI
NI
NI
SI
NI
NI
10R
PF
RF
R2/
3/2
0/0/
00/
0/0
TI
NI
NI
TI
NI
NI
MI
NI
NI
11R
PC
RP
SC
RP
S2/
3/3
2/2/
12/
2/1
SI
MI
SI
SI
MI
MI
MI
MI
MI
12R
PR
PR
P5/
5/3
2/2/
22/
2/2
TI
MI
MI
TI
MI
MI
TI
MI
MI
13R
PF
RF
R5/
6/3
1/0/
00/
0/0
TI
MI
NI
TI
MI
NI
TI
MI
NI
14F
RF
RR
P4/
2/2
1/1/
00/
1/0
SI
MI
NI
TI
NI
NI
MI
NI
NI
15F
RR
PR
P2/
2/1
0/0/
00/
0/0
SI
MI
MI
TI
MI
MI
SI
MI
NI
16F
RF
RF
R3/
3/2
0/0/
00/
0/0
SI
NI
NI
SI
NI
NI
SI
NI
NI
17F
RF
RF
R1/
1/0
0/0/
00/
0/0
SI
MI
NI
SI
NI
NI
TI
NI
NI
18R
PR
PC
RP
S4/
4/2
0/1/
10/
0/1
SI
MI
MI
TI
MI
MI
TI
MI
MI
19F
RF
RF
R4/
4/3
0/0/
00/
0/0
TI
NI
NI
TI
NI
NI
TI
NI
NI
20F
RR
PR
P3/
4/2
0/0/
10/
0/1
SI
NI
MI
SI
MI
MI
TI
MI
MI
FR
=fu
llre
mis
sion
;R
P=
recu
rrin
gpa
in;
CR
PS
=co
mpl
exre
gion
alpa
insy
ndro
me-
rela
pse;
NI=
noim
pairm
ent;
MI=
mod
erat
eim
pairm
ent;
SI=
seve
reim
pairm
ent;
TI=
tota
lim
pairm
ent.
Efficacy of Ketamine in Anesthetic Dosage 13
most severe in the initial days following emer-gence from anesthesia and resembled an acutewithdrawal. These symptoms were successfullytreated with small doses of clonidine and/or ben-zodiazepines. The psychotropic side effects fadedwithin the first week following treatment in themajority of patients. However, five patientsreported difficulties with sleeping and recurringnightmares for a month following treatment.Muscular weakness was reported in all patients foras long as 4–6 weeks following treatment.
Adverse Treatment EffectsInfectious ComplicationsNo major or life threatening complications wereobserved. The majority of complications wereinfections associated with the intensive care natureof treatment. Seven patients had respiratory infec-tions, tracheobronchitis in five, and pneumonia intwo patients. Fever was observed early (within24–48 hours) following the initiation of anestheticdoses of ketamine, with concomitant leucocytosis(12,000–16,000/mL) and elevation of the CRP(6–25 mg/dL). Culture of tracheal secretionsrevealed S. aureus (methycillin sensible S. aureus,N = 6), Klebsiella pneumoniae (N = 2), and Proteusmirabilis (N = 1), as the pathogens in these cases.Lower urinary tract infections were seen in sixpatients, and urine cultures revealed enterococcusspecies (E. faecium, E. faecalis), and E. coli as thepathogens. These infectious complications weresuccessfully treated with antibiogram-guided anti-biotic therapy.
Laboratory EvaluationDuring treatment, transient rises in liver enzymes,CPK and CKMB were observed. Blood tests priorto the start of therapy revealed elevated liverenzymes (g-GT: 20–60 U/L in five patients, andGOT: 20–38 U/L in five patients), all of whomhad been taking combinations of analgesics, anti-depressants, and seizure medications. Under anes-thesia, elevations of liver enzymes were noted in16 patients for g-GT (range: 30–94 U/L), GOT(range 30–98 U/L), and GPT (20–94 U/L), themaximal elevations occurred on days 5–6 of treat-ment. Elevations in CPK (range: 20–800 U/L)were observed in 16 patients, all of whom hadnormal ratios for CPK/CKMB which wherebelow 10%. Both the elevation of liver enzymesand CPK decreased following treatment andreturned to reference values within 10–14 days.
Discussion
This open-label study suggests an impressiveeffect of anesthetic ketamine in advanced andrefractory CRPS patients. Pain scores were signifi-cantly improved and long-term complete painrelief was observed in 50% of patients. Patientsthat suffered recurring pain alone and recurringpain in conjunction with a CRPS relapse alsomaintained significant relief during the courseof the study. In addition, there was significantimprovement of the movement disorder, ability toperform activities of daily living, and the abilityto work in concert with the decrement in pain.
Figure 5 Ketamine and norketamineplasma concentrations. Summarizesby the HPLC determined plasma con-centrations for racemic ketamine andthe primary active metabolite norket-amine (mg/mL) over the five treatmentdays with anesthetic days and sub-siding in the three consecutivedays after anesthetic ketamine treat-ment. HPLC = high-pressure liquidchromatography.
0
1
2
3
4
5
6
7
8
9
10
Day 1
Ketamine Treatment
co
nc
en
tra
tio
n [
µg
/ml
]
Ketamine [µg/ml] Norketamine [µg/ml]
Following Ketamine
Day 2 Day 3 Day 4 Day 5 Day 1 Day 2 Day 3
Kiefer et al.14
However, the dramatic nature of the interventionwould be expected to cause a strong placeboresponse and the nonrandomized uncontrolleddesign of this study leave its results suggestive butunproven.
There are many possible mechanisms thatunderlie the marked and long-lasting effects ofanesthetic ketamine in these severely affectedCRPS patients. Because this is an open-label phaseII study with lack of controls, the results may not becompletely attributable to ketamine. Anestheticdoses of ketamine have not been studied in thetherapy of chronic pain states. Existing evidence forthe efficacy of ketamine in chronic pain disorderswas obtained by utilizing low subanesthetic doseprotocols primarily for neuropathic pain statesother than CRPS. The first data on the beneficialeffects of ketamine for CRPS were obtained fromcase reports and small case series [23–26,28]. Inthese studies, subanesthetic ketamine was adminis-tered via systemic, epidural or topical routes andprovided dramatic relief from pain and associatedCRPS symptoms in some patients. However, thesestudies differ in the routes of ketamine administra-tion, dosage, treatment time, patient clinical pro-files, and the duration of observation followingtreatment. The main limitations in determiningthe benefit of ketamine in these studies are samplesize, lack of a control population and standardiza-tion of the treatment and measurement protocols.Long-term pain relief for 8 months was observedfollowing a 10-day course of epidural ketamine(0.25 mg/kg/h) in a patient with lower extremityCRPS [23]. Harbut utilized continuous subanes-thetic ketamine for 6 days in a patient that hadsuffered 9 years of CRPS and achieved pain relieffor 5 months [28]. Recently, a larger-scale retro-spective case series described long-term relief frompain following continuous low-dose ketamine [27].In this series, the best response to ketamine wasobserved in patients with early CRPS whose symp-toms and signs were well localized to the distalaspects of one extremity. In a subgroup of refrac-tory CRPS patients, we recently showed subanes-thetic continuous S(+)-ketamine (500 mg/day)administered over 10 days (exceeding the equian-algesic ketamine dosages used by Correll) was inef-fective in relieving pain or attenuating severethermal and mechanical allodynia [29]. To ourknowledge, there are no randomized controlledtrials on the efficacy of ketamine in the treatmentof CRPS.
Complex regional pain syndrome is generallythought to be a subset of neuropathic pain [2,4].
Although as noted above, inflammatory compo-nents are often predominant in early stages [40,41],the exact pathophysiology is unknown but strideshave been made in the understanding of possiblemechanisms that underlie the generation andmaintenance of this possible neuropathic pain[8,17]. A critical role for NMDA-receptors thatcontribute to central sensitization in chronic neu-ropathic pain is well established [16,17]. Conse-quently, the efficacy of several NMDA-receptorantagonists has been investigated in various neuro-pathic pain conditions. In human and animalstudies, ketamine was shown to have a dose-dependent effect on neuropathic pain features,such as secondary hyperalgesia, allodynia, long-term potentiation, and wind-up [42–46]. Severalclinical trials in neuropathic pain conditions haveconfirmed beneficial effects of ketamine in thetherapy of chronic pain. In a randomized con-trolled trial of postherpetic neuralgia, iv ketaminesignificantly reduced pain, allodynia, and hyper-pathia [47]. Similarly, intravenous ketamine hasbeen shown to produce significant pain relief andreduction of wind-up pain in a randomized con-trolled trial of chronic phantom pain [48]. A ran-domized trial of intramuscular ketamine provided24 hours of significant pain relief in patients withfacial neuralgia [49]. Several trials have noted long-term affects of ketamine that outlast its pharmaco-logical profile [18–20,49]. In addition, animal andclinical studies have demonstrated that the efficacyof ketamine is dose-dependent [19,43,44,50]. Asthe incidence and degree of ketamine side effectsalso depends on dosage, most trials in pain medi-cine have been performed with low doses [14]. Thistrial of anesthetic dosage of ketamine in refractoryCRPS, as well as the first patient treated on acompassionate care basis [51] demonstrated long-term significant pain relief that outlasts its pharma-cological profile.
Many aspects of the pathophysiology of CRPSremain unclear. Recently, CRPS has been positedto be a disease of the CNS [7]. The molecularmechanisms underlying CRPS are hindered bylack of an exact animal model that is completelyvalid for this complex clinical entity [52]. Its char-acteristic signs and symptoms may occur as a con-sequence of dysregulated efferent central controlof several systems (i.e., somatosensory, motor, andsympathetic) and appears to be maintained from aperipheral sensitizing afferent nociceptive barrage.The molecular mechanisms responsible forinducing and maintaining these lasting and self-maintaining neuroplastic changes in CRPS are not
Efficacy of Ketamine in Anesthetic Dosage 15
known but there is evidence for NMDA-receptormediated neuronal plasticity and facilitation ofcentral pain processing [8]. Another potentialmechanism underlying the syndrome is injuryinduced activation of central microglia that secreteinflammatory cytokines which activate centralpain projecting neurons [53]. The relative impor-tance of mechanisms for central sensitizationmediated by the NMDA-receptor and subsequentcalcium cascades or effects of inflammatory cytok-ines on pain transmission neurons or both inconcert is not known [17,21]. Recent evidence in arat model of neuropathic pain demonstrated acomparable long-term suppression of allodynia byketamine that outlasted the duration of its NMDAblockade [50]. Thus, down-regulation of centralsensitization mediated by NMDA-receptor block-ade might explain in part long-term effects of ket-amine in neuropathic pain.
Other relevant mechanisms mediated by ket-amine that contribute to pain relief in thesepatients must be considered. These include poten-tial modulation of peripheral NMDA- and non-NMDA-receptors. Ketamine inhibits peripheralglutamate receptors which play a role in bothperipheral and subsequent central sensitization[54]. In addition, ketamine interacts with variousreceptors involved in nociception that includeAMPA and kainate glutamate receptors, voltage-dependent ion channels, sodium and L-typecalcium channels, opioid receptors (m-, k-, andd-opioid receptors), GABAA-receptors, and nico-tinic and muscarinic acetylcholine receptors [15].Ketamine induced inhibition of nitric-oxide syn-thase might also contribute to its analgesic effects[15]. As noted above, proinflammatory mediatorsare known to play an essential role in the processesof peripheral and central sensitization [55].Ketamine induces a profound inhibition of pro-inflammatory cytokines and other inflammatorymediators, both in experimental and clinicalstudies [15,22]. A recent study demonstrated sig-nificant increases in proinflammatory cytokines inthe cerebrospinal fluid of CRPS patients, whichsuggests a potential role of neuroimmune activa-tion in CRPS [56]. The anti-inflammatory effectsof ketamine administered in anesthetic doses mayalso play a role in its effects on these patients.Alternatively or in addition to ketamine, mida-zolam and clonidine may also contribute to theeffectiveness of this treatment. Clonidine, acentral a2-adrenergic agonist, has analgesic prop-erties [57]. Its analgesic potency is weak but haseffect when administered by epidural, intrathecal
or a transdermal route. Although the analgesiceffects of intravenous clonidine are controversial,a synergistic interaction with ketamine in ourpatients is possible [57]. Another synergistic effectof this treatment may be due to midazolam, ashort-acting GABAA agonist. In the course ofcentral sensitization, GABA-ergic inhibitorytransmission is depressed by NMDA-dependentmechanisms which leads to prolonged depressionof inhibitory transmission and thus potentiation ofcentral pain projecting neuron hyperexcitability[17,58]. The large doses of midazolam adminis-tered during treatment would be expected toenhance GABA-ergic induced inhibition duringthis treatment while its role as an analgesic isunclear [17,58]. The possible contributions of theplacebo effect and or resetting of pain processingmechanisms due to 5 days of anesthesia in thebeneficial effects of this treatment are unknown.
A most relevant concern of this invasive proce-dure is patient safety. Modern intensive care medi-cine standards achieve a high level of patientsafety. Ketamine has been safely used for over 30years in clinical anesthesia and also in intensivecare. However, a potential concern is NMDAR-antagonist induced neurotoxicity that has beendemonstrated in animal experimental work in thedeveloping and adult rat brain [59]. Neurotoxiceffects are prevented by administration of cloni-dine and GABAA-agonists [60,61]. To the best ofour knowledge, neurotoxicity of ketamine to datehas not been demonstrated in humans [62]. Initialstudies investigating ketamine sedation in braininjured patients in the intensive care setting werenot associated with significant morbidity or mor-tality [63,64]. However, these studies were notpowered for a valid assessment of safety. Thereported duration of ketamine sedation (6.1 � 3.2days) and the dosage of ketamine (maximal dose:94 � 23 mg/kg/min) are comparable to our study(5 days of sedation; maximal dose: ~84 mg/kg/min)[63].
Nonetheless, it must be emphasized that thisprotocol is associated with serious risks. Themajor complications observed in this study wererespiratory and urinary tract infections, represent-ing typical infections in intensive care. Although,in this series, infections resolved under antibiotictreatment, it must be emphasized that infectiouscomplications still represent the main source ofmorbidity and mortality in modern intensive caremedicine. Transient ketamine-specific psychotro-pic side effects occurred on emergence from ket-amine anesthesia and were successfully controlled
Kiefer et al.16
by benzodiazepines and clonidine. There were nolong-term psychiatric or cognitive impairments inany patient [65]. Moderate muscle weakness per-sisted for a month to 6 weeks.
In addition to all of the limitations inherent ina nonrandomized uncontrolled trial, there areseveral other limitations of this study: 1) the move-ment disorder, social integration, activities of dailyliving and ability to work measures were subjectiveand have not been validated in CRPS patient; 2)the CRPS patient population studied is not repre-sentative of that seen in most pain centers as it isdrawn from the entire USA; 3) the mechanism ofthe spread of other validated factors of CRPS fromthe area of original injury is not known. The sever-ity of this clinical component in these patients isunusual and may represent or be a consequence ofthe role of central glia pathophysiology in chronicpain states, central sensitization, functional reor-ganization of pain processing systems or dysfunc-tion of descending pain control mechanisms. Thearea of primary CRPS may be maintaining a moregeneralized pain state.
A complete double blind placebo controlledrandomized clinical trial would be logistically andethically at least difficult, but its realization repre-sents a major challenge of future work to possiblyconfirm the observed effect.
Conclusion
This phase II open-label study utilizing anestheticdoses of ketamine with midazolam and clonidinesuggests possible effectiveness for severe CRPSpatients that have failed all available standardtherapies. A definitive, large multicenter random-ized controlled trial is needed to confirm theseresults.
Acknowledgments
PR and RTK wish to thank Prof. Robert J. Schwartzman,Prof. Karl-Heinz Altemeyer, and Prof. Klaus Unertl fortheir belief and support in a new clinical concept and theirsupport, which enabled the clinical realization of this study.
The authors wish to thank the nursing staff and physi-cians of the intensive care units: Station 43, KlinikumSaarbrücken, Germany, and A5-Nord/A5-Ost, UniverstiyHospital Tübingen, Germany, for their support of thisstudy and especially the excellent clinical care of thepatients, which highly contributed to the success and aboveall the safe treatment of the patients.
The authors sincerely thank Dr. Birgit Schönfisch, PhD(Institute of Medical Biometry, Eberhard-Karls University,Tübingen, Germany) for her statistical expertise, and
Professor Marcel E. Durieux (Department of Anesthe-siology, University of Virginia, Charlottesville, VA) forstimulating discussions of the data and his expertiseand constructive criticism in preparing and revising thismanuscript.
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Efficacy of Ketamine in Anesthetic Dosage 19
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alpl
exus
dist
ribut
ions
,V
1-V
3fa
cial
dist
ribut
ions
bila
tera
llyH
yper
alge
sia
topi
npric
k;sp
onta
neou
sbu
rnin
gpa
in;
evok
edsh
ootin
gpa
in;
mec
hani
cal
allo
dyni
a(d
ynam
ican
dst
atic
);th
erm
alal
lody
nia
toco
ld
Tem
pera
ture
asym
met
ry:
incr
ease
drig
htar
man
dfa
ce>
left;
eryt
hem
atou
srig
htar
man
dfa
ce;
fluct
uatin
ger
ythe
ma
right
arm
and
face
Ede
ma
ofrig
htar
man
dfa
ce;
hype
rhid
rosi
sgr
eate
rrig
htar
mth
anle
ft
Dec
reas
edra
nge
ofm
otio
nrig
htha
nd(u
nabl
eto
com
plet
ely
flex
finge
rs);
wea
knes
sof
dist
alha
ndm
uscl
es;
decr
ease
dab
ility
toin
itiat
efin
ger
mov
emen
ts;
incr
ease
dna
ilrid
ging
;lo
ssof
hair
right
hand
and
fore
arm
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
am
irror
dist
ribut
ion
Pos
itive
inup
per
trun
kle
ftbr
achi
alpl
exus
dist
ribut
ion
(hyp
eral
gesi
ato
pinp
rick;
mec
hani
cald
ynam
ican
dst
atic
allo
dyni
a;co
ldal
lody
nia)
Dec
reas
edab
ility
toin
itiat
em
ovem
ent
offin
gers
ofle
ftha
nd
No.
325
yom
ale
CR
PS
24m
onth
sB
asel
ine
Pai
nN
RS
9A
SA
Cla
ssII
Rig
htbr
achi
alpl
exus
;H
odgk
in’s
dise
ase;
com
pres
sion
ofth
ebr
achi
alpl
exus
byly
mph
oma
Rig
htbr
achi
alpl
exus
;V
1-V
3H
yper
alge
sia
topi
npric
k;sp
onta
neou
sbu
rnin
gpa
in;
evok
edla
ncin
atin
gan
dtin
glin
gpa
in;
deep
ache
;m
echa
nica
lallo
dyni
a(d
ynam
ican
dst
atic
);jo
int
pain
(sm
allj
oint
sof
the
finge
rs);
ther
mal
allo
dyni
ato
cold
Tem
pera
ture
asym
met
ry:
incr
ease
din
the
right
arm
and
face
>th
ele
ftar
man
dfa
ce;
eryt
hem
atou
sen
tire
right
arm
and
face
;no
fluct
uatio
nof
eryt
hem
ain
right
arm
and
face
Sev
ere
edem
aof
the
face
;m
oder
ate
edem
aof
the
right
arm
and
hand
;hy
perh
idro
sis
bila
tera
llyof
the
arm
san
drig
htfa
ce;
edem
ast
atic
inrig
htar
man
dfa
ce
Diff
icul
tyin
itiat
ing
fine
finge
rm
ovem
ents
right
hand
;w
eakn
ess
ofdo
rsal
and
vola
rin
tero
ssei
and
abdu
ctor
polli
cis
brev
isrig
htha
nd;
supr
aspi
natu
san
din
fras
pina
tus
wea
knes
sof
the
right
arm
;oc
casi
onal
myo
clon
icje
rkof
right
arm
;in
crea
sed
nail
grow
th,
ridgi
ngan
dth
ickn
ess
offin
gers
ofrig
htha
nd
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
the
left
arm
and
hand
Hyp
eral
gesi
ato
pinp
rick;
mec
hani
cal
dyna
mic
and
stat
ical
lody
nia;
cold
allo
dyni
a;le
ssse
vere
spon
tane
ous
burn
ing
pain
;le
ssse
vere
evok
edla
ncin
atin
gpa
in
Nor
mal
tem
pera
ture
arm
and
face
;sl
ight
eryt
hem
aof
the
left
ear;
stat
icco
lor
chan
geof
the
ear
(ery
rhem
a)
Slig
htly
slow
initi
atio
nof
mov
emen
t;fu
llst
reng
th;
noad
vent
itial
mov
emen
t;fu
llra
nge
ofm
ovem
ent
Kiefer et al.20
No.
446
yofe
mal
eC
RP
S60
mon
ths
Bas
elin
eP
ain
NR
S9.
5A
SA
Cla
ssII
Rig
htbr
achi
alpl
exus
trac
tion
inju
ryH
yper
alge
sia
topi
npric
krig
htfa
ce,
arm
,an
terio
rch
est
and
tota
lleg
;sp
onta
neou
sbu
rnin
gpa
in,
deep
ache
entir
erig
htsi
deof
the
body
;se
vere
right
L5-S
1di
strib
utio
nla
ncin
atin
gpa
in;
mec
hani
cal,
dyna
mic
and
stat
ical
lody
nia
ofen
tire
right
side
ofth
ebo
dy;
ther
mal
allo
dyni
ato
both
cold
and
heat
;co
ldal
lody
nia
spre
adsi
xin
ches
toei
ther
side
ofth
est
imul
us(t
unin
gfo
rk)
Tem
pera
ture
asym
met
ry;
right
arm
and
face
>th
anle
ft(h
ighe
r);
eryt
hem
aof
the
right
arm
and
face
;no
rmal
skin
colo
rof
the
left
arm
and
face
;flu
ctua
ting
colo
rch
ange
ofth
erig
htar
man
dfa
ce
Con
stan
ted
ema
ofth
erig
htha
nd,
arm
and
face
;hy
perh
idro
sis
ofrig
htar
man
dfa
ce;
cons
tant
edem
aof
right
face
and
hand
;sy
mpt
oms
oftig
htne
ssin
the
hand
Dec
reas
edra
nge
ofm
otio
nof
all
finge
rsof
right
hand
;un
able
tofle
xth
efin
gers
fully
;w
eakn
ess
ofal
ldi
stal
mus
cles
ofrig
htha
nd;
exag
gera
tion
ofph
ysio
logi
ctr
emor
ofrig
htup
per
extr
emity
;oc
casi
onal
myo
clon
icje
rkof
right
uppe
rex
trem
ity;
flexi
ondy
ston
icpo
stur
eof
arm
and
wris
t;m
otor
negl
ect
ofrig
htar
m;
loss
ofha
iron
the
right
fore
arm
;th
icke
ned
ridge
dan
dbr
ittle
nails
ofrig
htha
nd
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
othe
rth
anpr
imar
yar
eas
ofin
volv
emen
trig
htar
mC
linic
alcr
iterio
nfa
ctor
sth
atw
ere
posi
tive
inot
her
than
prim
ary
area
sof
invo
lvem
ent
right
leg
Tact
ilem
echa
nica
ldyn
amic
and
stat
ical
lody
nia
(upp
eran
dlo
wer
trun
k,br
achi
alpl
exus
dist
ribut
ions
onth
ele
ft);
hype
ralg
esia
topi
npric
k(u
pper
and
low
ertr
unk
brac
hial
plex
usdi
strib
utio
ns);
cold
allo
dyni
a(u
pper
and
low
ertr
unk)
;le
ftar
mM
echa
noal
lody
nia
(sta
tican
ddy
nam
ic)
ofth
erig
htup
per
leg
inre
gion
aldi
strib
utio
n
Min
imal
hype
rhid
rosi
sof
left
arm
;no
rmal
tem
pera
ture
ofle
ftar
mM
inim
aler
ythe
ma
(rar
ely)
ofth
ele
ftar
mS
light
diffi
culty
initi
atin
gan
dm
aint
aini
ngle
ftha
ndfin
ger
mov
emen
ts
Add
ition
alfe
atur
esS
ever
eno
n-flu
ctua
ting
veno
usdi
sten
tion
inha
ndan
dfo
rear
mve
ins;
L4-L
5;L5
-S1
radi
cula
rm
otor
and
sens
ory
chan
ges
onth
ele
ftsi
de;
eryt
hem
atou
sea
ron
the
right
;up
per
trun
kof
brac
hial
plex
us;
low
ertr
unk
brac
hial
plex
us
No.
529
yofe
mal
eC
RP
S30
mon
ths
Bas
elin
eP
ain
NR
S8.
5A
SA
Cla
ssII
Rig
htbr
achi
alpl
exus
(ele
ctric
alin
jury
;te
arof
the
labr
umof
the
glen
oid
foss
aof
the
hum
erus
)
Sev
ere
hype
ralg
esia
topi
npric
kre
gion
aldi
strib
utio
nof
the
right
uppe
rex
trem
ity;
spon
tane
ous
burn
ing
pain
;lig
hten
ing-
like
pain
right
uppe
rex
trem
ity;
mec
hani
cal
dyna
mic
and
stat
ical
lody
nia;
cold
allo
dyni
a;de
epm
uscl
ese
nsiti
zatio
nto
pres
sure
ofrig
htup
per
extr
emity
inre
gion
aldi
strib
utio
n
Hig
her
tem
pera
ture
right
uppe
rex
trem
ityth
anle
ftup
per
extr
emity
;er
ythe
ma
ofen
tire
right
uppe
rex
trem
ity;
left
trap
eziu
srid
geha
dco
lor
chan
ge;
eryt
hem
ast
atic
inaf
fect
edar
eas
Ede
ma
ofth
erig
htup
per
extr
emity
and
face
;hy
perh
idro
sis
ofrig
htup
per
extr
emity
;sw
olle
nst
iffrig
htha
nd
Rig
htha
ndde
mon
stra
ted
diffi
culty
initi
atin
gfin
ger
mov
emen
ts;
wea
knes
sof
alld
ista
lrig
htha
ndm
uscu
latu
re;
spas
mof
the
right
uppe
rex
trem
ity;
loss
ofha
ir;br
ittle
atro
phic
nails
with
ridgi
ng;
loss
ofin
tegu
men
tof
the
4than
d5th
finge
rsrig
htha
nd;
shin
yth
insk
inof
the
right
hand
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
cont
iguo
usar
eas
Mec
hano
allo
dyni
a,(s
tatic
and
dyna
mic
)of
the
right
face
Allo
dyni
aan
dhy
pera
lges
iato
pinp
rick
inth
esa
me
dist
ribut
ion;
spon
tane
ous
burn
ing
pain
inth
efa
cean
dth
igh
Incr
ease
dte
mpe
ratu
refa
ceV
1-V
3,an
dre
gion
ally
inth
eup
per
thig
h;er
ythe
ma
ofth
efa
ce;
noflu
ctua
tion
ofer
ythe
ma
ofth
efa
ce
Ede
ma
and
hipe
rhid
rosi
sof
the
right
face
V1-
V3
dist
ribut
ion;
com
plai
nts
ofna
rrow
ing
ofpa
lpeb
ralfi
ssur
efr
omed
ema
right
V1
Add
ition
alfe
atur
esP
ain
inbi
occi
pita
lten
don;
seve
reTi
nels
igns
with
com
pres
sion
ofth
esu
prar
adic
ular
foss
a,pr
onat
orca
nal,
Arc
ade
ofF
rohs
ean
dca
rpal
tunn
el;
ante
rior
shou
lder
inst
abili
ty;
touc
hon
the
arm
spre
adto
the
face
Efficacy of Ketamine in Anesthetic Dosage 21
Ap
pen
dix
1:C
ontin
ued
Dem
ogra
phic
sTr
igge
ring
Inju
ryS
iteof
Prim
ary
CR
PS
Abn
orm
aliti
esin
Pai
nP
roce
ssin
gF
acto
r1
Ski
nC
olor
and
Tem
pera
ture
Cha
nges
Fac
tor
2
Fac
tor
Vas
omot
oran
dS
udom
otor
/Ede
ma
Cha
nges
Fac
tor
3
Mot
orD
ysfu
nctio
nan
dTr
ophi
cF
eatu
res
Fac
tor
4
No.
646
yofe
mal
eC
RP
S72
mon
ths
Bas
elin
eP
ain
NR
S8.
5A
SA
Cla
ssIII
Cru
shin
jury
ofth
erig
htan
kle
and
foot
;op
erat
ive
oste
osyn
thes
isof
the
right
foot
Hyp
eral
gesi
ato
pinp
rick
ofrig
htlo
wer
extr
emity
,bu
rnin
gpa
inm
ost
seve
reat
the
site
ofth
eor
igin
alfo
otsu
rger
y;jo
int
pain
right
foot
;lig
hten
ing-
like
pain
srig
htfo
otan
dle
g
Col
der
right
leg
toth
ekn
eeth
anle
ft;er
ythe
ma
ofth
erig
htlo
wer
extr
emity
Ede
ma
ofrig
htlo
wer
extr
emity
and
face
;st
iffne
ssan
dde
crea
sed
mob
ility
from
swel
ling
ofrig
htfo
otan
dha
nd;
hype
rhid
rosi
sof
the
right
low
erex
trem
ity,
hype
rhid
rosi
san
ded
ema
ofth
erig
htle
gto
the
thig
h,va
som
otor
and
sudo
mot
orch
ange
sV
1-V
3rig
htfa
ce
Diff
icul
tyin
itiat
ing
mov
emen
t;w
eakn
ess
ofin
vers
ion,
dors
iflex
ion
and
ever
sion
ofth
erig
htde
crea
sed
rang
eof
mot
ion
toal
lpla
nes
ofth
erig
ht;
feel
ing
asif
the
right
leg
wou
ldlo
sest
abili
ty;
thic
kene
d,br
ittle
nails
;lo
ssof
hair
over
the
dist
allo
wer
third
ofth
ele
gan
dfo
ot
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
cont
iguo
usip
sila
tera
lext
rem
ities
(leg
and
uppe
rex
trem
ity),
face
and
mirr
orfo
otdi
strib
utio
n
Rig
htco
ntig
uous
leg,
uppe
rex
trem
ityan
dfa
ce);
hype
ralg
esia
topi
npr
ick;
spon
tane
ous
burn
ing,
lanc
inat
ing
and
deep
pain
;m
echa
nica
l,dy
nam
ican
dst
atic
allo
dyni
a;de
epm
uscl
ese
nsiti
zatio
n;co
ldal
lody
nia
(rig
htfa
ce>
left
arm
)
Incr
ease
dte
mpe
ratu
reof
the
right
face
;de
crea
sed
tem
pera
ture
ofth
erig
htup
per
extr
emity
and
right
low
erex
trem
ity
Hyp
erhi
dros
is;
dusk
ycy
anos
isrig
htar
man
dup
per
thig
hP
oor
initi
atio
nan
dm
aint
enan
ceof
fine
mov
emen
ts;
wea
knes
sof
exte
rnal
halli
ces
long
usrig
htup
per
extr
emity
;de
crea
sed
initi
atio
nof
mov
emen
tle
ftto
esan
dan
kle
Add
ition
alfe
atur
esS
ever
ete
nder
ness
inar
eaof
surg
ical
scar
;sp
read
ofst
imul
us(p
inpr
ick
and
cold
)fr
omth
erig
htfo
otto
the
right
face
;V
2,ed
ema
and
hype
rhid
rosi
sof
right
face
,m
ost
seve
re;
spon
tane
ous
burn
ing
pain
No.
728
yofe
mal
eC
RP
S60
mon
ths
Bas
elin
eP
ain
NR
S9.
5A
SA
Cla
ssIII
Trau
ma
toth
elo
wer
back
and
right
leg
Hyp
eral
gesi
arig
htlo
wer
extr
emity
topi
npric
k;se
vere
spon
tane
ous
burn
ing
pain
ofrig
htlo
wer
extr
emity
(reg
iona
ldis
trib
utio
n);
deep
knee
join
tpa
in;
pain
atth
ein
jury
site
ofth
erig
htlo
wer
back
;m
echa
nica
l,dy
nam
ican
dst
atic
allo
dyni
arig
htle
g;co
ldal
lody
nia
right
low
erex
trem
ity
Rig
htle
gsl
ight
lyco
lder
than
left
leg;
both
cold
erth
anno
rmal
;flu
ctua
ting
eryt
hem
aof
the
right
low
erex
trem
ity
Ede
ma
ofrig
htle
g(s
ever
e);
hype
rhid
rosi
sof
right
leg
>le
ft;ed
ema
not
fluct
uatin
g(c
ompo
unde
d)by
the
patie
ntbe
ing
whe
elch
air
boun
d
Una
ble
toin
itiat
em
ovem
ent
ofth
eto
es;
wea
knes
sof
allm
uscl
egr
oups
ofth
erig
htle
g;de
crea
sed
rang
eof
mot
ion
ofth
erig
htfo
ot,
myo
clon
icje
rks;
dyst
onia
right
foot
;po
stur
e(p
lant
arfle
xed
and
inve
rted
);th
icke
ned
nails
;br
awny
edem
a;ar
eas
ofdy
stro
phic
skin
Kiefer et al.22
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
cont
iguo
usar
eas
ofth
eip
sila
tera
lext
rem
ity,
face
and
cont
rala
tera
lleg
Ipsi
late
rala
rmhy
pera
lges
iato
pinp
rick;
dyna
mic
and
stat
icm
echa
noal
lody
nia;
cold
and
hot
allo
dyni
a;jo
int
pain
;de
epm
uscl
eal
lody
nia
topr
essu
re;
spon
tane
ous
burn
ing
pain
,lig
hten
ing-
like
pain
;tin
glin
gpa
inF
ace
right
side
(V1-
V3)
hype
ralg
esia
topi
npric
k;dy
nam
ican
dst
atic
mec
hano
allo
dyni
a;co
ldal
lody
nia
Rig
htup
per
extr
emity
war
mer
than
left
uppe
rex
trem
ity;
eryt
hem
atou
srig
htar
man
dha
nd;
varie
dw
ithpa
in,
mov
emen
tan
dem
otio
nals
tres
s
War
mer
than
the
left
face
(par
ticul
arly
V2)
;er
ythe
mat
ous
chee
kan
drig
htea
r;no
n-va
ryin
ger
ythe
ma
Mod
erat
eed
ema
ofth
erig
htha
nd;
hype
rhid
rosi
sco
mpa
red
tole
ftup
per
extr
emity
;no
nvar
ying
degr
eeof
edem
aof
right
uppe
rex
trem
ity
Ede
ma
ofrig
ht>
left
uppe
rex
trem
ity;
hype
rhid
rosi
s>
left
uppe
rex
trem
ity;
cons
tant
edem
aof
the
face
Poo
rin
itiat
ion
and
mai
nten
ance
offin
ger
mov
emen
t;w
eakn
ess
ofal
lm
uscl
egr
oups
ofth
erig
htup
per
extr
emity
;m
yocl
onic
jerk
san
dsp
asm
spr
ovok
edw
ithex
erci
se
Add
ition
alfe
atur
esTi
nels
igns
very
posi
tive
atsu
prac
lavi
cula
rfo
ssa,
Arc
ade
ofF
rohs
e,pr
onat
orca
nala
ndca
rpal
tunn
elbi
late
rally
;st
imul
ussp
read
from
arm
tofa
cerig
htsi
de;
leg
tofa
cerig
htsi
de
Mirr
ordi
strib
utio
nof
left
leg
hype
ralg
esia
topi
npric
k;dy
nam
ican
dst
atic
mec
hano
allo
dyni
a;co
ldal
lody
nia
(equ
alth
roug
hout
the
leg)
Coo
ler
than
right
leg;
min
imal
eryt
hem
aco
mpa
red
torig
htle
g;co
lor
chan
geva
ried
with
emot
iona
lstr
ess
and
cold
Ede
ma
ofth
ele
ftle
g>
dist
ally
(com
poun
ded
bybe
ing
whe
elch
air
boun
d);
non-
vary
ing
edem
a;sl
ight
lyle
sshy
perh
idro
ticth
anrig
htsi
de
Una
ble
toin
itiat
em
ovem
ent
ofth
eto
esor
low
erle
g;m
inim
alm
ovem
ent
ofili
opso
as;
myo
clon
icje
rks;
dyst
onia
ofth
ele
ftfo
ot(in
vert
edan
dpl
anta
rfle
xed)
;th
icke
ned,
ridge
dan
dbr
ittle
nails
,sh
iny
thin
skin
ofth
efo
ot
No.
842
yofe
mal
eC
RP
S30
mon
ths
Bas
elin
eP
ain
NR
S8.
5A
SA
Cla
ssII
Cru
ciat
elig
amen
tte
ar;
tibia
lpl
ate
frac
ture
ofth
erig
htkn
eeH
yper
alge
sia
ofth
erig
htkn
eean
dle
gin
are
gion
aldi
strib
utio
n;dy
nam
ican
dst
atic
mec
hano
allo
dyni
aof
the
skin
;de
epse
nsiti
zatio
nof
the
quad
ricep
sm
uscl
e;sp
onta
neou
sbu
rnin
gpa
inof
the
knee
that
was
cont
inuo
us;
evok
edlig
hten
ing-
like
pain
and
deep
ache
with
wei
ght
bear
ing
Tem
pera
ture
asym
met
ry(w
arm
er)
than
left
knee
;er
ythe
ma
ofrig
htkn
ee;
lived
ore
ticul
aris
and
dusk
ycy
anos
is;
incr
ease
der
ythe
ma
with
exer
cise
and
heat
ofth
erig
htkn
eear
eaan
dup
per
leg
Ede
ma
ofrig
htkn
eear
ea;
min
imal
edem
aof
the
right
uppe
rle
g;sw
eatin
gas
ymm
etry
>th
anle
ftkn
eean
dle
g;va
riabl
eed
ema
afte
rex
erci
se(s
wim
min
gan
dw
alki
ng)
Poo
rin
itiat
ion
and
mai
nten
ance
offin
em
ovem
ent
ofto
eson
the
right
;de
crea
sed
rang
eof
mot
ion
ofrig
htkn
ee;
wea
knes
sof
quad
ricep
san
dex
tens
orha
lluci
slo
ngus
onth
erig
ht;
min
imal
nail,
hair
and
skin
chan
geof
the
right
leg
and
foot
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
ipsi
late
rala
rman
dfa
ceas
wel
las
ina
mirr
ordi
strib
utio
n
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
inth
eup
per
extr
emiti
esof
the
supr
acla
vicu
lar
foss
a;C
2-C
3ex
itfo
ram
ina;
Arc
ade
ofF
rohs
e;pr
onat
orca
nal,
cubi
tala
ndca
rpal
tunn
el;
stim
ulus
appl
ied
toR
knee
(pin
pric
k)at
times
felt
inth
eR
orL
face
.
Ipsi
late
ralr
ight
arm
;ip
si-
late
ralf
ace;
mirr
orle
ftle
g,hy
pera
lges
iaan
dal
lody
nia
(sta
tican
ddy
nam
ic)
V1-
V3
edem
aan
dhy
perh
idro
sis
right
face
Ipsi
late
ralr
ight
arm
;le
ftle
gpo
orin
itiat
ion
ofm
ovem
ent
Efficacy of Ketamine in Anesthetic Dosage 23
Ap
pen
dix
1:C
ontin
ued
Dem
ogra
phic
sTr
igge
ring
Inju
ryS
iteof
Prim
ary
CR
PS
Abn
orm
aliti
esin
Pai
nP
roce
ssin
gF
acto
r1
Ski
nC
olor
and
Tem
pera
ture
Cha
nges
Fac
tor
2
Fac
tor
Vas
omot
oran
dS
udom
otor
/Ede
ma
Cha
nges
Fac
tor
3
Mot
orD
ysfu
nctio
nan
dTr
ophi
cF
eatu
res
Fac
tor
4
No.
922
yofe
mal
eC
RP
S72
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Tend
onru
ptur
edi
git
IV;
oper
ativ
ere
pair
inth
erig
htha
ndH
yper
alge
sia
topi
npric
kof
right
uppe
rex
trem
ity;
dyna
mic
and
stat
icm
echa
noal
lody
nia
ofth
een
tire
right
uppe
rex
trem
itybu
tm
ore
seve
rein
the
late
ralh
and;
spon
tane
ous
deep
ache
and
burn
ing
lanc
inat
ing
pain
ofth
erig
htha
ndan
drig
htup
per
extr
emity
Tem
pera
ture
asym
met
ry,
prim
arily
war
mer
ofrig
htve
rsus
left
hand
;er
ythe
ma
ofrig
htha
nd;
colo
rch
ange
varie
dfr
omer
ythe
ma
todu
sky
cyan
osis
;liv
edo
retic
ular
isof
right
uppe
rex
trem
itym
ost
seve
rein
the
med
ialf
orea
rm
Ede
ma
ofrig
htha
nd(a
llfin
gers
);sw
eatin
gas
ymm
etry
right
>le
ftup
per
extr
emity
;m
ost
seve
rein
the
hand
;no
n-va
ryin
grig
htha
nded
ema
Wea
knes
sof
alli
ntrin
sic
hand
mus
cles
onth
erig
ht;
decr
ease
dra
nge
ofm
otio
nrig
htha
nd;
unab
leto
clos
efin
gers
into
afis
t;in
crea
sed
phys
iolo
gic
and
inte
ntio
ntr
emor
;sp
onta
neou
sdr
oppi
ngob
ject
s;sh
iny
skin
ofth
edo
rsum
ofth
erig
htha
nd;
loss
ofsu
bcut
aneo
ustis
sue
digi
tIV
,V
;br
ittle
,rid
ged
and
thic
kene
dna
ilsrig
htha
nd
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
the
ipsi
late
ral
uppe
ran
dlo
wer
extr
emity
;ip
sila
tera
lfac
ean
dco
ntra
late
ral
hand
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
insu
prac
lavi
cula
rfo
ssa,
Arc
ade
ofF
rohs
e,pr
onat
orca
nal,
cubi
tal
tunn
elrig
ht>
left;
spre
adof
pinp
rick
from
the
hand
toth
efa
cean
dar
m
Ipsi
late
rala
rman
dle
g;ip
sila
tera
lfa
ce(V
1-V
3)sp
onta
neou
sbu
rnin
gpa
in,
hype
ralg
esia
topi
npr
ick
Ipsi
late
rala
rman
dle
g;ip
sila
tera
lfac
e(V
1-V
3)hy
perh
idro
sis
and
war
mer
;co
ntra
late
ralh
and
(muc
hle
ssde
gree
than
Rha
nd)
Ipsi
late
rala
rman
dle
g;ip
sila
tera
lfac
e(V
1-V
3)hy
perh
idro
sis
and
edem
a;co
ntra
late
ralh
and
(muc
hle
ssde
gree
than
right
hand
)
Ipsi
late
rala
rman
dle
g;co
ntra
late
ral
hand
(poo
rin
itiat
ion
offin
ger
and
toe
mov
emen
t)
No.
1019
yofe
mal
eC
RP
S60
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Fra
ctur
eof
met
atar
salV
ofth
erig
htfo
otH
yper
alge
sia
topi
npric
kof
the
right
leg
and
right
foot
atar
eaof
inju
ry(m
ost)
seve
re;
dyna
mic
and
stat
icm
echa
no-a
llody
nia
ofth
erig
htfo
ot;
cold
allo
dyni
aof
the
right
foot
;sp
onta
neou
sbu
rnin
gpa
inof
the
foot
;m
ost
seve
repa
inat
the
area
ofth
eor
igin
alfr
actu
re;
evok
edla
ncin
atin
gpa
inan
dde
epac
hew
ithw
alki
ng;
occa
sion
alsp
onta
neou
ssq
ueez
ing
pain
ofth
erig
htfo
otan
dle
g
Tem
pera
ture
asym
met
ryrig
htfo
otco
lder
than
left;
fluct
uate
sw
ithoc
casi
onal
right
foot
war
mer
than
left;
colo
rch
ange
with
eryt
hem
aal
tern
atin
gw
ithdu
sky
cyan
osis
ofrig
htfo
ot>
left
foot
;he
atan
dco
ldev
oked
eryt
hem
aor
cyan
osis
resp
ectiv
ely
Ede
ma
ofdo
rsum
ofrig
ht>
left
foot
;sw
eatin
gas
ymm
etry
right
>le
ftfo
ot;
posi
tion
(dep
ende
nt)
incr
ease
ded
ema
but
alw
ays
pres
ent
right
>le
ftfo
ot
Dec
reas
edex
tens
ion
and
flexi
onof
the
right
foot
;st
iffne
ssof
the
right
foot
;sl
ight
dyst
onia
atre
stw
ithpl
anta
rfle
xion
and
inve
rsio
nof
right
foot
;ra
rem
yocl
onic
jerk
ofth
erig
htsi
de
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
the
ipsi
late
ral
face
and
extr
emiti
es
Left
leg;
right
arm
;rig
htfa
ce(V
1-V
3)sp
onta
neou
spa
inan
dm
echa
noal
lody
nia
(sta
tican
ddy
nam
ic)
Left
leg;
right
face
(V1-
V3)
usua
llyer
ythe
mat
ous
but
alte
rnat
ing
blan
ched
Left
leg;
right
face
(V1-
V3)
edem
atou
san
dus
ually
dusk
yan
dcy
anot
ic
Left
leg;
right
arm
;le
ftar
m;
left
foot
;po
orin
itiat
ion
ofm
ovem
ent;
wea
knes
sof
left
intr
insi
cha
ndm
uscl
es
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
bila
tera
llysu
prac
lavi
cula
rfo
ssa,
Arc
ade
ofF
rohs
e,pr
onat
orca
nal,
fora
min
aex
itar
eas
C2–
C3;
spre
adof
pinp
rick,
hype
ralg
esia
and
cold
stim
ulus
toth
een
tire
right
side
from
ast
imul
usto
right
foot
.
Kiefer et al.24
No.
1120
yofe
mal
eC
RP
S36
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Trau
ma
torig
htsh
ould
eran
drig
htar
m(b
lunt
trau
ma
from
falli
ngob
ject
)
Hyp
eral
gesi
ato
pinp
rick
right
uppe
rex
trem
ity;
dyna
mic
and
stat
icm
echa
noal
lody
nia
ofrig
htup
per
extr
emity
;co
ldan
dw
arm
allo
dyni
aof
right
uppe
rex
trem
ity;
spon
tane
ous
burn
ing
pain
;de
epac
he;
evok
edla
ncin
atin
gpa
in;
pain
fult
ingl
ing
ofen
tire
right
uppe
rex
trem
ity;
spon
tane
ous
pain
wor
serig
htbr
achi
alpl
exus
dist
ribut
ions
Tem
pera
ture
asym
met
ryrig
ht>
left
uppe
rex
trem
ity;
eryt
hem
aof
right
>le
ftup
per
extr
emity
;va
riabl
eco
lor
chan
gew
ithem
otio
nals
tres
s,ex
erci
sean
dco
ld
Ede
ma
ofth
erig
htup
per
extr
emity
;hy
perh
idro
sis
right
>le
ftup
per
extr
emity
;pi
tting
edem
a(m
ild)
offo
rear
m
Dec
reas
edra
nge
ofm
otio
nof
right
hand
inex
tens
ion;
inab
ility
tocl
ose
hand
into
afis
t;po
orin
itiat
ion
offin
efin
ger
mov
emen
t;sp
asm
and
myo
clon
us(v
aria
ble
ofrig
htup
per
extr
emity
wea
knes
sof
dors
alan
dvo
lar
inte
ross
eian
dab
duct
orpo
llice
sbr
evis
;sl
ight
delto
id.
bice
ps,
tric
eps,
supr
aspi
natu
sw
eakn
ess;
britt
le,
ridge
dna
ils;
loss
ofin
tegu
men
tdi
git
IV,
V
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
the
ipsi
late
ral
face
,le
gan
dco
ntra
late
rala
rm
Spo
ntan
eous
pain
inip
sila
tera
lfac
e(V
1-V
33)
;ip
sila
tera
lleg
;co
ntra
late
ralu
pper
extr
emity
both
ina
regi
onal
dist
ribut
ion;
dyna
mic
and
stat
icm
echa
noal
lody
nia
inth
esa
me
dist
ribut
ions
Ede
ma
and
hype
rhid
rosi
sV
1-V
3of
ipsi
late
ralf
ace,
ipsi
late
rall
eg;
uppe
rex
trem
ityex
trem
itypr
imar
ilyth
eha
nd
Ipsi
late
rall
eg;
cont
rala
tera
lupp
erex
trem
ityde
crea
sed
abili
tyto
initi
ate
mov
emen
ts,
wea
knes
sof
intr
insi
cha
ndan
dfo
otm
uscl
es
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
inth
esu
prac
lavi
cula
rfo
ssa;
exit
fora
min
aof
C2-
CV
asom
otor
and
Sud
omot
or/E
dem
aC
hang
es,
CV
asom
otor
and
Sud
omot
or/E
dem
aC
hang
es-C
4;pr
onat
orca
nal,
cubi
tala
ndca
rpal
tunn
el;
dyst
roph
icpu
nche
dou
tsk
inul
cers
;br
own
papu
lar
skin
lesi
ons
ofrig
htup
per
extr
emity
No.
1235
yofe
mal
eC
RP
S72
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
III
Trau
ma
torig
htsh
ould
eran
drig
htar
mH
yper
alge
sia
topi
npric
kof
the
entir
eup
per
extr
emity
;dy
nam
ican
dst
atic
mec
hano
allo
dyni
aen
tire
right
uppe
rex
trem
ity;
cold
allo
dyni
arig
htup
per
extr
emity
;al
lody
nia
tode
epso
mat
icpr
essu
re;
pain
fulj
oint
mov
emen
t(b
oth
smal
land
larg
ejo
ints
ofrig
htup
per
extr
emity
)
Tem
pera
ture
asym
met
ry;
right
uppe
rex
trem
ityco
lder
than
left;
cyan
otic
,bl
uish
,liv
edo
retic
ular
isrig
ht>
left
uppe
rex
trem
ity
Ede
ma
ofrig
htup
per
extr
emity
;ha
nd>
fore
arm
;hy
perh
idro
sis
ofha
ndan
dfo
rear
m;
varia
tion
ined
ema
due
tode
pend
ency
and
hand
use
Dec
reas
edra
nge
ofm
otio
nof
flexo
rsof
the
hand
and
prox
imal
shou
lder
gird
lem
uscl
es;
mot
orne
glec
tof
the
right
;in
crea
sed
phys
iolo
gic
trem
or;
atro
phy
ofin
tegu
men
tof
digi
tIV
,V
;br
ittle
ridge
nails
onrig
htha
nd;
loss
ofrig
htfo
rear
mha
ir
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
right
face
and
leg
and
left
arm
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
bila
tera
llysu
prac
lavi
cula
rfo
ssa,
pron
ator
cana
l,cu
bita
land
carp
altu
nnel
s;sp
read
ofpi
npric
kan
dco
ldst
imul
usco
ntig
uous
lyfr
omar
eaof
appl
icat
ion
(12–
14in
ches
).
Ery
them
aan
din
crea
sed
tem
pera
ture
ofV
1-V
3of
right
face
Ede
ma
and
hype
rhid
rosi
sof
the
right
face
(V1-
V3)
Rig
htle
gde
crea
sed
initi
atio
nof
mov
emen
t
Efficacy of Ketamine in Anesthetic Dosage 25
Ap
pen
dix
1:C
ontin
ued
Dem
ogra
phic
sTr
igge
ring
Inju
ryS
iteof
Prim
ary
CR
PS
Abn
orm
aliti
esin
Pai
nP
roce
ssin
gF
acto
r1
Ski
nC
olor
and
Tem
pera
ture
Cha
nges
Fac
tor
2
Fac
tor
Vas
omot
oran
dS
udom
otor
/Ede
ma
Cha
nges
Fac
tor
3
Mot
orD
ysfu
nctio
nan
dTr
ophi
cF
eatu
res
Fac
tor
4
No.
1338
yofe
mal
eC
RP
S24
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
III
Cru
shin
jury
digi
tIII
right
hand
,po
stop
erat
ive
wou
ndin
fect
ion
and
ampu
tatio
nof
the
digi
t
Hyp
eral
gesi
ato
pinp
rick
ofth
een
tire
Rha
ndan
dar
m,
site
ofam
puta
tion
scar
mos
tse
vere
;dy
nam
ican
dst
atic
mec
hano
allo
dyni
aof
the
entir
eR
arm
;de
epso
mat
icse
nsiti
zatio
nan
dal
lody
nia
offo
rear
man
dup
per
arm
mus
cula
ture
;jo
int
pain
inth
eha
ndw
ithm
ovem
ent
Tem
pera
ture
asym
met
ryrig
htha
ndco
lder
than
left;
dusk
ycy
anos
isof
the
right
hand
>le
ft;liv
edo
retic
ular
isrig
htfo
rear
m>
left;
colo
rch
ange
right
hand
varia
ble
with
emot
iona
lstr
ess,
cold
and
exer
cise
Ede
ma
ofrig
htha
nd>
left
hand
;hy
perh
idro
sis
ofth
erig
htup
per
extr
emity
>th
anle
ft;sw
ellin
gof
the
hand
incr
ease
dw
ithus
ean
dde
pend
ency
Dec
reas
edra
nge
ofm
otio
nof
all
join
tsin
right
hand
;de
crea
sed
abili
tyto
clen
chth
eha
ndin
toa
fist;
wea
knes
sof
intr
insi
cha
ndm
uscl
es;
poor
initi
atio
nan
dm
aint
enan
ceof
frac
tiona
ted
finge
rm
ovem
ent;
dyst
onic
hand
post
ure
(flex
ion)
;th
inat
roph
icsk
in;
britt
le,
thic
kene
dan
dat
roph
icna
ils
Clin
ical
crite
rion
fact
ors
that
wer
epo
sitiv
ein
right
face
and
right
leg;
left
arm
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
bila
tera
llyin
supr
acl
avic
ular
foss
a;A
rcad
eof
Fro
hse,
pron
ator
cana
l,cu
bita
ltu
nnel
and
carp
altu
nnel
;sp
read
ofco
ldst
imul
usap
prox
imat
ely
12in
ches
from
the
hand
upth
ear
m;
spre
adof
pinp
rick
from
the
Rha
ndto
the
ipsi
late
ralf
ace
onth
eR
Rig
htfa
ce(V
1-V
3)er
ythe
mat
ous,
war
mer
than
leg
Ede
ma
and
hype
rgid
rosi
sof
right
face
,rig
htle
gan
dle
ftar
mR
ight
leg;
poor
initi
atio
nan
dfin
em
ovem
ents
No.
1419
yom
ale
CR
PS
84m
onth
sB
asel
ine
Pai
nN
RS
9A
SA
Cla
ssII
Spr
ain
inju
ryof
the
right
hand
Hyp
eral
gesi
ato
pinp
rick
over
the
entir
erig
htup
per
quad
rant
;sp
onta
neou
sbu
rnin
gpa
inin
right
brac
hial
plex
usdi
strib
utio
ns;
chro
nic
deep
som
atic
achi
ngpa
in;
evok
edpa
roxy
smal
pain
inrig
htbr
achi
alpl
exus
dist
ribut
ions
;m
echa
nica
l,dy
nam
ican
dst
atic
tact
ileal
lody
nia
ofth
ebr
achi
alpl
exus
dist
ribut
ions
and
V1-
V3
Tem
pera
ture
asym
met
ry,
the
right
hand
and
arm
war
mer
than
the
left;
eryt
hem
aof
the
right
arm
and
face
toa
grea
ter
degr
eeth
anth
ele
ft;er
ythe
ma
incr
ease
dw
ithpr
ovoc
ativ
em
aneu
vers
ofst
ress
and
cold
Ede
mat
ous
right
arm
and
face
;hy
perh
idro
sis
ofrig
htar
man
dfa
ce;
tight
ness
ofso
fttis
sues
ofha
ndan
dfo
rear
m;
eye
alm
ost
swol
len
shut
durin
gse
vere
exac
erba
tions
Wea
knes
sof
intr
insi
crig
htha
ndm
uscl
es;
decr
ease
dra
nge
ofm
otio
nof
right
finge
rsan
drig
htw
rist;
inab
ility
toin
itiat
efin
em
ovem
ents
;in
crea
sed
phys
iolo
gic
trem
orof
right
hand
;br
ittle
,rid
ged
nails
ofrig
htha
nd;
som
eha
irth
icke
ned
onrig
htfo
rear
m
Clin
ical
crite
rion
fact
ors
inot
her
area
ofC
RP
Sin
volv
emen
t
Add
ition
alfe
atur
esS
prea
ding
pain
from
aco
ldst
imul
us6–
7in
ches
from
site
ofap
plic
atio
nrig
htsi
de;
spre
adin
gpa
infr
ompi
npric
kst
imul
usfr
omth
ear
mto
the
face
Rig
htfa
ce(V
1-V
3)er
ythe
mat
ous
Ede
ma
prim
arily
dors
umof
the
fore
arm
and
hand
onth
ele
ftsi
de
Left
arm
wea
knes
sof
intr
insi
cha
ndm
uscl
es;
decr
ease
din
itiat
ion
ofm
ovem
ent
ofle
ftto
es
Kiefer et al.26
No.
1536
yofe
mal
eC
RP
S60
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Par
aven
ous
IVlin
ein
filtr
atio
nof
the
left
fore
arm
Hyp
eral
gesi
ato
pinp
rick
over
the
entir
ele
ftup
per
extr
emity
;sp
onta
neou
sbu
rnin
gpa
inov
erth
een
tire
left
uppe
rqu
adra
ntin
clud
ing
neck
,fa
ce,
arm
and
ches
t(a
bdom
ensp
ared
);m
echa
nica
ltac
tile
dyna
mic
and
stat
ical
lody
nia
over
the
left
uppe
rqu
adra
ntan
dfa
ce;
tric
eps,
fore
arm
mus
cles
;co
ldal
lody
nia
over
the
left
uppe
rqu
adra
ntin
clud
ing
the
neck
and
face
;sm
alla
ndla
rge
join
tpa
inw
ithm
ovem
ent
Tem
pera
ture
asym
met
ryle
ftup
per
quad
rant
>th
anrig
ht;
redn
ess
ofth
ele
ftup
per
extr
emity
and
face
(prim
arily
V2-
V3)
;er
ythe
ma
incr
ease
dw
ithpr
ovok
ing
fact
ors
ofst
ress
Ede
ma
ofle
ftfa
ce,
arm
and
hand
;hy
perh
idro
sis
ofle
ftfa
ce,
arm
and
hand
;ed
ema
ofaf
fect
edar
eas
varie
sw
ithem
otio
nals
tres
san
dpo
sitio
nof
extr
emity
Dec
reas
edra
nge
ofm
ovem
ent
ofle
ftfin
ger
and
wris
tex
tens
oran
dfle
xor
mus
cles
;in
abili
tyto
fully
mak
ea
fist
inle
ftha
nd;
poor
initi
atio
nof
mov
emen
tof
the
left
hand
;w
eakn
ess
ofdo
rsal
and
vola
rin
tero
ssei
,ab
duct
orpo
llice
sbr
evis
ofth
ele
ftha
nd;
britt
le,
thic
kene
dna
ilsof
allfi
nger
sof
the
left
hand
;sl
ight
loss
ofha
iron
the
left
fore
arm
Clin
ical
crite
rion
fact
ors
inot
her
area
ofC
RP
Sin
volv
emen
tR
ight
uppe
rtr
unk
brac
hial
plex
us;
left
leg
(mec
hani
cala
ndth
erm
alal
lody
nia)
;rig
htar
m,
hype
ralg
esia
topi
npric
kan
dm
echa
noal
lody
nia
(sta
tican
dm
echa
nic)
Wea
knes
sof
dors
alan
dvo
lar
inte
ross
ei;
left
leg;
right
arm
;
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
atsu
prac
lavi
cula
rfo
ssa,
pron
ator
cana
l,cu
bita
ltun
nela
ndA
rcad
eof
Fro
hse;
spre
adin
gpa
infr
omco
ldst
imul
usan
dpi
npric
kfr
omth
ele
ftha
ndto
face
No.
1625
yofe
mal
eC
RP
S25
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Arn
old
Chi
arir
epai
rop
erat
ion;
trac
tion
ofth
ebr
achi
alpl
exus
left
shou
lder
Hyp
eral
gesi
ato
pinp
rick
over
the
entir
ele
ftup
per
quad
rant
;sp
onta
neou
sbu
rnin
gan
dla
ncin
atin
gpa
inle
ftbr
achi
alpl
exus
dist
ribut
ions
;ev
oked
tingl
ing
pain
with
mov
emen
t;m
echa
nica
l,dy
nam
ican
dst
atic
allo
dyni
ain
brac
hial
plex
usdi
strib
utio
ns
Tem
pera
ture
asym
met
ryle
ftar
m,
face
and
hand
war
mer
than
right
;er
ythe
ma
left
arm
and
face
;co
lor
chan
geal
way
spr
esen
tbe
cam
em
ore
evid
ent
with
cold
and
emot
iona
lstr
ess
Ede
ma
ofL
hand
,ar
m;
swea
ting
asym
met
ryw
ithhy
perh
idro
sis
ofth
eL
arm
and
uppe
rex
trem
ity;
edem
aal
way
spr
esen
t;ev
oked
toa
grea
ter
degr
eew
ithde
pend
ency
and
use
Dec
reas
edra
nge
ofm
otio
nof
all
finge
rsin
flexi
onan
dex
tens
ion
left
hand
;w
eakn
ess
ofin
trin
sic
hand
mus
cles
;m
otor
negl
ect
ofth
ele
ftsi
de;
britt
le,
thic
kene
d,rid
ged
nails
inth
ele
ftha
nd;
shin
yth
insk
inof
left
hand
Clin
ical
crite
rion
fact
ors
inot
her
area
sof
CR
PS
invo
lvem
ent
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
atsu
prac
lavi
cula
rfo
ssa,
neur
ovas
cula
rbu
ndle
,Arc
ade
ofF
rohs
ean
dpr
onat
orca
nal;
cold
allo
dyni
aan
dpi
npric
kst
imul
ussp
read
from
the
hand
toth
esh
ould
eran
dfa
ce
Left
face
(V1-
V3)
eryt
hem
atou
san
dw
arm
erLe
ftfa
ce(V
1-V
3)ed
emat
ous
and
slig
hthy
perh
idro
sis
Rig
htar
mde
crea
sed
initi
atio
nof
mov
emen
t
Efficacy of Ketamine in Anesthetic Dosage 27
Ap
pen
dix
1:C
ontin
ued
Dem
ogra
phic
sTr
igge
ring
Inju
ryS
iteof
Prim
ary
CR
PS
Abn
orm
aliti
esin
Pai
nP
roce
ssin
gF
acto
r1
Ski
nC
olor
and
Tem
pera
ture
Cha
nges
Fac
tor
2
Fac
tor
Vas
omot
oran
dS
udom
otor
/Ede
ma
Cha
nges
Fac
tor
3
Mot
orD
ysfu
nctio
nan
dTr
ophi
cF
eatu
res
Fac
tor
4
No.
1748
yofe
mal
eC
RP
S72
mon
ths
Bas
elin
eP
ain
NR
S8.
5A
SA
Cla
ssII
Ext
ensi
on/d
iste
ntio
ntr
aum
aof
the
right
hand
Hyp
eral
gesi
ato
pinp
rick
ofth
erig
htar
min
are
gion
aldi
strib
utio
n;sp
onta
neou
sbu
rnin
gpa
in,
deep
ache
,tin
glin
gof
right
arm
;ev
oked
lanc
inat
ing
pain
with
mov
emen
t;dy
nam
ican
dst
atic
mec
hano
allo
dyni
aof
the
right
arm
;de
epso
mat
icse
nsiti
zatio
nof
right
arm
;sm
allj
oint
pain
ofth
erig
htha
nd;
cold
allo
dyni
aof
the
right
arm
Tem
pera
ture
asym
met
ry,
right
arm
war
mer
than
the
left;
min
imal
eryt
hem
aof
the
right
hand
;co
lor
chan
gein
crea
sed
with
use,
depe
nden
cyan
dte
mpe
ratu
rech
ange
Ede
ma
ofrig
htha
nd;
swea
ting
asym
met
ryrig
ht>
left
hand
;m
inim
alch
ange
(incr
ease
)of
edem
aw
ithde
pend
ency
and
use
Dec
reas
edra
nge
ofm
otio
n(fl
exio
nan
dex
tens
ion
offin
gers
and
wris
t)of
right
hand
;w
eakn
ess
ofrig
htha
nddo
rsal
and
vola
rin
tero
ssei
,fle
xor
polli
cis
long
usan
dop
pone
nspo
llici
s;in
crea
sed
phys
iolo
gic
trem
orof
right
hand
and
arm
;br
ittle
nails
and
shin
ysk
inof
right
hand
Clin
ical
crite
rion
fact
ors
inot
her
area
sof
CR
PS
invo
lvem
ent
Add
ition
alfe
atur
esP
ositi
veTi
nels
igns
supr
aan
din
frac
lavi
cula
rfo
ssa;
neur
ovas
cula
rbu
ndle
,pr
onat
orca
nal;
spre
adof
pinp
rick
stim
ulus
from
the
right
hand
toth
erig
htar
man
dfa
ce(V
2)
Rig
htfa
ce(V
1-V
3)er
ythe
mat
ous
and
war
mer
and
uppe
rth
igh
ofth
erig
htle
gw
arm
erth
anle
ft
Rig
htfa
ce(V
1-V
3)ed
emat
ous
and
slig
hthy
perh
idro
sis
Rig
htle
g;le
ftar
m;
wea
knes
sof
intr
insi
cha
ndm
uscl
esrig
htha
nd;
poor
initi
atio
nof
toe
mov
emen
tsrig
htle
g
No.
1841
yofe
mal
eC
RP
S84
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Mot
orve
hicl
eac
cide
nt;
exte
nsio
n/fle
xion
inju
ryof
the
brac
hial
plex
uson
the
right
Hyp
eral
gesi
ato
pinp
rick
right
arm
ina
regi
onal
dist
ribut
ion;
spon
tane
ous
burn
ing
pain
;de
epso
mat
icpa
in;
join
tpa
inof
the
right
hand
;ev
oked
tingl
ing
and
hand
pain
with
mov
emen
t;dy
nam
ican
dst
atic
mec
hano
allo
dyni
aof
allb
rach
ial
plex
usdi
strib
utio
nsof
the
right
uppe
rex
trem
ity;
cold
allo
dyni
aan
dhe
atal
lody
nia
right
arm
and
hand
>th
anth
esh
ould
er
Tem
pera
ture
asym
met
ryrig
htar
mco
lder
than
left;
eryt
hem
aof
right
arm
and
hand
;co
lor
chan
geva
ries
thro
ugho
utth
eda
y;at
times
spon
tane
ousl
yan
dat
othe
rtim
esby
emot
iona
lstr
ess;
mov
emen
tan
dte
mpe
ratu
rech
ange
Sw
ellin
gof
dors
um>
vent
ral
area
sof
the
hand
;sw
ellin
gof
the
arm
and
shou
lder
;hy
perh
idro
sis
>rig
htth
anle
ftup
per
extr
emity
;sw
ellin
gin
crea
sed
with
arm
use
Wea
knes
sof
alli
ntrin
sic
mus
cles
ofth
eha
nd;
poor
abili
tyto
oppo
seth
umb
and
fore
finge
r;sp
onta
neou
sm
yocl
onic
jerk
s;ex
agge
ratio
nof
her
phys
iolo
gica
ltre
mor
ofth
erig
htar
m
Clin
ical
crite
rion
fact
ors
inot
her
area
sof
CR
PS
invo
lvem
ent
Rig
htfa
ce(V
1-V
3)hy
pera
lges
iaan
dm
echa
noal
lody
nia
(dyn
amic
and
stat
ic)
War
mer
and
eryt
hem
atou
srig
htfa
ceR
ight
face
(V1-
V3)
edem
atou
san
dhy
perh
idro
ticR
ight
leg;
left
arm
poor
initi
atio
nof
mov
emen
t
Add
ition
alfe
atur
esS
prea
ding
pain
from
pinp
rick
and
cold
stim
ulif
rom
the
hand
toen
tire
extr
emity
and
toco
ntra
late
ralf
ace;
posi
tive
Tine
lsi
gns
supr
aan
din
frac
lavi
cula
rfo
ssa,
neur
ovas
cula
rbu
ndle
,A
rcad
eof
Fro
hse,
pron
ator
cana
l,cu
bita
ltun
nell
eft>
right
arm
Kiefer et al.28
No.
1914
yofe
mal
eC
RP
S7
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
III
Bro
wn
recl
use
spid
erbi
teof
the
inne
rrig
htth
igh
Hyp
eral
gesi
ato
pinp
rick
ofth
een
tire
right
leg
ina
regi
onal
dist
ribut
ion;
mos
tse
vere
surr
ound
ing
the
area
ofth
esp
ider
bite
;sp
onta
neou
sbu
rnin
gpa
inof
the
entir
eth
igh;
seve
rebu
rnin
gin
the
six
inch
essu
rrou
ndin
gth
een
veno
mat
ion
site
;de
epso
mat
icpa
in;
join
tpa
inat
the
knee
;ta
ctile
and
dyna
mic
mec
hano
allo
dyni
aof
the
right
leg;
cold
allo
dyni
am
ost
seve
resi
xin
ches
surr
ound
ing
the
site
ofen
veno
mat
ion
but
affe
ctin
gth
een
tire
thig
h;de
epso
mat
icse
nsiti
zatio
nof
allm
uscl
esof
the
thig
h
Tem
pera
ture
asym
met
ryrig
htle
gw
arm
erth
anth
ele
ft;er
ythe
mat
ous
right
leg;
fluct
uatin
gco
lor
chan
gedu
eto
activ
ity,
cold
and
emot
iona
lstr
ess
Ede
ma
ofth
erig
htle
g(t
high
>lo
wer
leg)
;hy
per
hidr
osis
ofrig
htle
g;ed
ema
cons
tant
Wea
knes
sof
iliop
soas
,qu
adric
eps;
diffi
culty
initi
atin
gm
ovem
ents
ofrig
htle
g;dy
ston
icpl
anta
rfle
xed
inve
rted
foot
;pa
tient
unab
leto
bear
wei
ght
onrig
htle
g;th
icke
ned
and
britt
lena
ilsrig
htfo
ot
Clin
ical
crite
rion
fact
ors
inar
eas
othe
rth
anpr
imar
yC
RP
Sre
gion
Rig
htfa
ce;
right
arm
;rig
htle
gsp
onta
neou
spa
in,
mec
hano
allo
dyni
a(S
tatic
and
dyna
mic
)an
dth
erm
oallo
dyni
ato
cold
stim
uli
Rig
htfa
ce;
right
arm
;rig
htle
ger
ythe
mat
ous
Rig
htar
m;
right
leg
poor
initi
atio
nof
mov
emen
tof
dist
alm
uscl
es
Add
ition
alfe
atur
esP
ositi
veTi
nels
ign
ofth
esc
iatic
nerv
ein
the
right
scia
ticno
tch;
post
erio
rpo
plite
alpo
sitiv
eTi
nel
sign
onth
erig
ht;
abno
rmal
spre
adin
gpa
infr
omco
ldor
pinp
rick
stim
uliu
pth
een
tire
leg
ifth
epa
tient
rece
ives
the
stim
ulus
near
the
site
ofth
eor
igin
alin
jury
No.
2033
yofe
mal
eC
RP
S63
mon
ths
Bas
elin
eP
ain
NR
S9
AS
AC
lass
II
Tibi
alto
rsio
nfr
actu
re;
oste
osyn
thes
isop
erat
ion,
left
low
erle
g
Hyp
eral
gesi
ato
pinp
rick
left
knee
and
low
erle
g;sp
onta
neou
sbu
rnin
gpa
in,
deep
ache
ofm
uscl
esan
djo
ints
;pr
ovok
edla
ncin
atin
gpa
inw
ithm
ovem
ent
orw
eigh
tbe
arin
g;m
echa
nica
land
ther
mal
allo
dyni
ale
ftle
g
Tem
pera
ture
asym
met
ry;
left
leg
cold
erth
anrig
ht;
slig
hter
ythe
ma
ofth
ele
ftfo
ot;
fluct
uatio
nof
colo
rch
ange
with
mov
emen
tan
dw
eigh
tbe
arin
gof
left
foot
Ede
ma
ofle
ftlo
wer
extr
emity
belo
wth
ekn
ee(m
ore
seve
rein
the
foot
);sw
eatin
gas
ymm
etry
left
low
erle
g>
than
right
;hy
perh
idro
sis
fluct
uate
dm
ildly
with
exer
cise
,co
ldan
dem
otio
nals
tres
s
Wea
knes
sof
ante
rior
tibia
lis,
exte
nsor
hallu
cis
long
usan
dga
stro
cnem
ius
mus
cle
left
leg;
decr
ease
dra
nge
ofm
otio
nat
the
ankl
ean
dkn
eejo
int;
poor
initi
atio
nan
dm
aint
enan
ceof
mov
emen
trig
htle
gan
dto
es;
thic
kene
d,rid
ged,
britt
lena
ilsle
ftfo
ot;
atro
phy,
shin
ysk
inle
ftfo
ot
Crit
erio
nfa
ctor
sin
othe
rth
anpr
imar
yar
eaof
CR
PS
Add
ition
alfe
atur
esS
prea
ding
pain
from
cold
stim
uli
from
foot
toth
ekn
ee;
and
from
pinp
rick
stim
ulif
rom
the
foot
toth
ele
ftfa
ce
Left
face
(V1-
V3)
,le
ftar
m;
right
leg
spon
tane
ous
pain
,m
echa
noal
lody
nia
(sta
tican
ddy
nam
ic)
and
ther
moa
llody
nia
toco
ldst
imul
i
Left
face
(V1-
V3)
;rig
htle
ger
ythe
mat
ous;
cyan
otic
buis
hrig
htle
gLe
ftar
m;
right
leg
poor
initi
atio
nof
mov
emen
tof
dist
alm
uscl
es
Efficacy of Ketamine in Anesthetic Dosage 29