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Original Contribution

The  rst 500: initial experience with widespread use of low-doseketamine for acute pain management in the ED☆ ,☆☆ ,★,★★

Terence L. Ahern, MD a,⁎, Andrew A. Herring, MD a,b, Erik S. Anderson, MD a, Virat A. Madia, MD a, Jahan Fahimi, MD a,b, Bradley W. Frazee, MD a,b

a Department of Emergency Medicine, Alameda Health System, Highland Hospital, Oakland CAb Department of Emergency Medicine, University of California, San Francisco, San Francisco CA

a b s t r a c ta r t i c l e i n f o

 Article history:Received 17 September 2014

Received in revised form 5 November 2014

Accepted 7 November 2014

Objectives: Theobjective ofthisstudyis to describe theclinical useand safety prole of low-dose ketamine(LDK)(0.1-0.3 mg/kg) for pain management in the emergency department (ED).

Methods: This was a retrospective case series of consecutive patients given LDK for pain at a single urban ED be-

tween 2012 and 2013. Using a standardized data abstraction form, 2 physicians reviewed patient records to de-

termine demographics, indication, dose, route, disposition, and occurrence of adverse events. Adverse events

were categorized as minor (emesis, psychomimetic or dysphoric reaction, and transient hypoxia) and serious

(apnea, laryngospasm, hypertensive emergency, and cardiac arrest). Additional parameters measured were

heart rate and systolic blood pressure.

Results: Five hundred thirty patients received LDK in the ED over a 2-year period. Indications for LDK were di-

verse. Median patient age was 41 years, 55% were women, and 63% were discharged. Route of administration

was intravenous in 93% and intramuscular in 7%. Most patients (92%) received a dose of 10 to 15 mg. Comorbid

diseases includedhypertension (26%), psychiatric disorder (12%), obstructive airwaydisease (11%), andcoronary

artery disease (4%). There was no signicant change in heart rate or systolic blood pressure. Thirty patients (6%)

met our criteria for adverse events. Eighteen patients (3.5%) experienced psychomimetic or dysphoric reactions.

Seven patients (1.5%) developedtransient hypoxia. Fivepatients (1%) had emesis. There wereno cases of serious

adverse events. Agreement between abstractors was almost perfect.

Conclusion:  Use of LDK as an analgesic in a diverse ED patient population appears to be safe and feasible for the

treatment of many types of pain.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

The Institute of Medicine report, Relieving pain in America: a blue-

print for transforming prevention, care, education, and research,

highlighted inadequate emergency department (ED) treatment of 

pain as a major public health concern [1]. However, strategies to suc-

cessfully manage acute pain in a safe and expeditious manner are the

source of considerable debate, and there is wide variation in clinical

practice [2]. Current pharmacologic strategies in the ED rely heavily

on monotherapy with opioids; but adverse events such as sedation,

bradypnea, hypotension, and tolerance limit their utility in many pa-

tients [3-8]. In addition, the epidemic of opioid pain medication misuse

has become a nationally recognized problem, and emergency physi-

cians have been tasked with carefully assessing opioid administration

and prescriptions [9]. More thanever,emergency physicians areconsid-

ering alternative, complimentary medications, such as ketamine, that

can be combined with traditional drugs such as opioids and nonsteroi-

dal antiinammatory drugs, to achieve multimodal analgesia in the

acute setting.

Ketamine has been used extensively in the ED for procedural seda-

tionand rapid sequence intubation. An alternative,off-label, useof keta-

mine is for pain control, using subanesthetic dosing—typically 0.1 to 0.3

mg/kg. Research conducted over the last 15 years has demonstrated

that such low-dose ketamine (LDK) is safe, effective, and improves

pain management when combined with opioid analgesics  [10-13].

Low-dose ketamine has been shown to potentiate the analgesic effect

of opioids, have opioid-sparing effects, and to attenuate development

of centralized chronic pain states [14-20]. For these reasons, LDK for an-

algesia has been widely adopted in the anesthesia, surgical, and

American Journal of Emergency Medicine 33 (2015) 197–201

☆   Prior presentations: Accepted for presentation,American Societyof RegionalAnesthesia

and Pain Medicine, Annual Pain Medicine Meeting in San Francisco, CA, November 2014.☆☆   Conicts of interest: The authors report no conicts of interest.★   Source of support: None.

★★   Author contributions: TA, EA, VM, AH, JF, and BF conceived the study and designed

the trial. All authors participated in the conduct of the trial, data collection,and organized

the work of research assistants. TA, EA, and JF analyzed the data. TA drafted the manu-

script, and all authors contributed substantially to its revision. TA takes responsibility for

the manuscript as a whole.

⁎   Corresponding author. Department of EmergencyMedicine,Highland Hospital–Alameda

Heath System, 1411 East 31st St,Oakland,CA 94602-1018. Tel.: +1 510437 8497;fax: +1 510

437 8322.

E-mail address:  terryahern@gmail.com (T.L. Ahern).

http://dx.doi.org/10.1016/j.ajem.2014.11.010

0735-6757/© 2014 Elsevier Inc. All rights reserved.

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

 j o u r n a l h o m e p a g e :  w w w . e l s e v i e r . c o m / l o c a t e / a j e m

http://dx.doi.org/10.1016/j.ajem.2014.11.010http://dx.doi.org/10.1016/j.ajem.2014.11.010http://dx.doi.org/10.1016/j.ajem.2014.11.010mailto:terryahern@gmail.comhttp://dx.doi.org/10.1016/j.ajem.2014.11.010http://www.sciencedirect.com/science/journal/http://www.sciencedirect.com/science/journal/http://dx.doi.org/10.1016/j.ajem.2014.11.010mailto:terryahern@gmail.comhttp://dx.doi.org/10.1016/j.ajem.2014.11.010http://crossmark.crossref.org/dialog/?doi=10.1016/j.ajem.2014.11.010&domain=pdf

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palliative care settings for the treatment of postoperative and chronic

cancer-related pain.

Emergency medicine has been slower to incorporate LDK for anal-

gesia into routine practice, likely due to lack of familiarity with this in-

dication as well as concerns over adverse effects, particularly

emergence phenomena. But a small yet growing body of evidence

has emerged over the last 10 years documenting the successful use

of LDK in the ED and prehospital environment [12,21-25]. These stud-

ies consistently show that the safety and side effect prole of LDK is

similar to that of opioids and that LDK causes few signicant

pyschomimetic reactions. In response, some institutions have begun

to routinely incorporate LDKinto acute pain management as a compli-

mentary and rescue analgesic. Two years ago, in collaboration with

emergency physicians, nursing, and pharmacy staff, we developed

an ED-specic LDKprotocol to facilitate usefor a broad array of painful

conditions in our department.

The aim of this study is to document theclinical use, safety, and side

effect prole of LDK for pain management in the ED.

2. Methods

 2.1. Setting 

This retrospective, consecutive case series was conducted in a

single ED at an urban trauma center. We obtained a database, de-

rived from our electronic medical record (EMR) (Wellsoft Corpora-

tion, Sumerset, NJ), of all patients receiving ketamine in our ED

during a 2-year period from January 2012 to December 2013. This

2-year timeframe coincided with an increase in popularity and

awareness of ketamine on the part of ED providers after the creation

of an ED-specic LDK protocol in 2012. With broad inclusion criteria,

the protocol proposed LDK as an agent for analgesia in patients with

many types of acute or chronic pain, either alone or in combination

with additional pain relieving drugs. The protocol recommended

doses of 5 to 20 mg intravenous (IV) or 10 to 25 mg intramuscular

(IM). There were no absolute contraindications except for known al-

lergy to ketamine. Relative contraindications included age youngerthan 18 years, uncontrolled seizure activity, severe signs of elevated

intracranial pressure, renal and/or liver failure, and women who are

pregnant or breastfeeding. Patients were not specically excluded

for having abnormal vital signs (ie, hypertension, tachycardia, or

hypoxia), and the ultimate decision whether to order LDK was left

up to provider preference.

Our ED uses computerized drug storage units (Pyxis Corporation,

San Diego, CA) and EMRs that permit accurate tracking of department

drug ordering and administration, including dosage and route of ad-

ministration. To facilitate ease of use and cut down on unnecessary

waste, our pharmacy began stocking preloaded syringes of 15 mg keta-

mine for IV administration, which were kept in the drug storage units.

Our hospital's institutional review board approved this retrospective

review.

 2.2. Study population

We extracted data from electronic systems to include all ED pa-

tients for whom ketamine was ordered during the study period.

The data included medical record number, arrival date, age, sex, dis-

position, and chief complaint. Chief complaints were categorized

into 7 broad groups of indications for LDK before chart review. The

groups included muscular-skeletal pain, abdominal pain, chest

pain, skin and soft tissue infections, headache, back pain, and other.

For the purposes of this study, we dened LDK as a dose less than

or equal to 20 mg IV or 25 mg IM or roughly 0.1 to 0.3 mg/kg in the

average size adult.

 2.3. Data abstraction

After a formal training period and data abstraction pilot trial, a stan-

dardized data abstractionform wasused to review patient records inde-

pendently by 2 authors. We abstracted ketamine dose (milligram),

route of administration (IV or IM) and systolic blood pressure (SBP),

and heart rate (HR) at 2 time points: at triage and within 1 hour of 

LDK administration.

Detailed review of the clinical chart was done to ascertain the pres-

ence or absence of specic, predened adverse events with one hour of 

LDK administration including cardiac arrest, apnea (respiratory rate

b10 breaths per minute or need for jaw thrust and/or bag valve mask

ventilation), hypoxia (oxygen saturation,  b 90% on room air or  N 5% de-

creased in oxygen saturation from baseline value if  N 90% at triage), hy-

pertensive emergency (SBP,  N180 and the acute onset of chest pain,

shortness of breath, or severe headache), laryngospasm, emesis,

psychomimetic reaction (agitation, hallucinations, or unusual behavior

recorded by provider), and other (nurse or physician documentation

of specic problem relatedto LDKadministration).Lastly, comorbidities

including a history of hypertension, coronary artery disease (CAD), psy-

chiatric illness (schizophrenia, bipolar, and depression requiring medi-

cation), and chronic obstructive pulmonary disease (COPD) or asthma

were recorded. If not documented in the medical record, each of these

adverse events and comorbidities was assumed to be absent.Frequent meetings were held between abstractors and study coordi-

nators to answer questions, resolve disputes, and review identied ad-

verse events. A random sample of 10% of charts reviewed was

duplicated to assess interrater reliability.

 2.4. Data analysis

We report descriptive statistics and 95% condence intervals (CIs),

where appropriate. Interrater reliability was ascertained through the

Cohen κ  statistic for route of administration and absence or presence

of any adverse events and theSpearman rank correlation for dose of ad-

ministration. Statistical analysis was done using Stata version 11

(StataCorp, College Station, TX).

3. Results

We found almost perfect agreement between the 2 abstractors: κ =

0.98 for route of administration,  κ  = 0.90 for presence of adverse reac-

tion, and r  = 0.99 for dose of administration.

The initial database included 683 patients who received ketamine in

ourED over the study period. We excluded all cases of ketamine admin-

istration that did not meet our denition of LDK (≥20 mg IV or 25 mg

IM). Using this denition, 153 cases were excluded from the analysis.

The excluded cases primarily comprised ketamine used for conscious

sedation and rapid sequence intubation.

This series ultimately included 530 consecutive ED LDK administra-

tions, of which 294 (55.5%) were female. The median age was 40 years,

and the distribution of patients was fairly even between the second tofth decades of life (Table 1). Indications for LDK were diverse, and

many of the patients had substantial underlying illness including hyper-

tension (26%), psychiatric disorder (12%), COPD (11%), and CAD (4%).

Ultimately, near two-thirds (63%) were discharged home from the ED.

Low-dose ketamine was administered IV in the vast majority of 

cases (93%) and IM in theremaining cases. Most patient (92%) received

a single dose of either 10 or 15 mg, although the dose range was 5 to

25 mg IV/IM. There was no signicant change in SBP and HR within 1

hour of LDK administration, as compared with triage values. Mean tri-

age SBP and HR was 141 (99% CI, 138-144) and 93 (99% CI, 91-95),

whereas SBP and HR within 1 hour of LDK administration were 138

(99% CI, 135-141) and 86 (99% CI, 84-88), respectively.

Of 530 LDK cases, only 30 (6%) met our criteria for an adverse event.

Each event is specically detailedin Table 2. There were 7 patients (1.5%)

198   T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197 – 201

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who developed transient hypoxia, 4 of whom had concurrently received

1 to 2 mg of hydromorphone. Most of the 7 had transient oxygen

desaturations to between 86% and 92%, and all but 1 patient responded

to 2 L oxygen by nasal cannula. Five patients (1%) had emesis, 3 received

ondansetron for symptomatic relief, and all 5 cleared their airway with-

out assistance. There was no evidence of aspiration in any patient.

Eighteen patients (3.5%) experienced psychomimetic or dysphoric

reactions (hallucinations, agitation, unusual behavior, or provider docu-mentation of LDK-related patient complaint), none of which were long

lasting or led to a change in ultimate disposition. Three patients were

given lorazepam for symptomatic anxiety or agitation. Most patients

improved without intervention or after reassurance by nurse or physi-

cian. There was 1 case of moderate-to-severe agitation in a 57-year-

old man with metastatic cancer who was noted by the nurse to open

his eyes widely and scream while pulling at the gurney side rails after

receiving ketamine 15 mg IV and fentanyl 50   μ g IV; he was treated

with lorazepam resulting in resolution of his symptoms. Another pa-

tient was noted by the nurse to have  “a bad dream-like state” and “felt

like she might die in her dream,” after receiving ketamine 10 mg IV.

Other notable patient quotations in the medical record included,   “I

feel like a zombie,” “if this is what people feel like on drugs, then I

don't want them,” “my pain is gone, but I feel crazy,” “I feel like I'm y-ing,” and “you all look like aliens.”

4. Discussion

To our knowledge, this is largest series reported of LDK administra-

tion for pain in the ED. We found that LDK is feasible and safe for treat-

ment of a wide variety of painful conditions. The adverse event rate was

6% overall, but the events were easily identied and dealt with by ED

staff. Furthermore, this adverse event rate is lower than that of opioid

medications in hospitalized patients, although a direct comparison is

problematic   [26,27]. None of the adverse events caused harm or

changed disposition. Importantly, no patients experienced apnea,

laryngospasm, hypertensive emergency, or cardiac arrest.

Concerns over adverse psychomimetic affects, particularly emer-

gence phenomena, have traditionally limited widespread use of LDK in

adult ED patients [28]. Our results conrm those of prior smaller studies

of LDK showing that psychomimetic reactions are mostly mild in nature

and rarely alter a patient's clinical course [10,12,21-24,29]. In our cohort,

18 patients (3.5%) had documented psychomimetic or dysphoric reac-

tions within 1 hour of LDK administration. Although 3 patients required

lorazepamfor sedation during the episode,mostreactionswere mildand

improved without intervention or with reassurance from ED staff.

It is now apparent that mild dysphoric effects of LDK occasional

occur with doses lower than what is traditionally considered the disso-

ciative range (1-2 mg/kg IV), at which actual emergence phenomenon

can occur. The rate of such reactions in recent prospective studies

ranges from 16% to 26% [21,22,30]. It is important to note that the neg-

ative reactions are universally short lived and differ substantially from

emergence phenomenon. Our rate of mild dysphoric events is much

lower than described in previous prospective studies; but this is likely

due to the inherent limitations of retrospective chart review, reliance

on the medical records for documentation of events, and the sensitivity

of screening instruments for such events used in prospective studies.

Nonetheless, we suspect that some patients reported the effects as neg-

ative experiences primarily because they were taken by surprise. Based

upon our (the investigators) growing experience with LDK, we believe

that advising patients about the possibility of psychomimetic effects re-duces the likelihood that the effect will be perceived as negativeif it oc-

curs. In addition, a prior prospective trial on LDK showed that the same

patient who reports very bothersome dissociative effects might report

high satisfaction at discharge [21]. It seems prudent that providers

who administer LDK should routinely coach patients just before admin-

istration,reassuring them that any dysphoricreaction will be short lived

and create as calm an environment as possible.

Other types of adverseevents were infrequent. Seven patients (1.5%)

experienced transient oxygen desaturation within 1 hour of ketamine

administration. Of these patients, 4 were given concomitant opioids

with LDK, and all but 1 patient responded quickly with 2 to 4 L nasal

cannula oxygen. One patient required 2 hours of bilevel positive airway

pressure (bipap) support; but she had been hypoxic at triage, required

oxygen support via non-rebreather facemask and bipap before LDK,and was already admitted for a COPD exacerbation. According to

provider's documentation, the indication for LDK in this case was to

treat chest pain but, perhaps, more importantly, to facilitate therapy

for hypoxia by way of providing anxiolysis and bronchodilation.Overall,

the rate of hypoxia is substantially less than reported in prior prospec-

tive research on opioid-based pain protocols in the ED  [31]. For exam-

ple, in the widely cited   “1 + 1”  hydromorphone titration protocol

study, Chang et al [31] found a 5% rate of hypoxia in patients receiving

hydromorphone. In addition, their study excluded patients with base-

line oxygen saturation less than 95%. However, a direct comparison

with our heterogeneous cohort is not possible because some patients

may have been given LDK in spite of their hypoxia.

Similarly, we found a lower rate of emesis in our cohort than what

was reported in patients receiving hydromorphone in the study of Chang et al [31] (1% vs 7%, respectively).Furthermore, most of our eme-

sis cases were in patients who had experienced nausea and/or vomiting

before receiving LDK (reference, Table 2 for details), whereas such pa-

tients would have been excluded from the reporting of emesis in the

study of Chang et al [31].

We observed no signicant change in blood pressure or HR within 1

hourof administeringLDK as compared with triagevalues. Patients who

were tachycardic, hypertensive, or hypoxic at triage remained so after

receiving LDK. This is not surprising given the well-established favor-

able hemodynamic prole of ketamine [32]. Although these  ndings

suggest that LDK may be safe in patients who have abnormal vital

signs,thereis much uncertainty in this patientpopulation given thelim-

itations of retrospective data. Furthermore, our LDK protocol does not

explicitly exclude patients with abnormal vital signs and allows for

 Table 1

Patient characteristics and indications for LDK

N o. of patie nts Percentage (%)

Age (y)

19-29 132 25

30-39 125 24

40-49 120 22

50-59 114 22

60-69 35 6

N

70 4 1Sex

Male 236 44

Female 294 56

Disposition

Discharge 335 63

Admission 195 37

Indications

Musculoskeletal pain 63 12

Abdominal pain 178 33

Chest pain 24 5

Skin and soft

tissue infection

62 12

Back pain 66 12

Headache 13 3

Othera 124 23

Comorbidities

Hypertension 139 26

CAD 21 4

COPD 57 11

Psychiatric illness  b 63 12

a Included chronic pain, sickle cell crisis, genitourinary disorders, painful rashes, psy-

chiatric complaints, and other miscellaneous painful complaints.b Included depression, bipolar disorder, and schizophrenia.

199T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197 – 201

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 Table 2

All 30 adverse events that occurred within 1 hour of LDK bolus, among 530 patients

Adverse eventa Age Sex Disposition Indication Dose Route Comorbiditiesb Details

Hypoxiac

41 F Home Abdominal

pain

15 IV LDK given for chronic pelvic pain. Hypoxi a noted during LD K admi nistration

requiring non-rebreather facemask, which resolved within 1 h.

Patient had been given 2 mg hydromorphone 45 minutes before LDK.

43 M Admit Abdominal

pain

10 IV Hypertension LDK given for abdominal pain. Placed on 2-L nasal cannula after LDK, although no

desaturation was noted.

43 M Admit Abdominalpain 15 IV D epression,hypertension, CAD LDK given for abdominal pain secondary to diabetic ketoacidosis. 45 min priorreceived 2 mg hydromorphone. SpO2 dropped to 88%, transient

2-L NC applied.

42 M Admit Abscess 20 IV LDK given for abscess drainage. 1 h after administration noted to have SpO2 of 88%

when asleep, which improved with elevation head of bed.

Patient may have had undiagnosed obstructive sleep apnea.

58 M Home Cancer 15 IV LDK and 2 mg hydromorphone given for back pain related to metastatic lesion. SpO2dropped to 88%, transient 2-L NC applied.

48 F Admit COPD 15 IV Hypertension, COPD Patient was admitted for COPD. SpO2 95% on 2-L NC before LDK but dropped to 80%

with increased work of breathing and lethargy obstructive

lung disease noted by MD afterward. Placed on bipap for next 2 h then improved.

46 M Admit Trauma 20 IV LDK and 1 mg hydromorphone given for head laceration repair. SpO2 dropped to

90%, transient 2-L NC applied.

Emesis

21 M Admit Abdominal

pain

15 IV LDK and 8 mg onda nsetron gi ven for nausea and vomiting i n setti ng of  

pyelonephritis. Patient had 2 small episodes of emesis afterward but

stated “it's due to not eating.”

32 F Home Abdominal

pain

15 IV Hypertension LDK, 25 mg benedryl and 4 mg ondansetron given for nausea and vomiting in

setting of gastroparesis. Patient had large emesis 45 min

afterward, improved with 10 mg metoclopramide.5 1 M H om e B ack p ai n 1 5 IV H ype rt ens io n LDK, 3 0 mg k et or ol ac a nd 1 0 m g d ex ame th as on e gi ve n f or cau da e qu in a sy nd rom e.

Patient had small emesis 15 min afterward while lying  at

for electrocardiogram.

22 F Home Chronic

pain

15 IV LDK given for chronic abdomina l pai n and hyperemesi s syndrome. Pa tient

complained of continued nausea and vomiting after LDK.

7 5 F H om e F ra ct ure 1 5 IV H ype rt ens io n LDK a nd 1 mg hy dr om or pho ne g ive n f or h ume ru s fr actu re . Pa ti ent h ad l ar ge e mes is

10 min afterward, improved with 4 mg ondansetron.

Psychomimetic/dysphoricd

54 M Home Abdominal

pain

10 IV After LDK and 2 mg hydromorphone, patient reported,  “I feel dizzy.”

55 F Home Abdominal

pain

5 IV After LDK and 400 mg ibuprofen, patient reported, “I feel dizzy.”

39 F Home Abdominal

pain

15 IV COPD After LDK and 1 mg hydromorphone, patient stated her pain is improved, but the

medicine made her feel  “like I'm going to die.”

67 F Home Abdominal

pain

15 IV Hypertension After LDK, noted that  “she does not want ketamine again for pain; that it made her

hallucinate.”

33 F Home Abdominal

pain

1 5 IV C AD, C OPD Af te r LDK a nd 4 m g m or phi ne, p at ien t r ep ort ed  “pain gone” but  “I feel crazy.” Given

1 mg lorazepam.

43 F Home Abdominal

pain

15 IV After L DK and 4 mg morphine, patient noted by nurse to become unresponsive to

verbal stimuli. Awakened with sternal rub and began crying.

Vital signs normal except for HR of 110. Given 1 mg lorazepam.

22 F Admit Abdominal

pain

20 IV After LDK, patient reported “I feel dizzy, but the pain is gone.” Later noted by RN to

patting the wall with hand repeatedly with eyes closed. She remained alert and

oriented but no explanation offered.

55 F Admit Abscess 10 IV LDK and 25 μ g fentanyl given forabscess drainage.Noted tobecome anxious andwas

crying because she  “didn't like the effect of the drug.”

4 2 F H om e B ack p ai n 1 0 IV H ype rt ens io n LDK a nd 2 mg hy dr om orp ho ne g ive n f or b ack p ai n. Not ed to b e v er y a nx iou s fo r

10 min afterward.

40 F Home Back pain 15 IV After LDK, patient became highly anxious and was crying. Reported  “I feel like a

zombie.” Improved with reassurance by nurse.

57 M Admit Cancer 15 IV After LDK and 50 μ g fentanyl, patient noted to have enlarged eyes and be screaming

in pain while pulling at side rails. Required 2 mg

lorazepam and was calmed by MD

65 F Admit Chest pain 15 IV COPD After L DK, noted to be anxious and disoriented by nurse. Patient sta ted “If this is

what people feel like on drugs, then I don't want them. ”

Feelings resolved spontaneously within 10 min.

67 F Admit Chest pain 15 IV Hypertension, coronary Patient did not like feeling of LDK immediately, and the bolus was stopped beforecompletion.

36 M Home Chest pain 15 IV Hypertension Received LDK for asthma exacerbation. Afterward, noted to be more calm and stated

“I feel like I'm  ying,” then  “I'm going to sleep.”

38 F Home Chest pain 10 IV During LDK administration, noted to have  “a bad dream-like state,” and  “felt like she

was going to die in her dream.”

54 F Home Chest pain 15 IV Hypertension After LDK noted, “I feel weird. I feel funny … What is wrong with me?” Symptoms

resolved without intervention.

44 M Home Hematoma 15 IV After LDK and 1 mg hydromorphone, patient reported pain is gone, but  “we all look

like aliens.”

43 F Home Sickle cell pain 15 IV Depression, hypertension After LDK, patient became nauseated and  ushed feeling. Improved with 25 mg

phenergan.

Abbreviations:  M , male; F , female; SpO 2, oxygen saturation as measured by pulse oximetry; NC , nasal cannula; MD, doctor of medicine; RN , registered nurse.a No patient experienced cardiac arrest, apnea, hypertensive emergency, or laryngospasm.b Signicant comorbities abstracted included history of hypertension, pyschiatric illness (depression, bipolar, and schizophrenia), CAD, and COPD.c Hypoxia was dened as oxygen saturation as measured by pulse oximetry less than 90% or decrease in oxygen saturation more than 5% from triage vital signs.d Pyschomimetic /dysphoric side effects weredened as hallucinations, agitation, unusual behavior, or registered nurse/doctor of medicine documentation of aspecic problem

related to ketamine.

200   T.L. Ahern et al. / American Journal of Emergency Medicine 33 (2015) 197 – 201

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provider preference, so we cannot account for individual practice pat-

terns and must assume some avoided LDK in these situations.

The favorable safety prole of LDK is especially notable given the

wide age distribution and prevalence of comorbidities in our cohort

(Table 1). To date, prior studies of LDKhad rigorous inclusion and exclu-

sion criteria and represented a tightly controlled cohort of patients. We

believe that our cohort represents a typical diverse, urban ED popula-

tion, where many patients have chronic medical and psychiatric disease,

substance abuse, and lack of social support. In spite of this, ourndings

are consistent withthose of a prior small retrospective study in a similar

setting [25] and recent prospectivedata [21,22,24,30], showing that LDK

is feasible, generally well tolerated, and very safe in the ED.

This study has the usual limitations inherent in a retrospective re-

view. Quality of the data was dependent on that of the medical record,

particularly nursing documentation. To mitigate this, we focused on

data that were objective and not prone to interpretation or abstractor

bias using a standardized abstraction protocol based upon accepted

guidelines for chart review methodology [33]. Our EMRs include exten-

sive documentation from nursing and physicians, so it is unlikely that

we missed any major adverse events (ie, cardiac arrest, apnea, hypoxia,

laryngospasm, and hypertensive emergency). Despite this, it is likely

our data underestimate minor adverse events, such as emesis or tran-

sient psychomimetic and dysphoric events.

Although emergency physicians should be encouraged by the safetyof LDKin this large and diverse cohortof ED patients, we emphasize that

data from prospective, randomized blinded trials are needed to deni-

tively determine the ef cacy, safety, and side effect prole of LDK com-

pared with standard opioid analgesics and other opioid adjuncts.

5. Conclusion

Use of LDK alone or in combination with other pain medications as a

primary or rescue analgesicin a diverse ED patient population appears to

be safe and feasible for the treatment of many types of pain. Minor

psychomimetic side effects were observed but easily addressed by ED

personnel and did not alter disposition. Other sideeffects, including eme-

sisand hypoxia, appear to be equally or less common than reported with

opioids. Prospective randomized trials are needed to determine theef cacy and further elucidate the safety and side effect prole of LDK.

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8/19/2019 The First 500

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ORIGINAL RESEARCH

Safety of Peripheral Intravenous Administration of  Vasoactive Medication

Jose Cardenas-Garcia, MD1*, Karen F. Schaub, BS1, Yuly G. Belchikov, PharmD2, Mangala Narasimhan, DO1,

Seth J. Koenig, MD1, Paul H. Mayo, MD1

1

Division of Pulmonary, Critical Care and Sleep Medicine, Hofstra North Shore–Long Island Jewish School of Medicine, Hempstead, New York; 2Clinical Pharmacy Services, Department of Pharmacy, Westchester Medical Center, Valhalla, New York.

BACKGROUND:  Central venous access is commonly per-formed to administer vasoactive medication. The adminis-tration of vasoactive medication via peripheral intravenousaccess is a potential method of reducing the need for cen-tral venous access. The aim of this study was to evaluatethe safety of vasoactive medication administered throughperipheral intravenous access.

METHODS:   Over a 20-month period starting in September2012, we monitored the use of vasoactive medication viaperipheral intravenous access in an 18-bed medical intensive

care unit. Norepinephrine, dopamine, and phenylephrinewere all approved for use through peripheral intravenousaccess.

RESULTS:   A total of 734 patients (age 726 15 years,male/female 398/336, SAPS II score 75615) receivedvasoactive medication via peripheral intravenous access783 times. Vasoactive medication used was norepineph-rine (n5 506), dopamine (n5 101), and phenylephrine(n5 176). The duration of vasoactive medication via

peripheral intravenous access was 496 22 hours. Extra-vasation of the peripheral intravenous access duringadministration of vasoactive medication occurred in 19patients (2%) without any tissue injury following treatment,with local phentolamine injection and application of localnitroglycerin paste. There were 95 patients (13%) receiv-ing vasoactive medication through peripheral intravenousaccess who eventually required central intravenousaccess.

CONCLUSIONS:   Administration of norepinephrine, dopa-

mine, or phenylephrine by peripheral intravenous accesswas feasible and safe in this single-center medical intensivecare unit. Extravasation from the peripheral intravenous linewas uncommon, and phentolamine with nitroglycerin pastewere effective in preventing local ischemic injury. Cliniciansshould not regard the use of vasoactive medication is anautomatic indication for central venous access.  Journal of Hospital Medicine   2015;000:000–000.   VC   2015 Society of Hospital Medicine

Vasoactive medications (VMs) are often required toimprove hemodynamic function in patients with

shock. They are usually given through central venouscatheter (CVC) access, primarily out of concern thatextravasation of peripheral intravenous (PIV) accessmay result in local tissue injury due to the vasocon-strictive effect of the VM. However, insertion of CVCis associated with a variety of mechanical complica-tions and risk of central line–associated bacteremia.To examine the feasibility and safety of using VM viaPIV access, we report on the administration of VM inthe form of norepinephrine, dopamine, and phenyl-ephrine via PIV access, with the rationale that thiswould be a method of reducing the need of CVC use.Our hypotheses are that VM via PIV access is both

feasible and safe.

MATERIAL AND METHODS

Study Design

This was a single-arm, consecutive-patient study con-ducted from September 2012 to June 2014. The studysite was an 18-bed medical intensive care unit (MICU)staffed by full-time attendings, fellows, and residentsat the Long Island Jewish Medical Center, which is an827-bed tertiary care teaching hospital that is part of the North Shore–Long Island Jewish Health System.The primary outcome measure was the rate of localtissue injury resulting from use of VM via PIV access.The study was approved by the hospital institutionalreview board (study #13–583A), which waivedrequirement for informed consent.

Protocol for Administration of VM via PIV AccessIn cooperation with the Department of Pharmacy, med-ical and nursing staff developed a written protocol foradministration of VM via PIV access. The protocol wasreviewed and approved by the hospital pharmacy andtherapeutics committee and the MICU nursing leader-ship. The MICU nursing staff received in-service train-ing before rollout of the protocol, which includedtraining on the recognition of PIV access extravasationand the type of line that could be used. The MICUhousestaff teams were given specific instructionsconcerning the protocol during their MICU rotations.

* Address for correspondence and reprint requests: JoseCardenas-Garcia, MD, Department of Medicine, Division of Pulmonary,Critical Care and Sleep Medicine, Hofstra–North Shore LIJ School of Medicine, 410 Lakeville Rd, Suite 107, New Hyde Park, NY 11042;E-mail: jdecardenasg@gmail.com

 Additional Supporting Information may be found in the online version of this article.

Received:  February 28, 2015; Revised: April 30, 2015; Accepted: April30, 2015

2015 Society of Hospital Medicine DOI 10.1002/jhm.2394

Published online in Wiley Online Library (Wileyonlinelibrary.com).

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Catheter length was 30 mm, 45 mm, or 48 mmdepending on availability. The 22-gauge catheter,which was a deviation from standard protocol, infil-

trated shortly following insertion. We did not for-mally record the anatomic position of the PIV accessin the standard data-collection sheet; anecdotally, themajority of PIV accesses were placed in the upper armbasilic or cephalic vein. The duration of VM via PIVaccess was 49622 hours. Central intravenous accesswas required in 95/734 (13%) of patients who ini-tially had VM via PIV access. These catheters areincluded in the 170 triple-lumen CVCs that wereinserted by the MICU team during the study period.The type and highest dose of VM administered viaPIV access are presented in Table 4.

A total of 734 patients received VM via PIV accessduring the 20-month study period; 49 of thesepatients required 2 or more PIV access insertions, asthe initial and/or subsequent site timed out at 72hours, resulting in a total of 783 separate interven-tions. Infiltration of the PIV access site occurred in19/783 (2%) of interventions. All of them were identi-fied by nursing staff with prompt response using localinjection of phentolamine and application of nitro-glycerin paste at the site of the extravasation. Therewas no tissue injury at the site of VM extravasation.Sixteen of the extravasations occurred with norepi-nephrine infusions and 3 with dopamine infusions.

There were no infections of the PIV access sites usedfor VM. Use of phentolamine and nitroglycerin pastewas not associated with hypotension, as defined asmean arterial pressure less than 65 mm Hg.

DISCUSSION

Our study demonstrates that administration of VMvia PIV access is feasible, carries a low rate of compli-cations, and offers an alternative to CVC access.There are several elements that may have allowed safeuse of VM via PIV access. We developed a protocolthat involved a multidisciplinary team. The hospital

pharmacy performed an extensive literature searchand formulated the initial protocol with the MICUattending staff. The protocol was then subjected toiterative process improvement by a hospital committeeand nursing leadership in the MICU. Before programrollout, the MICU nursing staff were educated andtrained to use the protocol. This was a key componentof the program, as the nurses were responsible formany of the line insertions, line maintenance, andidentification of infiltration. Although we did not per-form any formal measurement of the impact of PIVaccess use on nursing workflow, we note that leader-ship and frontline nurses have been enthusiastic aboutthe implementation of VM via PIV access. The MICUhousestaff teams were given an in-service instructionconcerning the importance of prompt initiation of local treatment in case of infiltration of the PIV accesssite. Specific elements of the protocol that may haveimproved safety were the use of ultrasonography toinsert difficult PIV access and confirmation of all PIVaccess insertions using ultrasonography by the MICU

housestaff. The requirement for frequent checks of PIV access function, prompt recognition of infiltra-tion, and specific antidote to extravasation wereimportant elements of safety. The low rate of PIVaccess extravasation (2%) may be related to the useof ultrasonography to guide PIV access insertion inpatients who had challenging anatomy (eg, obesity,edema, recreational drug use, history of multiple PIVinsertions), and ultrasonography was used to checkthat the PIV access was well positioned before VMinfusion.

There were early literature reports that subcutane-ous extravasation of catecholamines could result inlocal ischemic injury both in human patients and ani-mal models.1–5 Local phentolamine injection has beenidentified as a specific antidote to block the localischemic injury.6–15 More recently, there have beenanecdotal reports showing that local application of nitroglycerin paste blocks ischemic injury in the pedi-atric population.5,16,17 With this information, our

TABLE 3.  Demographic and Disease Characteristicsof the Study Population

Total Study Group

No. of patients 734

 Age, y 726 15

Gender

Male 398 (54%)

Female 336 (46%)

SAPS II score 756 15

Patients on mechanical ventilation 235 (32%)

Patients on hemodialysis 90 (12%)

MICU mortality 177 (23%)

Use of VM via PIV access 783

Extravasations of VM via PIV access 19 (2%)

Total MICU admissions during study period 2,462

NOTE: Abbreviations: MICU, medical intensive care unit; PIV, peripheral intravenous; SAPS II, simplifiedacute physiology score II; VM, vasoactive medication.

TABLE 4.   Frequency, Highest Dose, andComplications of Vasoactive Medication Admi nistered via PIV Access

Norepinephrine

Interventions 506Dose, mg/kg/min, mean6 SD 0.706 0.23

PIV access extravasations 16

Dopamine

Interventions 101

Dose, mg/kg/min, mean6 SD 12.76 5.23

PIV access extravasations 3

Phenylephrine

Interventions 176

Dose, mg/kg/min, mean6 SD 3.256 1.69

PIV access extravasations 0

NOTE: Abbreviations: PIV, peripheral intravenous; SD, standard deviation.

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protocol included the requirement of prompt treat-ment of local extravasation with phentolamine andnitroglycerin paste at the site of VM via PIV accessextravasation. In theory, both phentolamine and nitro-glycerin might cause hypotension. In our study,administration of both phentolamine and nitroglycerinpaste was not associated with more hypotension nordid it increase requirements for VM.

Multilumen small bore CVCs may be used for sev-eral reasons, some of which need to be reconsidered.First, before introduction of the VM via PIV accessprotocol, a common indication for triple lumen CVCinsertion in our MICU was the perception that VMcould only be administered through CVC access, forfear of local tissue injury should extravasation of theVM occur through the PIV access site. Our resultsindicate that VM use is not an automatic indicationfor CVC insertion. Second, a possible indication forCVC insertion is to measure central venous pressurefor the purpose of guiding volume resuscitation inpatients with hemodynamic failure. As the utility of 

central venous pressure monitoring has been calledinto serious question,18–20 we do not consider thisindication for CVC use to be valid. Third, CVC accessmay be required due to anatomic constraints (ie, thereis no suitable PIV site). Fourth, there may be need forsuch a large number of intravenous medications thatPIV access cannot support. Fifth, there is occasionalsituation where the patient requires use of medicationswhere extravasation of PIV access would cause localtissue injury without local antidote (eg, certain chemo-therapeutic agents). The continued need for CVCaccess in some patients is reflected in the finding that13% of our study patients who received VM via PIVaccess eventually required triple-lumen CVC insertion.However, our results indicate that the rate of CVCuse may be reduced by using PIV access for VMadministration.

Our study has some methodological limitations.Study design was single center and observational. Thefocus of this study was to examine the safety of VMvia PIV access. We cannot comment on its effective-ness, indications, or influence on patient outcome noron why some patients required CVC insertion whereasothers did not. The decision to administer VM wasmade by the clinical team, as was the route of its

administration and concentration, without any inputfrom the investigators. We did not collect data onwho performed the PIV access insertion (medical ornursing staff), demographics, and disease characteris-tics of the CVC group, nor to what extent ultrasonog-raphy was used to guide PIV insertion. We did notattempt to define whether there were any factors thatidentified risk for PIV access extravasation, nor didwe evaluate for any differences between the PIV andCVC group in terms of demographics and diseasecharacteristics. Lacking a control group, we cannotsay definitively that VM via PIV access is safer than

VM via CVC. Being a single-center study, it is notpossible to say that the results are transferable toanother clinical environment; this applies particularlyto the use of ultrasonography, which is a user-dependent skill. We cannot determine which, if any,component of the protocol was responsible for thesafe use of VM via PIV access. The rate of PIV accessextravasation was low, so it is possible that a largersample size is required to identify incidents of tissuenecrosis from extravasation of VM delivered via PIVaccess despite the use of local antidote.

CONCLUSIONS

The delivery of VM via PIV access is safe and feasible.Tto reduce the risk of extravasation leading to possi-ble local tissue injury, we developed a protocol thatemphasized close cooperation between the nursingand medical staff, routine use of ultrasonography,rapid identification of extravasation of the PIV access,and prompt response to local extravasation of VM

using phentolamine and nitroglycerin paste. Thisapproach offers a means of reducing CVC use, inboth intensive care unit (ICU) and non-ICU settings,including hospital wards and emergency departments.Clinicians should no longer consider administration of norepinephrine, dopamine, or phenylephrine to be anautomatic indication for CVC access. This studyfocused on the safety of VM administered via PIVaccess, with emphasis on local complications relatedto extravasation, and should be considered a prelimi-nary single-center study that demonstrates that admin-istration of certain vasoactive medications may notuniversally require central venous access. A broader

study regarding assessment of safety and efficacy willrequire a multicenter design.

Disclosures: J.C.-G., K.F.S., Y.G.B., M.N., S.J.K., and P.H.M. partici-pated in the study design, statistical review, and manuscript writing. J.C.-G. is the guarantor of the article, taking responsibility for the integ-rity of the work as a whole from inception to published article. Thiswork is original, and all authors meet the criteria for authorship, includ-ing acceptance of responsibility for the scientific content of the article.This article is not under consideration in any other journal, and all of the authors have read and approved the content of the article. Nopotential conflict of interest exists with any companies or organizationswhose products or services are discussed in this article. This article hasnot been funded by the National Institutes of Health, the WellcomeTrust, or their agencies. All financial support of the study was derivedfrom the Division of Pulmonary, Critical Care and Sleep Medicine at

North Shore–Long Island Jewish Medical Center, New Hyde Park, NewYork.

References1. Close AS, Frackelton WH, Kory RC. Cutaneous necrosis due to

norepinephrine. II. Mechanism and prevention.  Ann Surg.  1958;147:44–50.

2. Alexander CS, Sako Y, Mikulic E. Pedal gangrene associated with theuse of dopamine. N Engl J Med.  1975;293:591.

3. Julka NK, Nora JR. Gangrene aggravation after use of dopamine[letter]. JAMA. 1976;235:2812.

4. Greene SI, Smith JW. Dopamine gangrene [letter].   N Engl J Med.1976;294:114.

5. Chen JL, O’Shea M. Extravasation injury associated with low-dosedopamine. Ann Pharmacother. 1998;32:545–548.

6. Zucker G. Use of phenytolamine to prevent necrosis due to levarterenol. JAMA.  1957;163:1477–1479.

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7. Close AS. Phentolamine hydrochloride in prevention of cutaneousnecrosis due to levarterenol. JAMA. 1959;170:1916–1917.

8. Stetson JB, Reading GP. Avoidance of vascular complications associ-ated with the use of dopamine.  Can Anaesth Soc J.  1977;24:727–733.

9. Zenk KE. Management of intravenous extravasations. Infusion. 1984;6:77–79.

10. Siwy BK, Sadove AM. Acute management of dopamine infiltrationinjury with Regitine. Plast Reconstr Surg. 1987;80:610–612.

11. Cooper BE. High dose phentolamine for extravasation of pressors [let-ter]. Clin Pharm. 1989;8:689.

12. Hinterberger JW, Kintzi HE. Phentolamine reversal of epinephrine-induced digital vasospasm. How to save an ischemic finger. Arch FamMed. 1994;3:193–195.

13. Subhani M, Sridhar S, DeCristofaro JD. Phentolamine use in a neo-nate for the prevention of dermal necrosis caused by dopamine: a casereport. J Perinatol. 2001;21:324–326.

14. Sinclair MD, Bailey MA, McAree BJ, Dewhurst D, Kent PJ. Images invascular medicine: rapid epinephrine ’reversal’ with phentolamine

following accidental autoinjector inoculation.   Vasc Med.   2011;16:215–216.

15. Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the lit-erature. Ann Pharmacother. 2014 8;48:870–886.

16. Denkler KA, Cohen BE. Reversal of dopamine extravasation injury withtopical nitroglycerin ointment. Plast Reconstr Surg. 1989;84:811–813.

17. Wong AF, McCulloch LM. Treatment of peripheral tissue ischemiawith topical nitroglycerin ointment in neonates.  J Pediatr.  1992;121:980–983.

18. Marik PE, Baram M, Vahid B. Does central venous pressure predictfluid responsiveness? A systematic review of the literature and the taleof seven mares. Chest. 2008;134:172–178.

19. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid

responsiveness? An updated meta-analysis and a plea for some com-mon sense. Crit Care Med. 2013;41:1774–1781.

20. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. Arandomized trial of protocol-based care for early septic shock.  N Engl  J Med.  2014;370:1683–1693.

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Clinical 

Review 

EMERGENCY EVALUATION FOR PULMONARY EMBOLISM, PART 2:

DIAGNOSTIC APPROACH

Jeffrey A. Kline,   MD* and Christopher Kabrhel,   MD,   MPH†

*Department of Emergency Medicine and Department of Cellular and Integrative Physiology, Indiana University School of Medicine,

Indianapolis, Indiana and †Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital and

Department of Emergency Medicine, Harvard Medical School, Boston, MassachusettsReprint Address: Jeffrey A. Kline,  MD, Department of Emergency Medicine and Department of Cellular and Integrative Physiology, Indiana

University School of Medicine, 720 Eskanazi Avenue, Indianapolis, IN 46202

, Abstract—Background: In part 1 of this two-part re-

view, we discussed which risk factors, historical features,

and physical findings increase risk for pulmonary embolism

(PE) in symptomatic emergency department (ED) patients.

Objectives: Use published evidence to describe criteria

that a reasonable and prudent clinician can use to initiate

and guide the process of excluding and diagnosing PE. Dis-

cussion: Thecareful anddiligentemergency physician canuse

clinical criteria to safely obviate a formal evaluation of PE,

including the use of gestalt reasoning and the pulmonary em-bolism rule-out criteria (PERC rule, Table 2, part 1). We pre-

sent published clinical and radiographic features of patients

with PE who eluded diagnosis in the ED. D-dimer can be

used to exclude PE in many patients, and employing age-

based adjustments to the threshold to define an abnormal

value can further reduce patient exposure to pulmonary

vascular imaging. Moreover, we discuss benefits, limitations,

and potential harms of computed tomographic pulmonary

vascular imaging relevantto patients andthe practice ofemer-

gency care. We present algorithms to guide exclusion and

diagnosis of PE in patients with suspected PE, including those

who are pregnant. Conclusions: Reasonable and prudent

emergency clinicians can exclude PE in symptomatic ED pa-tients on clinical grounds alone in many patients, and many

more can have PE ruled out by use of the D-dimer.   2015

Elsevier Inc.

, Keywords—pulmonary embolism; medicolegal; defen-

sive medicine; decision making; venous thromboembolism;

pregnancy; diagnosis; pregnancy

INTRODUCTION

This second part of a two-part review provides an

in-depth analysis of issues critical to deciding when to

initiate a formal diagnostic evaluation for pulmonary

embolism (PE) in emergency department (ED) patients,

and what diagnostic tests, if any, need to be ordered. We

explore evidence-based options for excluding PE to a

reasonable degree of diagnostic certainty but withminimal exposure to radiation and iodinated contrast

material.

DISCUSSION

 Decision to Initiate the Work-up and Empiric Treatment 

Figure 1 presents an algorithm for the diagnostic evalua-

tion of patients with possible PE. For PE to enter the

active differential diagnosis list for any patient, he or

she must have at least one possible physiologic manifes-

tation of PE. The physiologic manifestation may be a

symptom (e.g., dyspnea, pleuritic chest pain, or new

fatigue) or a sign (e.g., heart rate > 100 beats/min or pulse

oximetry < 95% near sea level) that is not explained by

another cause. Other bedside physiological signs of PE

include a low (

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in leads V1 to V4, incomplete or complete right bundle-

branch block, and the S1-Q3-T3 pattern (1,2).

Reasonable and prudent emergency care does not

dictate that all patients with a sign or symptom of PE

must be tested for PE. Nor does it dictate that a patient

with one or more risk factors for PE must undergo testingfor PE in the absence of a sign or symptom of PE. How-

ever, the authors believe that clinicians should consider

PE for patients with a sign or symptom of PE and a known

risk factor for PE (see Table 1, in part 1), and at least

mentally formulate an explanation why a work-up was

not pursued in the event that the patient had PE. If a

reasonable alternative disease explains the patient’s pre-

sentation, testing specifically directed at diagnosing PE

need not be ordered. The value of an alternative diagnosis

to obviate an evaluation for PE must be decided on a case-

by-case basis, and is often a nuanced decision-making

process. For example, if an emergency physician cares

for a patient with long-standing dyspnea and tachycardia

with a known lung cancer and a large pleural effusion,

this does not mandate a computed tomographic pulmo-

nary angiogram (CTPA). However, if the clinician was

aware that lung mass and effusion were radiographicallyunchanged, but the patient recently developed new severe

dyspnea and tachycardia, this patient may warrant further

testing for PE.

The next step is to assess the pretest probability using

either gestalt or a validated scoring method, such as the

Wells score, or the revised Geneva score (RGS) or the

simplified RGS (Tables 3 and 4, part 1)   (3–5). Gestalt

has the advantage of not requiring any memory aid, and

has similar diagnostic performance characteristics and

interobserver reliability as the Wells score and RGS

(3,6). If a patient has a high pretest probability (from

Figure 1. Diagnostic algorithm for pulmonary embolism (PE) in patients who prompt enough clinical suspicion to warrant the docu-mentedconsiderationof PE.*Assumes a cutoff for abnormal of$500 ng/mL.Nondiagnosticventilation-perfusion (V/Q) scan findingsrequireconfirmation from results of another test,such as computed tomography pulmonary angiography (CTPA), if benefits outweighrisks. Abbreviations: + = positive for PE; = negative for PE;Cr = creatinine; GFR = glomerular filtration rate; High = high probability scan findings; LMWH = low-molecular-weight heparin; Nl = normal; Nondx = nondiagnostic (any reading other than normal or highprobability); PERC = pulmonary embolism rule-out criteria; quant = quantitative, sRGS = simplified revised Geneva score.

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any method), the clinician should consider immediately

administering heparin or low-molecular-weight heparin

for patients with low bleeding risk. However, the benefits

of ‘‘empiric’’ anticoagulation remain unproven. One re-

view suggested that the benefit of empiric systemic anti-

coagulation for 24 h exceeds the risks (bleeding and

heparin-induced thrombocytopenia) for any patient witha pretest probability of PE of >20% (7). Several studies

have suggested that delay in administration of heparin

to patients with PE can increase mortality, but no study

has found that heparin administered prior to imaging im-

proves morbidity or mortality (8–10).

Three studies have provided data on patients who

passed through the ED and were soon after diagnosed

with PE (8,11–13). These patients can be categorized as

those admitted to the hospital and those discharged

home. Compared with patients who were promptly

diagnosed and treated for PE, patients admitted to the

hospital who went on to have delayed recognition of PEtended to have a higher frequency of altered mental

status (either new or at baseline dementia) and

preexisting heart and lung disease   (8,11–13). Only one

study provided data on patients apparently discharged

with PE, and those patients were more likely to not have

dyspnea, have isolated pleuritic chest pain and

hemoptysis together with a pulmonary infiltrate on

imaging, and a lower D-dimer concentration with a small

distal clot seen on pulmonary vascular imaging (12). Coin-

cidentally, in an analysis of PE(+) but pulmonary embo-

lism rule-out criteria (PERC)() patients (see Table 2 in

part 1) in a large database, the presence of pleuritic chestpain emerged as a common feature (14). Thus, it seems

that highly competent emergency physicians may miss

distal lung clots that produce pulmonary infarction and a

clinical picture of pneumonia. More evidence is needed

to determine if patients with these small distal clots, in

the absence of deep venous thrombosis (DVT), actually

benefit from systemic anticoagulation.

Exclusion of PE at the Bedside

About two-thirds of patients who are considered for testing

for PE in the United States have a low pretest probability,regardless of the method used, and the prevalence of PE in

this group is

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IMAGING

CT Pulmonary Angiography (CTPA)

A good quality computed tomography (CT) scan, which

requires about 200 Hounsfield units of contrast opacifica-

tion in the main pulmonary artery, rules out PE at all pre-test probabilities on the day of examination   (42,43).

Chest CT does not rule out the possibility of future PE

from undiagnosed DVT. Chest CT angiography only

identifies filling defects in contrast-enhanced pulmonary

arteries. Most scanning protocols require the patient to

lie supine and hold his or her breath for a few seconds.

CT scanning requires injection of approximately

120 mL of contrast by a computer-controlled injection

device. The patient must have a peripheral intravenous

(i.v.) catheter (20 gauge or larger) or an approved

indwelling line to allow injection of the contrast. Equip-

ment with multiple detector heads (e.g., 64-head scan-ners) allows better resolution so that filling defects can

be observed even in subsegmental pulmonary arteries

(44). The diagnostic sensitivity and specificity of a tech-

nically adequate CT scan, performed on a multidetector

CT scanner in an ED population independently of pretest

probability, are both about 90% (43). Interobserver agree-

ment in identifying segmental or larger filling defects has

been consistently demonstrated to be very good, but inter-

observer agreement for subsegmental clots is poor  (45).

Benefits of CT scanning include a binary positive or nega-

tive result and the ability to detect evidence supporting a

clinically significant alternative diagnosis (where pneu-monia is most common, found in 8–22% of cases)

(33,46–50).

Radiologists indicate presence of suboptimal image

quality in about 10% of their formal interpretations of 

CTPA scans (45,51). Figure 2 (A and B) shows examples

of high-quality scan images and a degraded image. Im-

age quality is most commonly degraded by low arterial

opacification, or motion artifact (e.g., from severe ta-

chypnea)   (52). Obesity increases risk of inadequate

CTPA imaging   (53,54). Radiologists probably cannot

detect filling defects with

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Whether or not this laboratory finding represents clini-

cally important kidney injury remains controversial, but

contrast nephropathy has been associated with worse out-

comes   (76–79). At present, no specific prophylactic

measure beyond prehydration with intravenous saline

has demonstrated any beneficial effect to reduce the

incidence and significance of contrast nephropathy (80).

The increased resolution of multidetector-row

CT scanning has led to an increase in the detection of 

isolated subsegmental PE. About one-quarter of all

Figure 2. (A) Obvious saddle embolism (yellow arrowheads) in a main pulmonary artery with 329 Hounsfield units opacificationdensity. (B) Questionable filling defect (yellow arrowhead) within a left lower lobar artery associated with only 167 Hounsfieldunits of opacification. Note that visual inspection of the quality contrast opacification can be misleading without on-screen re-gion of interest measurement of the Hounsfield units. These images illustrate that computed tomography chest angiography canrange from highly certain to ambiguous and underscore the importance of talking to the radiologist about image quality.

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contrast-enhanced chest CT scans read as positive for PE

have isolated subsegmental PE   (81–83). Isolated

subsegmental PE refers to a filling defect seen in one

small pulmonary artery, usually 1) probably should not be treated (94). In

these situations, and in any case where the risks and ben-

efits of treatment are unclear, the patient should be

informed of the situation and help make the decision

about anticoagulation.

Ventilation Perfusion Scintillation (V/Q)

Ventilation-perfusion scintillation (V/Q) lung scanning

requires peripheral intravenous access, and for the patient

to sit upright during injection of a radioisotopic nuclide,

usually   99Tc macroaggregate, followed by positioningthe patient in front of a gamma camera to capture the

gamma emission from the radionuclide as it traverses

the pulmonary vasculature. Use of a central line to inject

isotope will often lead to inadequate images. If the perfu-

sion lung scan shows a homogenous perfusion pattern

(i.e., a ‘‘normal’’ perfusion scan; Figure 3A), this is asso-

ciated with a likelihood ratio negative of 0.05, and essen-

tially rules out PE (95,96). Patients without PE and with

normal chest radiographs are far more likely to have

normal V/Q scan than patients with intrinsic lung

disease seen on chest radiograph. In patients with

nonnormal perfusion, most U.S. radiology departments

also perform the ventilation phase of the V/Q scan,

which requires the patient to inhale an aerosol

containing   99mTc diethylenetriamine-pentaacetic acid

or   133Xe. Although starting with the perfusion scan may

obviate the need for the ventilation scan, and thereby

reduce radiation exposure, image quality is best if theventilation phase is performed first because the back-

ground emission from the perfusion scan persists for

hours. To diagnose PE, the perfusion scan must show

two or more apex-central, wedge-shaped defects in perfu-

sion pattern in a segmental or larger vascular distribution,

together with evidence of normal ventilation in the same

lung segments (Figure 3B). The primary technical limita-

tions of V/Q scanning include the availability of 

personnel to perform and interpret them and the availabil-

ity of isotope. Some emergency clinicians may not be

aware that the availability of the   99Tc isotope depends

upon a cyclotron particle accelerator to manufactureeach day. The primary clinical limitation of V/Q scanning

is the fact that approximately two-thirds of scans are

neither normal nor diagnostic of PE, which requires pa-

tients to undergo further testing.

 Bilateral Ultrasonography

Performing lower-extremity venous ultrasonography is

sensible due to its lack of ionizing radiation and the fact

that diagnosing DVT is tantamount to diagnosing PE

from the standpoint of the decision to administer heparin

anticoagulation in the ED. In fact, studies suggest that acombination of D-dimer testing and lower-extremity ul-

trasound may be the most cost-effective approach to the

initial evaluation of PE   (22,97). However, in the

absence of physical findings that suggest DVT, bilateral

ultrasonography is of limited usefulness for excluding

PE in the ED. Data from the largest study that

simultaneously performed bilateral leg ultrasonography

and performed pulmonary vascular imaging indicate

that a negative bilateral proximal lower-extremity venous

ultrasound has a sensitivity of 30% and a specificity of 

57% (LR for a negative test = 1.22) for PE  (98). Other

studies have yielded similar results, so all patients sus-pected of having PE for whom ultrasound findings are

negative require pulmonary vascular imaging   (51,99).

Nonetheless, following the logic that discovery of DVT

is tantamount to diagnosis of PE in terms of treatment

action in the ED, pursuing DVT first makes sense for

patients with a positive D-dimer and for patients who

object to pulmonary vascular imaging.

Follow-up bilateral venous ultrasound is also the best

option to rule out PE in patients with high pretest proba-

bility, a positive D-dimer, and a negative CTPA scan with

any radiologist comment about degraded image quality.

110 J. A. Kline and C. Kabrhel

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Management protocols using this approach find that 5%