VOL zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`JUL 1996 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`Urban Setting zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`MD zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`Karl zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`A. Sporer, MD, Jennifer Firestone, BS, S. Marshal Isaacs, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`hospital urban setting noted for a high prevalence of IV opioid use. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`Out-of-hospital Treatment of Opioid
`
`Overdoses
`
`in an
`
`I ABSTRACT
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`............................
`
`. . . . . . . . . .
`
`Objectives: To investigate clinical outcomes in a cohort of opioid
`
`overdose patients treated in an out-of-
`
`660
`
`ACADEMIC EMERGENCY MEDICINE
`
`3/NO 7
`
`Methods: A retrospective review was performed of presumed opioid overdoses that were managed in 1993
`by the emergency medical services (EMS) system in a single-tiered, urban advanced life support (ALS) EMS
`system. Specifically. all patients administered naloxone by the county paramedics were reviewed. Those pa-
`tients with at least 3 of 5 objective criteria of an opioid overdose [respiratory rate c6/min, pinpoint pupils,
`evidence of IV drug use, Glasgow Coma Scale (GCS) score <12, or cyanosis] were included. A response to
`naloxone was defined as improvement to a GCS 2 1 4 and a respiratory rate ZlOlmin within 5 minutes of
`naloxone administration. ED dispositions of opioid-overdose patients brought to the county hospital were
`reviewed. All medical examiner’s cases deemed to be opioid-overdose-related deaths by postmortem toxico-
`logic levels also were reviewed.
`
`Results: There were 726 patients identified with presumed opioid overdoses. Most patients (609/726, 85.4%)
`had an initial pulse and blood pressure (BP). Most (94%) of this group responded to naloxone and all were
`transported. Of the remainder, 101 (14%) had obvious signs of death and 16 (2.2%) were in cardiopulmonary
`arrest without obvious signs of death. Of the patients in full arrest, 2 had return of spontaneous circulation
`but neither survived. Of the 609 patients who had initial BPs, 487 (80%) received naloxone IM (plus bag-
`valve-mask ventilation) and 122 (20%) received the drug IV. Responses to naloxone were similar; 94% IM
`vs 90% IV. Of 443 patients transported to the county hospital, 12 (2.7%) were admitted. The admitted patients
`had noncardiogenic pulmonary edema ( n = 4). pneumonia (n = 2), other infections (n = 2), persistent respi-
`ratory depression (n = 2). and persistent alteration in mental status ( n = 2). The patients with pulmonary
`edema were clinically obvious upon ED arrival. Hypotension was never noted and bradycardia was seen in
`only 2% of our presumed-opioid:overdose population.
`Conclusions: The majority of the opioid-overdose patients who had initial BPs responded readily to naloxone,
`with few patients requiring admission. Noncardiogenic pulmonary edema was uncommon and when present,
`hypoxia was evident upon arrival to the ED. Naloxone administered IM in conjunction with bag-valve-mask
`ventilation was effective in this patient population. The opioid-overdose patients in cardiopulmonary arrest
`did not survive.
`Key words: heroin; opioid; opiate; overdose; poisoning; naloxone; emergency medical services; EMS, out-
`of-hospital; paramedic.
`
`Acad. Emerg. Med. 1996; 3~660-667.
`
`........................................................................................................
`
`From the University of California, San Francisco; San Francisco
`General Hospital, Base Hospital: San Francisco, CA. Department of
`Emergency Services (KAS. SMI): the University of California, Los
`Angeles. School of Medicine, Los Angeles. CA (JF): and the Depart-
`CA MI).
`ment of Public Health. Paramedic Division, sari ~
`~
`~
`
`Received: July 24, 1995; revision received: December 11. 1995: ac-
`cepted: December 13. 1995; updated: January 11, 19%.
`
`Prior presentation: In part at the SAEM annual meeting, San Antonio,
`TX, May 1995.
`
`Address for correspondence and reprints: Karl A. Sporer; MD. Emer-
`~
`~
`i
`~
`~
`~
`;
`gency Services, Room IE21. San Francisco General Hospital, I 0 0 1
`.
`-
`
`Potrero Avenue, San Francisco. CA 94110. Fax: 415-206-5818: e-mail:
`karlsporer@quickmail. ucsf: edu
`
`
`
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`Page 1
`
`

`

`Sporer et al. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`Out-of-hospital Opioid Overdoses, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`661
`
`I Opioid-related overdoses are a common toxicologic
`overdose in urban settings. The Drug Abuse Warning
`Network estimates that there were 63,000 opioid-related
`ED visits in 1993, with 36% of these visits related to an
`overdose.’ Reported opioid-related episodes have in-
`creased 65% from 1988 through 1993 nationwide and
`now account for 13% of all drug-related ED episodes.’
`A recent study of preventable deaths from 1986 through
`1991 in San Francisco revealed that poisoning and drug
`overdoses made up 27% of these deaths and was the
`leading category of preventable deaths.2 The largest sin-
`gle category of drug causing these deaths was the opioid
`agents, comprising 23% of the poisoning and drug-re-
`lated deaths.
`Although potentially fatal, the treatment for opioid-
`related overdoses with naloxone may be one of the more
`effective therapies rendered in the out-of-hospital arena.
`However, general management approaches for opioid
`overdoses have been adopted by emergency medical ser-
`vices (EMS) systems and EDs with limited (often only
`anecdotal) outcomes data. Hence, a methodical exami-
`nation of actual practice and outcomes is needed to val-
`idate or guide modification of current management ap-
`proaches. This study evaluates 12 months’ experience
`with presumed opioid-related overdoses initially man-
`San Francisco and
`addresses the clinical features that affect outcome.
`
`ulation of 750,000, and the EMS system answers ap-
`proximately 50,000 calls per year. There is a single base
`hospital that provides on-line medical consultation as
`needed to all ALS providers.
`
`Population
`
`Computerized records of the Department of Public
`Health Paramedic Division were searched for all patients
`during 1993 who received naloxone as part of their out-
`of-hospital care. These 1,856 charts were examined by
`a second-year medical student with prior specific train-
`ing in reading and interpreting the EMS medical record;
`any difficult clinical determinations were directly super-
`vised by one of the investigators (KAS).
`A diagnosis of presumed opioid overdose required at
`least 3 of the following clinical criteria: 1) circumstantial
`evidence of parenteral drug use (syringes, needles, by-
`stander stating heroin use); 2) a respiratory rate <6/min;
`3) cyanosis prior to oxygenation; 4) a Glasgow Coma
`5 ) pinpoint pupils. The
`EMS records of all patients which had the above criteria
`were reviewed and the information was entered into a
`computerized database.
`
`EMS Practice for Presumed Opioid Overdose
`
`The altered mental status protocol followed by the
`paramedics dictates that patients suspected of an opioid
`overdose are immediately treated with high-flow 0, via
`to assist ventilation and an IM or IV
`bag-valve-mask
`2-mg dose of naloxone. A repeat dose is given if no
`response is seen in 1-2 minutes, and a blood glucose
`level is checked (Chem-Strip BG, Boehringer Mann-
`heim, Montreal, Quebec, Canada). A patient with an al-
`tered mental status of an unknown etiology will receive
`a blood glucose measurement, and an IM or IV dose of
`2 mg of naloxone is given only in the setting of respi-
`ratory depression. On-line medical consultation is pro-
`vided by board-certified emergency physicians at San
`Francisco General Hospital (SFGH). The use of nalox-
`one or glucose does not require base hospital consul-
`tation.
`Patients in cardiopulmonary arrest and suspected
`opioid overdose receive endotracheal intubation, IV or
`endotracheal naloxone, defibrillation (if ventricular fib-
`rillation is present), and standard ALS medications. If a
`pulse or persistent ventricular fibrillation is obtained,
`then the patient is transported to the nearest medical fa-
`cility. If the patient has pulseless electrical activity or
`asystole after 20 minutes of ALS, then the patient is
`commonly pronounced dead in the field after contact
`with the base hospital physician. Patients found in ad-
`vanced stages of death (lividity, rigor mortis, or signs of
`decomposition) by the paramedics are referred to the
`medical examiner’s office.
`
`Scale (GCS) score 112; and zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`aged by paramedics in the city of zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`I METHODS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`...........................................................................
`
`Study Design
`
`A retrospective review of EMS records was per-
`formed for presumed-opioid-overdose patients who pre-
`sented in 1993 to the San Francisco EMS system to de-
`termine the out-of-hospital therapy and outcome.
`Reviews of hospital and medical examiner records were
`used to complement the EMS analysis. The study was
`approved by the Committee on Human Research of the
`University of California, San Francisco, the Emergency
`Medical Services Agency of the city of San Francisco,
`and the medical examiner’s office of San Francisco.
`
`Setting
`
`The city and county of San Francisco have a single-
`tiered 2-paramedic advanced life support (ALS) EMS
`system. The fire department serves as first responder to
`life-threatening calls (which would include a patient with
`an altered mental status) and provides basic life support
`(BLS) intervention as well as semiautomatic defibrilla-
`tion. An EMS medical record is generated for each pa-
`tient encounter. The catchment area of the medical ex-
`aminer’s office and that of the paramedic division both
`include all 49 square miles of San Francisco County. The
`city and county of San Francisco have an evening pop-
`
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`Page 2
`
`

`

`662
`
`ACADEMIC EMERGENCY MEDICINE JUL 1996 VOL 3/NO 7
`
`of Out-of-hospital Opioid Overdoses in zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`1993, San Francisco zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`4 TABLE 1 Outcomes zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`admitted to SFGH were evaluated. The practice at SFGH
`is for alert opioid-overdose patients to be evaluated for
`hypoxia and a recurrence of sedation during a 2-hour
`observation period before release. Patients with a per-
`sistent altered mental status are evaluated as usual with
`a blood glucose measurement, a repeat dose of naloxone,
`and a search for other potential causes of their symp-
`toms. Active injection drug users with a documented fe-
`ver >38.3”C are admitted to rule out acute bacterial en-
`docardit i s.
`In addition, all medical examiner’s cases for 1993 in
`the county of San Francisco were reviewed. Those cases
`seen by paramedics that were deemed to be opioid-re-
`lated deaths by circumstantial evidence and postmortem
`toxicologic analysis comprised the out-of-hospital over-
`dose deaths.
`
`...........................................................................
`
`Number
`
`%
`
`Total
`
`Opioid overdose with palpable blood pressure
`Transported to base hospital
`Advanced signs of death
`Asvstolic arrest (no advanced sien of death)
`
`726
`
`609
`443
`101
`16
`
`100
`
`84
`61
`14
`2
`
`Measurements
`
`The EMS records were reviewed for patient demo-
`graphics, verification of presumed opioid overdose (see
`population above), clinical presentation [especially pres-
`ence of respirations, pulse, and/or blood pressure (BP)],
`therapy administered, need for ALS therapy (other than
`naloxone), response to naloxone, survival of out-of-hos-
`pital care, receiving hospital, and complications. A re-
`sponse to naloxone was defined as improvement to a
`and a respiratory rate ?lO/min within 5
`minutes of naloxone administration. Return of sponta-
`neous circulation (ROSC) was defined as the return of
`sustained palpable pulses for a minimum of 5 minutes.
`Since 74% of the opioid-overdose patients were
`transported to SFGH. the dispositions of these patients
`were searched via a separate database that contains dem-
`ographic and clinical information including diagnosis
`and disposition. The inpatient charts of those patients
`
`I TABLE 2 Characteristics of the Opioid-overdose Groups
`...........................................................................
`
`~~
`
`GCS 2 1 4 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`Data Analysis
`
`Descriptive analyses were performed. In addition, the
`response rates to IV vs IM naloxone in the out-of-hos-
`pital setting were compared with chi-square analysis.
`
`I RESULTS
`...........................................................................
`
`There were 726 EMS responses to presumed-opioid-
`overdose cases in the city of San Francisco during 1993
`(Table 1). Of these, 609 (84%) had initial pulses and
`BPs and were transported to a hospital. One hundred one
`(14%) patients were found by paramedics to have evi-
`dence of advanced signs of death (lividity, rigor mortis,
`or signs of decomposition) and were concluded by the
`medical examiner’s toxicologic screening to have ex-
`perienced opioid-related deaths. Sixteen (2.2%) patients
`were found in asystolic arrest without advanced signs of
`death; the deaths were later determined by the medical
`examiner’s office to be opioid-related. The age, sex, and
`race distributions of these 3 groups are shown (Table 2).
`Most patients evaluated by the EMS system (443/
`726,61%) were taken to the base hospital (SFGH). Clin-
`ical outcomes are not known for the other 166 (26%)
`patients, but none was reported by the medical exami-
`ner’s office to be an opioid-related death.
`
`Out-of-hospital Clinical Characteristics of
`Opioid Overdoses
`The IV route of opioid administration accounted for
`
`the majority of the overdoses in which the route was
`
`noted (Table 3). Other routes of opioid administration
`
`such as IM. subcutaneous, smoked, nasal insufflation, or
`
`ingestion accounted for only 4% of the opioid overdoses.
`Hypotension defined as a systolic BP c 100 mm Hg
`was not seen in any patient who had an initial respiratory
`rate or palpable pulse. Bradycardia was surprisingly rel-
`
` zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`244 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`Opioid
`Overdose
`with Blood
`Pressure
`
`No.
`
`609
`
`16
`90
`
`207
`52
`
`%
`
`84
`
`3
`15
`40
`34
`9
`
`Cardiac
`Arrest
`
`Signs of
`Death
`
`No.
`
`16
`
`0
`2
`9
`5
`0
`
`%
`
`2
`
`0
`13
`56
`31
`0
`
`No.
`
`101
`
`0
`14
`37
`41
`9
`
`%
`
`14
`
`0
`14
`37
`41
`9
`
`170
`86
`37
`1
`5
`310
`
`476
`132
`
`28
`14
`6
`0
`1
`5 1
`
`78
`22
`
`4
`2
`
`
`
`10
`
`11
`5
`
`25
`12
`
`63
`
`69
`31
`
`80
`15
`6
`0
`0
`0
`
`79
`22
`
`80
`15
`6
`0
`0
`0
`
`78
`22
`
`Total
`
`Age (years)
`<20
`20 - 29
`30-39
`40-49
`>50
`
`Race
`White
`Black
`Hispanic
`Native American
`Asian
`Unknown
`
`Sex
`Male
`Female
`
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`
`

`

`Out-of-hospital Opioid Overdoses, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`sively among the patients in cardiopulmonary arrest. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`The 2-mg dose of naloxone was used for zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`patients, with higher doses such as 3-4 mg used for 28% zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`tients zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`10 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`Systolic blood pressure (mm Hg) zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`Sporer et al.
`
`atively rare in opioid-overdose patients who had initial
`vital signs. A pulse <40 beats/min was never docu-
`mented and a pulse c60 beats/min was noted in only 2%
`of this group.
`A respiratory rate <6/min was noted in 62% of the
`opioid-overdose patients and pinpoint pupils were noted
`in 94%. Large dilated pupils were found almost exclu-
`
`Out-of-hospital Treatment for Opioid
`Overdoses
`
`58% of the
`
`I TABLE 3 Clinical Characteristics of the Opioid-overdose Pa-
`...........................................................................
`
`~
`
`Opioid
`Overdose with
`Blood Pressure Cardiac Arrest
`
`%
`
`63
`0
`0
`0
`0
`0
`31
`
`0
`0
`0
`0
`0
`6
`
`16
`
`100
`
`I TABLE 4 Treatment of the Opioid-overdose Patients
`........................................................................
`
`Opioid Overdose
`with Blood
`Pressure
`
`Cardiac Arrest
`
`Total
`
`609
`
`16
`
`Naloxone route
`IM
`IV
`Both IM and IV
`Endotracheal tube
`
`Naloxone dose
`None
`0.4 mg
`1 mg
`2 mg
`3-4 mg
`A mg
`
`Response intervals
`Average
`Median
`SD
`
`First responders
`Fire department
`Paramedics
`
`487 (80%)
`69 (11%)
`53 (9%)
`0 (0%)
`
`1 (0.2%)
`8
`(1%)
`35 (6%)
`353 (6%)
`172 (28%)
`40 (7%)
`
`4.6 min
`4.0 min
`2.7 rnin
`
`429 (70%)
`180 (30%)
`
`2 (13%)
`8 (50%)
`2 (13%)
`4 (25%)
`
`0 (0%)
`0 (0%)
`0 (0%)
`8 (50%)
`6 (38%)
`2 (13%)
`
`5.2 min
`5.0 min
`2.3 min
`
`15 (94%)
`1 (6%)
`
`and >4 mg used for 7% (Table 4). For the patients who
`presented in cardiopulmonary arrest, the naloxone was
`administered IV more commonly (50%) than it was for
`the nonarrest patients (1 1%) and more often in higher
`doses.
`The paramedic response times to these 2 groups were
`similar. The 90th-percentile response for the opioid-
`overdose patients who had vital signs was 7 minutes,
`and that for the opioid-overdose patients who had car-
`diac arrest was 7.5 minutes. The fire department BLS
`responders were present in 94% of the cardiopulmonary
`arrest group and were the first responders for 70% of the
`group of opioid-overdose patients who had BPs.
`Forty-two patients (7%) required restraints for pro-
`tection of self and staff after receiving naloxone. Only
`5 patients escaped from the care of the paramedics post-
`naloxone and were not transported. Thirty patients (5%)
`gave a history of simultaneous use of cocaine and opioid
`(i.e.. “speedball”), but no different adverse event such
`as seizures, arrhythmia, o r an increased restraint use was
`noted in this group.
`
`Response to Naloxone in Patients with Initial
`BPs
`Of the 609 patients with any initial BP, 575 (94%)
`readily responded to naloxone by improving to a GCS
`2 1 4 and a respiratory rate 210 within 5 minutes of
`administration. The response rate for IM naloxone was
`
`%
`
`No.
`
`16
`
`Total
`
`Opioid route
`1v
`IM
`Nasal
`Smoked
`Subcutaneous
`Ingestion
`Unknown
`
`<loo
`loo- I 1 0
`111-120
`121-130
`>I30
`Unknown
`
`No.
`
`609
`
`353
`2
`5
`3
`3
`3
`240
`
`0
`111
`61
`106
`293
`38
`
`58.0
`0.3
`1 .o
`0.5
`0.5
`0.5
`40.0
`
`0
`18
`10
`17
`48
`6
`
`Pulse rate (beatshin)
`0-39
`40-60
`61-80
`81 - 100
`>loo
`
`Respiratory rate (breathdmin)
`0
`2
`3-6
`7-10
`11-20
`>20
`
`Pupils
`Pinpoint
`Equal, reactive to light
`Dilated
`Nonreactive
`Unknown
`
`0
`13
`79
`229
`288
`
`170
`72
`136
`92
`130
`9
`
`585
`14
`3
`2
`5
`
`16
`
`100
`
`16
`
`100
`
`0
`2
`13
`38
`47
`
`28
`12
`22
`15
`21
`2
`
`96.0
`2.0
`0.5
`0.3
`1.0
`
`1
`0
`11
`4
`0
`
`6
`0
`69
`25
`0
`
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`
`

`

`JUL 1996 VOL zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`664 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`(n zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`= zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`Transported to the Base Hospital zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`40-49 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`I TABLE 5 Characteristics of
`the Opioid-overdose Patients
`443)
`...........................................................................
`
`Age (years)
`>20
`20 - 29
`30-39
`
`>50
`
`No.
`
`10
`66
`177
`155
`35
`
`%
`
`2
`15
`40
`35
`8
`
`ACADEMIC EMERGENCY MEDICINE
`
`3/NO 7
`
`(90%) (p = NS). Another zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`Sixteen zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`Two patients were admitted for pneumonia and 1 was
`admitted to rule out acute bacterial endocarditis. Two
`patients were admitted with persistent altered mental
`status and other medical complications. One patient had
`toxicologic screening in support of the diagnosis of
`opioid-overdose and was admitted for persistent hypo-
`thermia. This patient had resolution of symptoms in 2
`days. The second patient who had an altered mental status
`was further complicated by the diagnosis of rhabdomy-
`olysis, mild renal insufficiency, and a transient metabolic
`acidosis, all of which resolved in 2 days. Toxicologic
`screening was positive for both cocaine and morphine.
`Three patients had persistent hypoventilation unre-
`sponsive to naloxone. The hypoventilation for 2 of these
`cases was explained by co-ingestions. One patient was
`ultimately diagnosed as having wound botulism and un-
`derwent prolonged ventilatory support with full neuro-
`logic recovery.
`
`I DISCUSSION
`............................
`
`The administration of naloxone in an opioid overdose
`with hypoventilation is probably one of the most effec-
`tive out-of-hospital treatments. A recent Italian study
`demonstrated that the mortality from opioid-related
`deaths was significantly lower in one city that adminis-
`tered out-of-hospital naloxone than it was in the rest of
`the country’s cities that did not use out-of-hospital nal-
`oxone.’ The authors excluded patients with advanced
`signs of death. Their median response interval for par-
`amedic arrival was 3 minutes (range 1-15). Many [52/
`126 (41.4%)] of their patients were in respiratory arrest
`(defined as apnea or gasping) but had spontaneous car-
`diac activity. They first endotracheally intubated the pa-
`tients and then gave them IV naloxone in 0.4-mg incre-
`ments. Most [30/52 (58%)] of the respiratory arrest
`patients were admitted to the hospital and all 52 patients
`survived with normal neurologic function. Acute pul-
`monary edema occurred in only l patient (0.8%). An-
`other 77 (53%) patients had altered mental status but
`little or no respiratory depression and were treated with
`naloxone. Only 2 (4.3%) of this group were admitted for
`reasons not stated.
`The Italian series had 7 (5%) patients in asystolic
`cardiopulmonary arrest, and 5 (71%) of these were re-
`suscitated with a combination of naloxone and ALS in-
`terventions. The median time delay until treatment for
`this group was significantly longer than it was for those
`not in cardiopulmonary arrest. Of these 5 patients, 1 later
`died of complications secondary to anoxic encephalop-
`athy and the other 4 were released without neurologic
`impairment.
`One U.S. study examined the courses of 124 patients
`who had opioid overdoses seen in an ED of an urban
`county h ~ s p i t a l . ~ The majority of these patients received
`
`Sex
`Male
`Female
`
`Outcome
`Released
`Admitted
`
`342
`101
`
`43 1
`I2
`
`77
`23
`
`97
`3
`
`ED arrival diagnosis
`Pulmonary edema
`Pneumonia
`Other infections
`Altered mental status
`Respiratory depression
`
`1 .oo
`0.50
`0.25
`0.50
`0.75
`
`4881518 (94%) and the rate for IV naloxone was 69/73
`52 patients (9%) received nal-
`oxone both IM and IV (response rate 98%). This sub-
`group revealed a similar early response rate to IM nal-
`oxone.
`
`Opioid Overdoses and Cardiopulmonary Arrest
`
`(2.2%) patients were found without advanced
`signs of death and in cardiopulmonary arrest. Standard
`ALS interventions and naloxone were given, with 2
`(17%) patients developing ROSC. One of these 2 pa-
`tients spent 3 weeks in an intensive care unit before suc-
`cumbing to multiorgan failure, and the other died in the
`ED. All of these patients were deemed by the medical
`examiner to have experienced opioid-related deaths.
`
`Opioid Overdoses with Hospital Data
`
`Of all the transported opioid-overdose patients, 444
`(74%) were taken to the ED of SFGH (Table 5). The
`age and sex distributions of the transported cohort were
`similar to those of the total group. Of these patients, the
`majority (97%) were released after evaluation and ob-
`servation. Only 12 patients (2.7%) were admitted.
`The 4 patients admitted for noncardiogenic pulmo-
`nary edema all had obvious symptoms of hypoxia upon
`admission to the ED. Two of these patients were intu-
`bated, and resolution of the pulmonary edema occurred
`in 1-3 days. All 4 patients with noncardiogenic pul-
`monary edema were discharged after 2-3 days of hos-
`pitalization, all with normal mental status.
`
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`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00695
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`

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`(n zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`diogenic pulmonary edema zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
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`665
`
`of the total patients had pulses zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA
`
`naloxone via the IM route. Five (4%) of these patients
`presented in cardiopulmonary arrest and did not improve
`with naloxone and ALS therapy. Twelve (9.6%) were
`admitted for a variety of reasons. These include noncar-
`= 3). hypoxic encepha-
`(n = 2), aspiration pneumonia (n = l), other
`overdoses ( n = 3), and detoxification ( n = 3). All 3 pa-
`tients found to have noncardiogenic pulmonary edema
`were clinically apparent within 30 minutes of their ar-
`rival in the ED. The remaining 107 patients were re-
`leased from the ED after an observation period of 2
`hours.
`Another U.S. study examined the safety and efficacy
`of out-of-hospital naloxone in patients with altered men-
`tal status. The rate of complications was small, and 7.4%
`of these patients responded to naloxone. The authors
`suggested that “those with evidence of recent opioid use
`are very likely to demonstrate the most improvement,”
`but also warned that some patients responded when
`opioid intoxication was not s ~ s p e c t e d . ~
`The current study demonstrates that the prognosis is
`excellent for the treatment of opioid overdose patients
`who are found with any vital signs. Approximately 94%
`of patients with clinically apparent opioid overdoses who
`present with BPs or pulses will improve with naloxone.
`Of the patients for whom outcome data are available, all
`of the opioid-overdose patients with initial vital signs
`survived.
`This group of opioid-overdose patients with initial
`vital signs had an admission rate of 2.7%. This was con-
`siderably lower than the 58% admission rate reported
`previously in Italy’ and closer to the 9.6% admission rate
`previously reported in the United state^.^ The high ad-
`mission rate in Italy may be explained by the practice
`of intubating all patients with agonal respirations prior
`to giving IV naloxone.
`The 9.6% admission rate reported in the U.S. study
`without out-of-hospital naloxone can be explained by a
`higher rate of noncardiogenic pulmonary edema, 2 cases
`of hypoxic encephalopathy, and admissions for detoxi-
`fication. The earlier out-of-hospital administration of
`naloxone may play a role in decreasing the number of
`patients with noncardiogenic pulmonary edema and/or
`hypoxic injury.
`The physical findings of our patients with opioid
`overdoses and initial vital signs were somewhat surpris-
`ing. The toxidrorne of an opioid overdose is usually de-
`scribed as a combination of pinpoint pupils, decreased
`respiratory rate, hypotension, and relative brady~ardia.~.’
`Our case definition undoubtedly led to a high rate of
`respiratory depression (77%) and pinpoint pupils (96%)
`in our population. However, it was surprising to find that
`bradycardia <40 beatdmin was never seen and only 2%
`4 0 beatdmin. Similarly,
`no patient with other vital signs was noted to have a
`
`systolic B P 4 0 0 mm Hg, and only 18% <110 mm Hg.
`Because of the retrospective nature of this study, we
`could not control the timing of these vital signs (i.e.
`pre- or post-naloxone use), but we were surprised that
`no hypotension was noted and bradycardia was rarely
`recorded. This finding is consistent with a recent study
`of in-hospital opioid overdoses that demonstrated that
`hypotension and bradycardia were rarely found.’
`The use of IM naloxone has not been recommended
`in the acute opioid overdose because of concerns that
`systemic absorption will b e erratic and i n e f f e ~ t i v e . ~ . ~ Be-
`cause rapid IV access in this particular patient population
`can be difficult and our experience indicates that hypo-
`tension is rare, our paramedics have been given an op-
`tion to use IM naloxone. The IM route of administration
`had a 94% response rate, which was similar to the re-
`sponse rate for IV naloxone (90%). A number of patients
`received both IM and IV naloxone. This subgroup had
`a slightly better response rate of 98%, but this may sim-
`ply represent a larger dose effect.
`Only 0.9% of our opioid overdose patients with ini-
`tial vital signs developed noncardiogenic pulmonary
`edema. The previously reported rates of noncardiogenic
`pulmonary edema in this patient population have ranged
`from 0.8% to 48%.39’0*” The 48% rate is based on a
`retrospective study of admitted opioid-overdose patients
`in a pre-naloxone era.” A n 8% noncardiogenic pulmo-
`nary edema rate was reported among admitted patients
`who had opioid and methadone overdoses.” The only
`studies that examined all opioid-overdose patients who
`present to an ED reported rates of 0.8%3 and 2.4%.4
`There also is much discussion concerning the appro-
`priate length of observation for a patient with an opioid
`overdose who has responded to naloxone. The short-
`term concern is resedation due to the relatively short
`half-life of naloxone (30 minutes). There also is concern
`regarding a delayed development of noncardiogenic pul-
`monary edema. One study looked at this issue specifi-
`cally, but was flawed because there was no true long-
`term f o l l o w - ~ p . ~ Almost all of the reported cases of
`opioid-related noncardiac pulmonary edema were clini-
`cally obvious upon arrival to the ED.4910*12-25
`There have
`been only 3 well-documented cases of late-appearing
`opioid-related pulmonary
`Unfortunately, our
`study was not designed to evaluate this question.
`Even though a large number of patients with opioid
`overdoses probably benefit from the early out-of-hospital
`administration of naloxone, a considerable number of
`deaths still occur each year in the city of San Francisco.
`Most of these cases (101/117) are reported only after the
`patient has advanced signs of death. However, changes
`in EMS system configurations or protocols would not
`benefit this group of opioid-overdose patients.
`The survival rate for those patients in cardiopulmo-
`
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`IPR2019-00695
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`666
`
`ACADEMIC EMERGENCY MEDICINE JUL 1996 VOL 3 / N O 7
`
`opioid-overdose patients found in cardiopulmonary ar-
`rest was not observed.
`
`This work was supported in part by the San Francisco Injury Center
`through grant #R491CCR903697-06 from the Centers for Disease
`Control and Prevention. The contents of this study are solely the re-
`sponsibility of the authors.
`
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