Intravenous vs Subcutaneous Naloxone for Out-of-hospital Management of Presumed Opioid Overdose

Objective : To determine whether naloxone administered IV to out-of-hospital patients with suspected opioid overdose would have a more rapid therapeutic onset than naloxone given subcutaneously (SQ).
Methods : A prospective, sequential, observational cohort study of 196 consecutive patients with suspected opioid overdose was conducted in an urban out-of-hospital setting, comparing time intervals from arrival at the patient's side to development of a respiratory rate ≥10 breaths/min, and durations of bag-valve-mask ventilation. Subjects received either naloxone 0.4 mg IV ( n = 74) or naloxone 0.8 mg SQ ( n = 122), for respiratory depression of <10 breaths/min.
Results : Mean interval from crew arrival to respiratory rate ≥ 10 breaths/min was 9.3 ± 4.2 min for the IV group vs 9.6 ± 4.58 min for the SQ group (95% CI of the difference -1.55, 1.00). Mean duration of bag-valve-mask ventilation was 8.1 ± 6.0 min for the IV group vs 9.1 ± 4.8 min for the SQ group. Cost of materials for administering naloxone 0.4 mg IV was $12.30/patient, compared with $10.70/patient for naloxone 0.8 mg SQ.
Conclusion : There was no clinical difference in the time interval to respiratory rate ≥10 breaths/min between naloxone 0.8 mg SQ and naloxone 0.4 mg IV for the out-of-hospital management of patients with suspected opioid overdose. The slower rate of absorption via the SQ route was offset by the delay in establishing an IV.     

Do heroin overdose patients require observation after receiving naloxone?

Context: Heroin use in the US has exploded in recent years, and heroin overdoses requiring naloxone are very common. After awakening, some heroin users refuse further treatment or transport to the hospital. These patients may be at risk for recurrent respiratory depression or pulmonary edema. In those transported to the emergency department, the duration of the observation period is controversial. Additionally, non-medical first responders and lay bystanders can administer naloxone for heroin and opioid overdoses. There are concerns about the outcomes and safety of this practice as well.

Objectives: To search the medical literature related to the following questions: (1) What are the medical risks to a heroin user who refuses ambulance transport after naloxone? (2) If the heroin user is treated in the emergency department with naloxone, how long must they be observed prior to discharge? (3) How effective in heroin users is naloxone administered by first responders and bystanders? Are there risks associated with naloxone distribution programs?

Methods: We searched PubMed and GoogleScholar with search terms related to each of the questions listed above. The search was limited to English language and excluded patents and citations. The search was last updated on September 31, 2016. The articles found were reviewed for relevance to our objective questions. Eight out of 1020 citations were relevant to the first 2 questions, 5 of 707 were relevant to the third question and 15 of 287 were relevant to the fourth question. In the prehospital environment, does a heroin user revived with naloxone always require ambulance transport and what are the medical risks if ambulance transport is refused after naloxone? The eight articles were all observational studies done either prospectively or retrospectively. Two studies focused on heroin overdoses and included 1069 patients not transported to the hospital. No deaths occurred in this group. In counting the patients from all eight studies, some of which included non-heroin opioid overdoses, there were 5443 patients treated without transport and four deaths from rebound opioid toxicity. The number needed to transport to save one life (NNT) is 1361. Adverse effects were mostly related to opioid withdrawal. If a heroin user is treated in the ED, how long must the patient stay under observation before being safe for discharge? Five articles addressing the duration of ED observation required for patients treated with naloxone for opioid overdoses. Although a wide range of observation durations were reported, one study supported observing patients for one hour. If after this period the patient mobilizes as usual, has normal vital signs, and a Glasgow Coma Scale of 15, they can be discharged safely. What are the likely risks in heroin users following naloxone use by lay bystanders or first responders? Of the 15 relevant papers, a systematic review reported a 100% survival rate in eleven studies and a range of 96–99% survival in the remaining four. Two other studies suffered from poor follow-up and had lower success rates of 83% and 89%. Few if any risks were associated with opioid overdose prevention programs in which lay people were trained to administer naloxone.

Conclusions: Patients revived with naloxone after heroin overdose may be safely released without transport to the hospital if they have normal mentation and vital signs. In the absence of co-intoxicants and further opioid use there is very low risk of death from rebound opioid toxicity. For those patients treated in the ED for opioid overdose, an observation period of one hour is sufficient if they ambulate as usual, have normal vital signs and a Glasgow Coma Scale of 15. Patients suffering opioid toxicity can be administered naloxone safely by first responders and trained lay people. Programs that train these individuals are likely safe and beneficial, however further research is necessary.     

Hot Off the Press: Hospital Observation Upon Reversal (HOUR) With Naloxone: A Prospective Clinical Prediction Rule Validation Study

This is a prospective observational study looking to validate a previously derived decision rule designed to help safely discharge opioid overdose patients from the emergency department after 1 hour. They included a convenience sample of 538 adult patients who had received naloxone pre‐hospital and compared the Hospital Observation Upon Reversal (HOUR) rule with clinical judgement. The primary outcome of interest was a broadly defined composite of adverse events. The HOUR rule had a sensitivity of 84.1% (95% CI 76.2‐92.1%) and a specificity of 62.1% (95% CI 57.6‐66.5%), which was very similar to clinical judgement. Clinical judgement would have missed 12 adverse events, while the HOUR rule would have missed 13, although most of those adverse events were probably minor.     

Measuring a Crisis: Questioning the Use of Naloxone Administrations as a Marker for Opioid Overdoses in a Large U.S. EMS System

Objective: The United States is currently experiencing a public health crisis of opioid overdoses. To determine where resources may be most needed, many public health officials utilize naloxone administration by EMS as an easily-measured surrogate marker for opioid overdoses in a community. Our objective was to evaluate whether naloxone administration by EMS accurately represents EMS calls for opioid overdose. We hypothesize that naloxone administration underestimates opioid overdose. Methods: We conducted a chart review of suspected overdose patients and any patients administered naloxone in Wake County, North Carolina, from January 2013 to December 2015. Patient care report narratives and other relevant data were extracted from electronic patient care records and the resultant database was analyzed by two EMS physicians. Cases were divided into categories including “known opioid use,” “presumed opioid use,” “no known opioid,” “altered mental status,” “cardiac arrest with known opioid use,” “cardiac arrest with no known opioid use,” or “suspected alcohol intoxication,” and then further separated based on whether naloxone was administered. Patient categories were compared by patient demographics and incident year. Using the chart review classification as the gold standard, we calculated the sensitivity and positive predictive value (PPV) of naloxone administration for opioid overdose. Results: A total of 4,758 overdose cases from years 2013–15 were identified. During the same period, 1,351 patients were administered naloxone. Of the 1,431 patients with known or presumed opioid use, 57% (810 patients) received naloxone and 43% (621 patients) did not. The sensitivity of naloxone administration for the identification of patients with known or presumed opioid use was 57% (95% CI: 54%–59%) and the PPV was 60% (95% CI: 57%–63%). Conclusion: Among patients receiving care in this large urban EMS system in the United States, the overall sensitivity and positive predictive value for naloxone administration for identifying opioid overdoses was low. Better methods of identifying opioid overdose trends are needed to accurately characterize the burden of opioid overdose within and among communities.     

Naloxone Use in a Tiered-Response Emergency Medical Services System

Objective. To examine the delivery andeffect of naloxone for opioid overdose in a tiered-response emergency medical services (EMS) system andto ascertain how much time could be saved if the first arriving emergency medical technicians (EMTs) could have administered intranasal naloxone. Methods. This was case series of all EMS-treated overdose patients who received naloxone by paramedics in a two-tiered EMS system during 2004. The system dispatches basic life support–trained fire fighter–EMTs and/or advanced life support–trained paramedics depending on the severity of cases. Main outcomes were geographic distribution of naloxone-treated overdose, severity of cases, response to naloxone, andtime interval between arrival of EMTs andarrival of paramedics at the scene. Results. There were 164 patients who received naloxone for suspected overdose. There were 75 patients (46%) initially unresponsive to painful stimulus. Respiratory rate was <10 breaths/min in 79 (48%). Death occurred in 36 (22%) at the scene or during transport. A full or partial response to naloxone occurred in 119 (73%). Recognized adverse reactions were limited to agitation/combativeness in 25 (15%) andemesis in six (4%). Average EMT arrival time was 5.9 minutes. Average paramedic arrival time was 11.6 minutes in most cases and16.1 minutes in 46 cases (28%) in which paramedics were requested by EMTs at the scene. Conclusions. There is potential for significantly earlier delivery of naloxone to patients in opioid overdose if EMTs could deliver intranasal naloxone. A pilot study training andauthorizing EMTs to administer intranasal naloxone in suspected opioid overdose is warranted.     

Suspected opioid-related emergency medical services encounters in a rural state, 1997-2002

Introduction

News organizations and governmental agencies have reported substantial increases in the number of opioid-related overdose cases in recent years.

Objective

To describe the utilization of emergency medical services (EMS) for suspected opioid-related overdose cases in a rural state during the period 1997 through 2002.

Methods

Statewide EMS records were reviewed for 1997 through 2002. Data reviewed included prehospital diagnosis and medications given to all patients by prehospital providers. For cases with a prehospital diagnosis of poisoning or overdose, data reviewed included medications given to patients by prehospital providers, pupil size, and respiratory rate. All records were reviewed in a defined sequence.

Results

The study period encompassed 1,175,781 patient encounters. Poisoning or overdose patients accounted for 19,808 (1.7%) encounters. Naloxone was administered by the EMS provider to 2,668 (0.2%) patients. For all poisoning or overdose patients, 1,308 (6.6%) had miotic pupils, 450 (2.2%) had a respiratory rate of <12 breaths/min, and 1,569 (7.9%) received naloxone. During the investigation period, total EMS patient encounters increased 25%, while patients with a complaint of poisoning or overdose increased 47%. The incidences of EMS overdose patients with miotic pupils, respiratory rate <10 breaths/min, and naloxone administration increased 167%, 295%, and 154%, respectively.

Conclusion

In this rural state, prehospital patients with findings suspicious for opioid overdose disproportionately outpaced the growth of all EMS encounters as well as general overdose encounters during the defined investigation period.     

Out-of-hospital Treatment of Opioid Overdoses in an Urban Setting

Objectives : To investigate clinical outcomes in a cohort of opioid overdose patients treated in an out-of-hospital urban setting noted for a high prevalence of IV opioid use. 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 patients with at least 3 of 5 objective criteria of an opioid overdose [respiratory rate <6/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 14 and a respiratory rate 10/min 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 toxicologic 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 respiratory 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.     

Opioid Toxicity Recurrence After an Initial Response to Naloxone

Abstract

Objective: To determine the frequency and potential predictors of opioid toxicity recurrence after a response to naloxone in adult Emergency Department patients. Methods: A retrospective case-control study of naloxone-treated patients with opioid toxicity over an 8-year period. Both the patient response to naloxone and recurrence of opioid toxicity was determined by an expert Delphi Panel. The frequency of opioid toxicity recurrence was compared by the duration of opioid effect, the route of opioid exposure, and the presence of other CNS depressant drugs. Results: Ninety of 221 (41%) cases with a discharge diagnosis of opioid toxicity were treated with naloxone; six patients were excluded because of a lack of toxicity. There was a response to naloxone in 50% of the 84 cases, and recurrence of toxicity in 31% (95% CI 17–45%) of naloxone responders. The most common opioids were codeine, heroin, propoxyphene, and oxycodone/hydrocodone. Recurrence of toxicity was more common with long-acting opioids (p = 0.04), and was not associated with the route of opioid exposure (p = 0.42), or presence of ethanol and other CNS depressants (p ± 0.87). Conclusion: Opioid toxicity recurrence after a response to naloxone occurred in approximately 1/3 of adult Emergency Department opioid overdose cases. Recurrence was more common with long-acting opioids and was not associated with the route of opioid exposure. Other clinically useful predictors of toxicity recurrence were not identified.     

Do Co‐intoxicants Increase Adverse Event Rates in the First 24 Hours in Patients Resuscitated from Acute Opioid Overdose?

Abstract

Background:?Patients frequently arrive in emergency departments (EDs) after being resuscitated from opioid overdose. Autopsy studies suggest that multidrug intoxication is a major risk factor for adverse outcomes after acute heroin overdose in patients. If this is true, there may be high‐risk drug combinations that identify patients who require more intensive monitoring and prolonged observation. Our objective was to determine the impact of co‐intoxication with alcohol, cocaine, or CNS depressant drugs on short‐term adverse event rates in patients resuscitated from acute opioid overdose. Methods:?Data were extracted from the database of a prospective opioid overdose cohort study conducted between May 1997 and 1999. Patients were prospectively enrolled if they received naloxone for presumed opioid overdose. Investigators gathered clinical, demographic, and other predictor variables, including co‐intoxicants used. Patients were followed to identify prespecified adverse outcome events occurring within 24 h, and multiple logistic regression was used to determine the association of concomitant drug use on short‐term adverse event rates. Results:?Of 1155 patients studied, 58 (5%) had pure opioid overdose and 922 (80%) reported co‐intoxicants, including alcohol, cocaine, and CNS depressants. Overall, out of 1056 patients with known outcome status there were 123 major adverse events (11.6%) and 194 minor adverse events (18.4%). After adjustment for age, gender, HIV status, cardiovascular disease, pulmonary disease and diabetes, we found that coadministration of alcohol, cocaine, or CNS depressants, alone or in combination, was not associated with increased risk of death or adverse events during the 24 h follow‐up period. Conclusion:?In patients resuscitated from acute opioid overdose, short‐term outcomes are similar for patients with pure opioid overdose and multidrug intoxications. A history of cointoxication cannot be used to identify high‐risk patients who require more intensive ED monitoring or prolonged observation.     

Cardiorespiratory effects of naloxone in children

BACKGROUND: Data on the cardiorespiratory changes and complications following administration of naloxone in children are limited. OBJECTIVE: To evaluate the cardiorespiratory changes and complications following naloxone treatment in children. METHODS: The maximal changes in respiratory rate (RR), heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure, and any complications within 1 and 2 hours following naloxone were tabulated. RESULTS: One hundred ninety-five children received naloxone over 3 years. The mean +/- SD age was 9.7 +/- 6 years. The total doses of naloxone ranged from 0.01 to 7 mg (0.001-0.5 mg/kg body weight), with a median dose of 0.1 mg. Group 1 patients consisted of 116 (60%) children who were postoperative and had been given naloxone by an anesthesiologist; group 2 patients consisted of 79 (40%) children who received naloxone in the emergency department or pediatric intensive care unit. Patients in group 1 were older: 10.6 +/- 5.3 versus 8.2 +/- 6.7 years (p < 0.006), but received significantly lower doses of naloxone (0.09 +/- 0.2 vs. 1.1 +/- 0.76 mg; p < 0.001). When the entire cohort was evaluated, a significant increase in RR (15 +/- 7 vs. 21 +/- 8 breaths/min; p < 0.001), HR (102 +/- 29 vs.107 +/- 29 beats/min; p < 0.001), SBP (109 +/- 17 vs. 115 +/- 15 mm Hg; p < 0.001), and DBP (56 +/- 10 vs. 60 +/- 13 mm Hg; p < 0.001) within 1 hour following naloxone was noted. When the 2 groups were compared, only the changes in RR were greater in group 2 patients (6.8 +/- 7.9 vs. 4.7 +/- 5 breaths/min; p < 0.001) following naloxone. Systolic hypertension occurred in 33 of 195 (16.9%) of all patients, while diastolic hypertension occurred in 13 (6.6%) of all patients after naloxone. Only the incidence of diastolic hypertension was higher in group 2 compared with group 1 patients following naloxone (16% vs. 2%; p < 0.001). Hypertension resolved spontaneously. One child developed pulmonary edema and required positive pressure ventilation for 22 hours. CONCLUSIONS: Moderate increases in RR, HR, and BP occur after naloxone administration to children, but development of more serious complications is rare.     

Third-degree AV block from extended-release diltiazem ingestion in a nine-month-old

Calcium channel blocker (CCB) overdose is associated with dysrhythmias and atrioventricular (AV) block, however, experience with infant CCB overdose is limited. A 9-month-old girl was found playing with tablets of extended-release diltiazem 120 mg. The patient had two episodes of emesis, which contained pill fragments, and was brought to the Emergency Department (ED) 4.5 h after being found. Vital signs were: rectal temperature 37.1 degrees C, pulse 87 beats/min, respiratory rate 30-40 breaths/min, blood pressure 72/48 mm Hg, and oxygen saturation (SpO(2)) 99% on room air. Otherwise, the patient was well-appearing, with normal skin color and examination. The electrocardiogram revealed third-degree atrioventricular block with a ventricular rate of 90 beats/min, QRS 68 ms, and QTc 411 ms. Atropine 0.1 mg i.v. was given, which increased the heart rate to 100-110 beats/min. Calcium gluconate 500 mg was also given intravenously. Laboratory evaluation revealed bicarbonate 17 mEq/L, anion gap 16, and glucose 129 mg/dL. On hospital day 1, the patient was noted to have a junctional rhythm with a rate of 90-100, and systolic blood pressure of 80-90 mm Hg. No additional medications were given. Early on day 2, the patient converted spontaneously to a normal sinus rhythm and was discharged approximately 42 h after presentation to the ED. In addition to bradycardia and hypotension, this 9-month-old patient manifested third-degree AV block after ingesting extended-release diltiazem.     

Comparison of lower-dose versus higher-dose intravenous naloxone on time to recurrence of opioid toxicity in the emergency department

Introduction: The initial dose of naloxone administered to patients who present to the emergency department (ED) with opioid overdose is highly variable. The objective of this study was to determine if the initial dose of intravenous (IV) naloxone given to these patients was associated with the time to recurrence of opioid toxicity.

Methods: This was a multicenter retrospective cohort study, conducted at two academic EDs in the United States. Consecutive adults who had a positive response to naloxone for opioid overdose in the ED were included. Patients were categorized into two groups based on initial IV naloxone dose administered: 0.4?mg (lower-dose) or 1–2?mg (higher-dose). The main outcome measure was the time to recurrence of opioid toxicity requiring a second dose of naloxone. Secondary outcomes included the need for naloxone continuous infusion and adverse events.

Results: The study included 84 patients with 42 patients receiving lower-dose and 42 patients receiving higher-dose naloxone. Median time to re-dose of naloxone was similar between the lower-dose (72 [IQR 46–139] minutes) and higher-dose (70 [IQR 44–126] minutes) groups (p=.810). There were 12 patients (29%) in the lower-dose group and 17 patients (41%) in the higher-dose group who subsequently required continuous infusions (p=.359). The proportion of patients with adverse events was similar between lower-dose and higher-dose groups (31% versus 41%, p=.495). There was no difference in the incidence of specific withdrawal related adverse effects.

Conclusions: The initial dose of naloxone given to patients in the ED does not influence the time to recurrence of opioid toxicity.     

Treatment of opioid overdose in a physician-based prehospital EMS: frequency and long-term prognosis

Background

Prehospital treatment of opioid overdose accounts for a significant proportion of the workload of the emergency system in most major cities. Treatment consists of basic life support and administering naloxone. In our physician-manned mobile emergency care unit (MECU), most patients are released and not admitted to hospital. In this study, we aimed to assess the pattern in the number of episodes with opioid overdose treated by MECU in Copenhagen during a 10-year period and to investigate risk factors for mortality of these patients beyond the initial contact.

Methods

Data were collected prospectively in the MECU database covering all cases of opioid overdose in a 10-year period between 1994 and 2003. The pattern in the number of opioid overdose was analysed in Poisson regression models, and mortality was analysed in Kaplan-Meier plots and in Cox regression models.

Results

A total of 4762 episodes of opioid overdose were recorded. Patients were identified in 3245 of these episodes. The annual number of episodes decreased significantly over the data-collection period: from 639 overdoses out of 4520 (14.1%) patients treated in 1994 to 311 out of 7263 patients treated (4.3%) in 2003. A total of 352 patients had cardiac arrest at the scene. The MECU released 2246 patients (69.3%) after treatment, while 675 (20.8%) were admitted to hospital and 322 (9.9%) died. Long-term prognosis was poor with 14% mortality at 1 year. Long-term mortality was significantly related to increasing age, time of the year and if the patient had previous episodes of opioid overdose.

Conclusions

There has been a significant decrease in the number of opioid overdoses during this 10-year-period. Long-term mortality is high in these patients and highest in those with advanced age and numerous episodes of opioid overdose.     

Rate of patients at elevated risk of opioid overdose visiting the emergency department

Objective

To determine the rate of patients visiting the emergency department who are at risk of opioid overdose.

The changing epidemiology of opioid overdose in Baltimore,Maryland, 2012–2017: insights from emergency medical services

IntroductionAn estimated 100,306 people died from an overdose from May 2020 to April 2021. Emergency Medical Services (EMS) are often the first responder to opioid overdose, and EMS encounter records can provide granular epidemiologic data on opioid overdose. This study describes the demographic, temporal, and geographic epidemiology of suspected opioid overdose in Baltimore City using data from Baltimore City Fire Department EMS encounters with the administration of the opioid antagonist naloxone.MethodThe present analyses used patient encounter data from 2012 to 2017 from the Baltimore City Fire Department, the city’s primary provider of EMS services. The analytic sample included patient encounters within the city that involved naloxone administration to patients 15 years of age or older (n = 20,592). Negative binomial regression was used to calculate the incidence rates based on demographic characteristics, year, and census tract. Choropleth maps were used to show the geographic distribution of overdose incidence across census tracts in 2013, 2015, and 2017.ResultsFrom 2012 to 2017, the annual number of EMS encounters with naloxone administrations approximately doubled every 2 years, and the temporal pattern of naloxone administration was similar to the pattern of fatal opioid-related overdoses. For most census tracts, incidence rates significantly increased over time. Population-based incidence of naloxone administration varied significantly by socio-demographic characteristics. Males, non-whites, and those 25–69 years of age had the highest incidence rates.ConclusionThe incidence of naloxone administration increased dramatically over the study period. Despite significant cross-sectional variation in incidence across demographically and geographically defined groups, there were significant proportional increases in incidence rates, consistent with fatal overdose rates over the period. This study demonstrated the value of EMS data for understanding the local epidemiology of opioid-related overdose.

Key Messages

• Patterns of EMS encounters with naloxone administration appear to be an excellent proxy for patterns of opioid-related overdoses based on the consistency of fatal overdose rates over time.
• EMS plays a central role in preventing fatal opioid-related overdoses through the administration of naloxone, provision of other emergency services, and transportation to medical facilities.
• EMS encounters with naloxone administration could also be used to evaluate the impact of overdose prevention interventions and public health services.