ORIGINAL CONTRIBUTION naloxone, prehospital administration The Safety of Prehospital Naloxone Administration by Paramedics We performed a retrospective review to investigate the safety of prehospital naloxone administration by paramedics as part of a protocol for all pa- tients presenting with an acutely depressed level of consciousness (LOC). The prevalence of naloxone-induced vomiting, seizures, hypotension, hy- pertension, and cardiac arrest was sought from the prehospital records of 813 patients treated during a 12-month period. The mean age of the treated patients was 42.4 +_ 9.7 years. The initial dose of naloxone was 0.4 to 0.8 rag, and the mean total dose was 0.9 +_ 0.6 rag. No patients lost a pulse within ten minutes of receiving naloxone. Two patients (0.2%) expe- rienced a significant drop in systolic blood pressure, and one patient (0.1%) demonstrated a significant rise in systolic blood pressure within five minutes of naloxone administration. Vomiting occurred in two pa- tients (0.2%), and one patient (0.1%) suffered a tonic-clonic seizure within five minutes of naloxone administration. Of the 813 patients treated, 60 patients (7.4%; mean age, 32.3 ++_ 6.7 years) were judged to have an im- proved LOC after naloxone, with 27 (3.3%) regaining a normal LOC. We conclude that in the above doses, naloxone is safe as part of prehospital protocols for paramedics treating patients with an acutely depressed LOC. However, the vast majority of patients treated empirically with naloxone in the field demonstrated no benefit. [Yealy DM, Paris PM, Kaplan RM, Heller MB, Marini SE: The safety of prehospital naloxone administration by paramedics. Ann Emerg Med August 1990;19:902-905.] INTRODUCTION Patients with an acutely depressed level of consciousness {LOC) often are initially treated by paramedics in the field. Among the many etiologies responsible for a depressed LOC, hypoglycemia and opiate narcosis are eas- ily reversed when the appropriate therapies are given. The initial treatment of opiate overdose is based on the maintenance of adequate oxygenation and ventilation. Following steps to achieve these goals, specific antidote therapy is indicated in narcotic-overdose patients. Naloxone is the pre- ferred agent for reversal of opiate-induced altered sensorium and respira- tory depression. 1-3 Although widely used, naloxone has been associated with such complications as vomiting, seizures, hypertension, hypotension, ventricular arrhythmias, and cardiac arrest. 4 9 The magnitude of the risk of these complications in the prehospital setting is undefined. Because of the potential for complications, some suggest smaller initial doses z and rou- tine intubation before naloxone administration. 4 We performed a retrospective review to define the safety of naloxone administration by paramedics as part of a protocol for the treatment of patients with an acutely depressed LOC. Specifically, the prevalence of vomiting, seizures, significant hypertension, hypotension, and precipita- tion of cardiac arrest was sought from the records of patients treated with naloxone. METHODS The P~ttsburgh Bureau of Emergency Medical Services (EMS) is staffed by 170 full-time paramedics and supervisory personnel, with 16 mobile ad- vanced life support units (ALS) available for dispatch. Patients are trans- ported to one of 16 hospital emergency departments in the metropolitan Donald M Yealy, MD*t Paul M Paris, MD, FACEP*I Richard M Kaplan, MSt Michael B Helle< MD, EACEP*t Sal E Marinit Pittsburgh, Pennsylvania From the Division of Emergency Medicine, University of Pittsburgh;* and the Center for Emergency Medicine of Western Pennsylvania,t Pittsburgh. Received for publication June 12, 1989. Revision received November 27, 1989. Accepted for publication February 1, 1990. Presented at the University Association for Emergency MEdicine Annual Meeting in Philadelphia, May 1987. Address for reprints: Paul M Paris, MD, FACEP, 230 McKee Place, Suite 500, Pittsburgh, Pennsylvania 15213. 19:8 August 1990 Annals of Emergency Medicine 902/95
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`PREHOSPITAL NALOXONE Yealy et al area. Each year, there are approx- imately 40,000 responses attended by the EMS personnel, with approx- imately 15% requiring ALS interven- tions. Second- and third-year emer- gency medicine residents serve as primary medical command for all ALS calls by a two-way radio, with continual monitoring of all calls by a faculty backup physician. In addi- tion, residents respond to many ALS calls in a separate vehicle to assist with diagnosis and treatment. Con- sult with tho medical command phy- sician is required before administra- tion of any medications. The protocol for the management of patients with an acutely altered LOC requires the paramedic to ob- tain a directed history, perform a brief physical examination, place ECG leads, administer supplemental oxygen, and insert a peripheral IV line while obtaining blood for glu- cose estimation. If hypoglycemia is diagnosed (Chemstrip ® bG reagent strip reading of 80 mg/dL or less), 50 to 100 mL of a 50% dextrose solution is administered. Patients with a de- pressed LOC and no response to IV glucose or those with a depressed LOC and a glucose estimation of nrore than 80 mg/dL received 0.4 to 0.8 nag naloxone by the IV catheter. In some cases, naloxone was given before glucose estimation, partic- ularly if the history and surrounding circumstances suggested opiate over- dose. The IV route was preferred, but IM, sublingual, SQ, and intratracheal (if intubated) routes were considered acceptable when approved by the command physician when IV access was unobtainable. The initial dose of naloxone was based on published recommenda- tions for the field treatment of opiate overdose at the time of treatment, to Only after recontact with the com- lnand physician were additional doses administered as needed based on initial response. Patients were maintained in the lateral decubitus position with nearby suction after the administra- tion of naloxone until normal LOC had returned; they were immobilized if cervical-spine injury was sus- pected. If clinically indicated, bag- valve-mask or endotracheat intu- bation was performed by the paramedics or field physicians. De- tailed trip sheets were maintained, with an emphasis on the presenting history, physical examination, and vital signs, as were chronological re- cordings of all interventions and clin- ical responses. The prehospital charts of all pa- tients treated with naloxone during the 12-month period from January through December 1986 were re- viewed. Any patients without a pal- pable pulse at the time of naloxone administration or who were treated as part of a combination of the al- tered response and multiple trauma protocols were excluded. In addition, although the altercd LOC protocol is applicable for patients with any change in sensorium, naloxone was administered only to patients with a subjective depressed sensorium or respiratory drive as judged by the paramedics. The charts were reviewed for age and sex; vital signs, subjective LOC (as judged by paramedics and re- corded in the narrative), and cardiac rhythm before and after each inter- vention; initial and total doses of naloxone and route; and develop- ment of vomiting or seizures within five minutes of the administration of naloxone and before admission to an ED. Before data analysis, we arbitrarily defined "significant hypotension" af- ter naloxone administration as occur- ring when the measured systolic blood pressure decreased to less than 30 mm Hg and obtained an absolute value of less than 120 mm Hg, and "significant hypertension" after naloxone administration as occurring when the systolic blood pressure in- creased to more than 30 mm Hg and obtained an absolute value of more than 160 mm Hg. The data were analyzed using de- scriptive methods, with continuous variables reported as the mean _+ standard deviation. Ninety-five per- cent upper limits of confidence (ULC) were calculated for the risk of each complication. ~ RESULTS A total of 81,3 patients met the cri- teria for review, with no patients ex- cluded because of missing charts. There were 480 male (59%) and 333 female (41%) patients (mean age, 42.4 +- 9.7 years). The total naloxone doses ranged from 0.4 to 2.4 mg (mean, 0.9 +_ 0.6 nrg). Administra- tion routes were IV (800), intra- tracheal (seven), sublingua] (four), IM (one), and SQ (one). Of all patients treated with naloxone, 60 (7.4%) de- veloped some subjective improve- ment in their LOC within five min- utes of administration as recorded by the attending paramedics. The mean age of the patients with any subjec- tive improvement in LOC after naloxone was 32.3 + 6.7 years. Also, 27 patients (3.3%} were judged to have regained a normal LOC before arrival at the receiving ED. In 22 of these 27 patients (82%), the prehospi- tal chart stated that witnesses ob- served or paramedics or peace offi- cers found evidence of recent opiate use at the scene. No patient developed ventricular tachycardia, fibrillation, or asystole after naloxone administration (0%, ULC - 0.4%). One patient (0.1%, ULC 0.5%) developed a gener- alized tonic-clonic seizure after re- ceiving 0.8 mg IV naloxone; no im- provement was noted, and further history revealed an underlying sei- zure disorder. Two patients (0.2%, ULC - 0.6%) vomited after receiv- ing 0.8 mg IV naloxone; one of these patients demonstrated a rapid im- provement in the observed LOC be- fore emesis. The other patient, ini- tially described as "slightly drowsy," had received ipecac before naloxone administration. The ED records of both patients reported no evidence of aspiration, and they were discharged by the treating physician without further follow-up. One patient (0.1%, ULC = 0.5%) developed significant hypertension after naloxone administration. This patient was observed to have no im- provenrent in the subject LOC by the paramedics, with a total dose of 1.2 mg administered. Another seven pa- tients (8.6%) had increases of more than 30 mm Hg, yet their post-treat- ment systolic blood pressures either remained at or returned to 100 to 160 mm Hg. Two patients (0.2%, ULC - 0.6%) developed significant hypoten- sion after naloxone administration; each received 0.8 mg, but only a par- tial improvement in LOC was ob- served in one patient. DISCUSSION These data confirm the safety of empiric naloxone therapy by para- medics when treating patients with an acutely depressed LOC; there was little risk of precipitating vomiting, seizures, cardiac arrest, or significant 96/903 Annals of Emergency Medicine 19:8 August 1990
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`hypertension and hypotension. This was true for patients with a clinical improvement after naloxone and for those with no subjective improve- ment who were given naloxone as part of a protocol. Case reports documenting cardiac arrest after naloxone reversal of opiate anesthesia in young, healthy adults have surfaced, s yet no data ex- ist on the overall prevalence of this complication in either the postopera- tive or emergency settings. In the aforementioned case reports, ven- tricular fibrillation developed rapidly after 0.2 to 0.4 mg IV naloxone, pre- sumably from a catecholamine surge precipitated by the agent. However, these patients may differ from those treated for acutely depressed LOC. Postoperative patients have often re- ceived a variety of agents capable of altering circulatory physiology and are still subject to the stress of sur- gery. Also, vomiting and seizures have been reported as a direct side effect of IV naloxone. 4 A literature search found no data on the prevalence of vomiting or sei- zures after naloxone administration. Nonetheless, it has been suggested that routine endotracheal intubation be performed before naloxone admin- istration to lessen the risk of aspira- tion of vomitus. 4 Others have sug- gested smaller initial doses of nalox- one (0.04 rag) in patients with a suspected opiate overdose to decrease the risk of complications. 7 However, present data do not support these recommendations. There are limitations to our study. One potential design bias lies within the data collection technique. The paramedics' recording of the pre- and post-treatment LOC was subjective; no predetermined ordinal scale (eg, modified Glasgow Coma Score) was used. Only systolic blood pressures were consistently available for eval- uation on each patient, thus interfer- ing with analyses of diastolic and mean arterial blood pressure changes. The accuracy of blood pressures ob- tained in the field may be ques- tioned, but previous researchers have suggested that any errors may be clinically insignificant.l'- Further- more, it is unlikely that an important bias was encountered because the ar- bitrary criteria for significant hyper- tension or hypotension were selected after the care was delivered but be- fore chart review. Our data collection was primarily from prehospital charts, with limited ED chart review. This was omitted because of the logistic difficulties in obtaining a standardized set of data on each patient when 16 receiving fa- cilities were involved. This does not allow analyses of response and com- plication rates based on final diag- noses. Also, no toxicologic screening data were available for analysis on the vast majority of patients. For similar reasons, we are not able to completely exclude the possibility of late development of symptoms con- sistent with pulmonary aspiration in the two patients who vomited after treatment. However, even if both de- veloped aspiration syndromes, the overall prevalence of this complica- tion would be equal to that seen with vomiting (0.2%). The retrospective nature of the present study does raise the issue of data accuracy. We chose to concen- trate on complications that were eas- ily observed and routinely recorded by the prehospital care personnel. The quality assurance system used by the EMS bureau stresses detailed, uniform data collection, with strict guidelines for documentation after all interventions during ALS calls. The presence of continuous on-line medical command physicians, with many ALS calls attended by the resi- dent physicians, also assists with de- tection of complications after ther- apy. Given the above system and study design, we feel that no cases of cardiac arrest, seizures, or vomiting were unrecorded. Pulmonary edema, another rare complication associated with nalox- one therapy,13, ~4 was not studied be- cause the field documentation of this disease is difficult. Opiate overdose alone can lead to pulmonary edema, ,3 further clouding any conclusions about a direct cause-and-effect rela- tionship between naloxone adminis- tration and this side effect. We did not assess the cost-effec- tiveness of routine prehospital nalox- one administration to all patients with an acutely depressed LOC; in our series, more than 92% of patients treated had no observable benefits. In addition, the vast majority of pa- tients who experienced a complete return to a normal LOC after nalox- one administration had a history strongly suspicious for recent nar- cotic use. Our design does not allow accurate identification of all patients likely to respond to naloxonc ther- apy, although those with evidence of recent opiate use are very likely to demonstrate the most improvement. However, it is clear that some pa- tients exhibited a complete response to naloxone when opiate narcosis was not suspected. The partial re- sponses of some patients may be the result of inadequate doses, multiple drug ingestions, or the alleged non- specific arousal properties of nalox- one in certain non-narcotic-induced conditions of depressed LOC. 15 Prospective research to identify the characteristics of patients most likely to respond to naloxone is needed to better tailor the use of this agent in the field. Furthermore, anal- ysis of the costs and benefits of selec- tive versus routine use of naloxone in patients with an acutely depressed LOC in a variety of prehospital sys- tems is needed before definitive rec- ommendations concerning protocols can be made. Our conclusions may not be valid with the use of larger doses of nalox- one, which are often used to counter- act the more potent synthetic opiate cogencrs. Previous research with higher doses of naloxone in overdose patients and healthy subjects has failed to document any significant side effects.~6, t7 The conclusions may also not apply with the use of newer opiate antagonists, such as nalmefene. CONCLUSION The use of naloxone in initial doses of 0.4 of 0.8 mg for the prehos- pital treatment of patients with acutely depressed LOC is safe, with little risk of precipitating vomiting, seizures, significant hypertension, hypotension, or cardiac arrest. Smaller doses and routine pread- ministration intubation appear un- warranted from our data. When given to all patients with a depressed LOC, the majority will not demonstrate any benefit, yet the overall cost-to- benefit ratio remains undefined. The authors thank Maurcen Havcr and Janet McGraw for their assistance with the preparation of this manuscript. They also express their appreciation to the City of Pittsburgh paramedics, whose coopera- tion made this study possible. 19:8 August 1990 Annals of Emergency Medicine 904/97
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`PREHOSPITAL NALOXONE Yealy et al REFERENCES 1. Handal KA, Schauben ]L, Salamone FR: Naloxone. Ann Emerg Med 1983;12:438-445. 2. Lewis JM, Klein-Schwartz W, Benson BE, et ah Continuous naloxone infusion in pediatric narcotic overdose. Am J Dis Child 1984;138: 944-946. 3. Jaffe J, Martin W: Opioid analgesics and an- tagonists, in Gilman AG, Goodman LS, Rail TW, et al (eds}: The Pharmacologic Basis of Therapeutics, ed 7. New York, MacMillan Pub- lishing Co, 1985, p 491-527. 4. Allen T: Narcotics, in Rosen P, Baker FJ, Braen GR, et al (eds): Emergency Medicine: Concepts and Clinical Practice, ed 2. St Louis, Missouri, CV Mosby, 1988, p 2125-2140. 5. Andree RA: Sudden death following nalox- one administration. Anesth Analg 1980;59: 782-784. 6. Knbrinsky NL, Pruden PB, Cheang MS, et ah Increased nausea and vomiting induced by naloxone in patients receiving cancer chemo therapy. Am J Pediatr HematoI Oncol 1988;10: 206-208. 7. Neal JM: Complications of naloxone. Ann Emerg Med 1988;17:765-766. 8. Mariani PJ: Seizure associated with low-dose naloxone. Am / Emerg Med 1989;7:127-129. 9. Michaelis LL, Hickey PR, Clark TA, et ah Ventricular irritability associated with the use of naloxone hydrochloride. Ann Thorac Surg 1974;18:608-614. 10. Epstein FB, Eilers MA: Poisoning, in Rosen P, Baker YJ, Braen GR, et al (eds): Emergency Medicine: Concepts and Clinical Practice, ed 1. St Louis, Missouri, CV Mosby, 1983, p 215-253. 11. Elston RC, Johnson WD: Essentials of Bio- statistics. Philadelphia, FA Davis, 1987, p 103q16. 12. Hunt RC, Allison EJ, Whitley TW, et ah Comparison of EMT blood pressure measure- ments with an automated blood pressure moni- tor: On scene, during transport, and in the emergency department. Ann Emerg Med 1985; 14:871-875. 13. Pantridge BL, Ward CF: Puhnonary edema following low-dose naloxone administration. Anesthesiology 1986;65:709-710. 14. Schwartz JA, Koenigsberg MD: Naloxone- induced pulmonary edema. Ann Emerg Med 1987;16:1294-1296. 15. Litovitz TL: The anecdotal antidotes. Emerg Med Clin North Am 1984;2:145-158. 16. Rumack BH, Temple AR: Lomotil poison- ing. Pediatrics 1974;53:495-500. 17. Cohen MR, Cohen RM, Pickar D, et ah Be- havioral effects after high dose naloxone admin- istration in normal volunteers. Lancet 1981; 2:1110. ERRATUM In the article "The Ability of Physicians to Predict Electrolyte Deficiency From the ECG," by Wrenn, Slovis, and Slovis [May 1990;19:580-583], parts A and B of the figure were inadvertently switched. 98/905 Annals of Emergency Medicine 19:8 August 1990
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