`
`Naloxone therapy in opioid overdose patients:
`intranasal or intravenous? A randomized clinical trial
`
`Ali Mohammad Sabzghabaee1, Nastaran Eizadi-Mood1, Ahmad Yaraghi2, Samaneh Zandifar3
`
`Corresponding author:
`Dr. Ahmad Yaraghi
`Isfahan Clinical Toxicology
`Research Centre
`Noor and Ali-Asghar [PBUH]
`University Hospital
`Isfahan University
`of Medical Sciences
`Ostandari Avenue
`81458-31451 Isfahan, Iran
`Phone: + 98 311 224 11 30
`Fax: +98 311 668 0011
`E-mail:
`yaraghi@med.mui.ac.ir
`
`1 Isfahan Clinical Toxicology Research Centre, Isfahan University of Medical Sciences,
`Isfahan, Iran
`2 Department of Anaesthesiology and Intensive Care, Isfahan University of Medical
`Sciences, Isfahan, Iran
`3 Noor and Ali-Asghar [PBUH] University Hospital, Isfahan University of Medical
`Sciences, Isfahan, Iran
`
`Submitted: 7 May 2011
`Accepted: 12 December 2011
`
`Arch Med Sci 2014; 10, 2: 309–314
`DOI: 10.5114/aoms.2014.42584
`Copyright © 2014 Termedia & Banach
`
`A b s t r a c t
`Introduction: This study was designed to compare the effects of intranasal
`(IN) and intravenous (IV) administration of naloxone in patients who had
`overdosed on opioids.
`Material and methods: This randomized clinical trial study was conducted
`in the Department of Poisoning Emergencies at Noor and Ali Asghar (PBUH)
`University Hospital. One hundred opioid overdose patients were assigned
`by random allocation software into two study groups (n = 50). Both groups
`received 0.4 mg naloxone: one group IN and the other IV. Outcomes included
`change in the level of consciousness (measured using a descriptive scale
`and the Glasgow Coma Scale (GCS)), time to response, vital signs (blood
`pressure, heart rate and respiratory rate), arterial blood O2 saturation be-
`fore and after naloxone administration, side-effects (agitation) and length
`of hospital stay.
`Results: Patients who had been administered IN naloxone demonstrated
`significantly higher levels of consciousness than those in the IV group using
`both descriptive and GCS scales (p < 0.001). There was a significant differ-
`ence in the heart rate between IN and IV groups (p = 0.003). However, blood
`pressure, respiratory rate and arterial O2 saturation were not significantly
`different between the two groups after naloxone administration (p = 0.18,
`p = 0.17, p = 0.32). There was also no significant difference in the length of
`hospital stay between the two groups (p = 0.14).
`Conclusions: Intranasal naloxone is as effective as IV naloxone in reversing
`both respiratory depression and depressive effects on the central nervous
`system caused by opioid overdose.
`
`Key words: opioid, intranasal, naloxone, intravenous, overdose.
`
`Introduction
`
`As a competitive antagonist of the mu-opioid receptors [1], naloxone
`can be used for resuscitating patients who have significant respiratory
`depression and impaired consciousness due to opioid toxicity. Cannu-
`lation is a particular difficulty in intravenous drug users (IDUs). Often
`pre-existing venous damage can delay or even prevent the administra-
`tion of an antidote. Additionally, IDUs are also at an increased risk of
`carrying blood borne infections that could be transmitted to healthcare
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`Ali Mohammad Sabzghabaee, Nastaran Eizadi-Mood, Ahmad Yaraghi, Samaneh Zandifar
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`workers through needle stick injuries [2]. Whilst
`patients with altered mental status or multiple
`narcotic overdose may require intravenous (IV)
`access for other reasons, those with isolated nar-
`cotic overdose who rapidly respond to intranasal
`(IN) naloxone may not require IV access at all [3,
`4]. The problems with the IV route of naloxone ad-
`ministration have led to efforts to find an effective
`alternative means of delivery.
`The IN route has been shown to be clinically
`effective for a number of medications including
`analgesics and sedatives [5, 6]. When used with
`carefully selected medications, this delivery route
`has the advantage of rapid onset, high plasma bio-
`availability, direct transport to the central nervous
`system across the olfactory mucosa, elimination
`of first pass metabolism and, perhaps most im-
`portantly, elimination of the use of needles [7–13].
`Some observational studies have suggested
`that intranasal naloxone may be safely adminis-
`tered for the reversal of opioid intoxication in the
`pre-hospital and hospital settings. Unfortunately
`such studies have suffered from several limita-
`tions such as lack of randomization or blinding
`and reliance on the subjective reporting of para-
`medics who were required to record times, admin-
`ister medications and assess appropriate patient
`responses [4, 14–18].
`This study was designed therefore to compare
`the effect of intranasal administration of nalox-
`one with those of intravenous administration in
`the treatment of suspected opioid overdose pa-
`tients in a managed clinical environment referring
`to the limitations pointed out above in previous
`studies.
`
`Material and methods
`Study design and setting
`
`This randomized trial study was conducted
`in the Department of Poisoning Emergencies at
`Noor and Ali Asghar (Peace Be Upon Him) Uni-
`versity Hospital. The study protocol was approved
`by the Ethics Committee of Isfahan University of
`Medical Sciences. The study was also registered
`at ClinicalTrials.gov (Reference number identifier:
`NCT01293058).
`
`Patient selection and treatment protocol
`
`Included in the study were all patients with the
`age range 15–50 suspected of opioid overdoses.
`This selection was based upon a history of opioid
`overdose and the display of clinical manifestations
`including myotic pupils and loss of consciousness
`(with or without respiratory depression defined by
`a respiratory rate of less than 12). One hundred el-
`igible patients were divided into two groups (each
`group containing 50 patients) in addition to basic
`
`life support following clinical practice guidelines
`[19]. One group was administered 0.4 mg nalox-
`one diluted down to a 2 ml nasal spray (1 ml into
`each nostril) whilst the other received 0.4 mg IV
`naloxone as a bolus dose. Normal saline was used
`as the solvent. The intranasal spray was adminis-
`tered to patients in lying position. All patients who
`failed to respond within 5 min of the initial nalox-
`one administration were given a further 0.4 mg
`naloxone by the same administration route (IN
`or IV). Patients failing to respond to the first 0.4 mg
`naloxone with an increased level of conscious-
`ness or a reversal of respiratory depression were
`excluded from the study. Naloxone hydrochloride
`was purchased from Tolid Daru Co, Tehran, Iran.
`
`Data collection
`
`The information collected for this study in-
`cluded patients’ demographics, the type of opi-
`oid used and the means of administration, vital
`signs (blood pressure, heart rate, respiratory rate),
`level of consciousness measured with descriptive
`scales (conscious, lethargic, obtundation, stupor,
`and coma) and the Glasgow Coma Scale (GCS),
`time to response, arterial blood oxygen (O2) sat-
`uration before and 5 min after naloxone admin-
`istration, side-effects (e.g. agitation) and duration
`of hospital stay. These data were collected from
`checklists including information on patient histo-
`ry, clinical assessments and records of treatment
`administered to the patient.
`Trained medical staff prospectively recorded
`demographic data and clinical features of patients
`including measurement of the eye, motor, verbal
`and GCS scores in an appropriate form. The GCS
`was determined based on three components: eyes
`(4 – opens spontaneously, 3 – to verbal command,
`2 – to pain, 1 – none), verbal (5 – oriented, 4 – dis-
`oriented, 3 – inappropriate words, 2 – incompre-
`hensible sounds, 1 – none), and motor (6 – obeys,
`5 – localizes pain, 4 – withdrawal, 3 – abnormal
`flexion, 2 – abnormal extension, 1 – none) [20].
`
`Key outcome measures
`
`The primary outcome measure was level of
`consciousness. Secondary outcomes were vital
`signs, the time interval to response, arterial blood
`O2 saturation, the frequency of side-effects (e.g.
`agitation) and the duration of hospital stay.
`
`Statistical analysis
`
`Randomization was carried out using random
`allocation software (Saghaei, 2004). Quantitative
`variables were compared using the independent
`t-test. Qualitative variables were compared using
`(cid:70)2 and Mann-Whitney tests. Data were analyzed
`using SPSS version 17.0 (SPSS Inc, Chicago, IL,
`
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`Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial
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`USA) with p < 0.05 being considered statistically
`significant.
`
`Results
`
`Age, gender, opioid agent and route of opioid
`use before naloxone administration between the
`two groups were not significantly different (Table I).
`The results regarding level of consciousness (in-
`cluding descriptive and Glasgow Coma Scales) af-
`ter naloxone administration are shown in Table II.
`The mean response time in the IN group and the
`IV group was 2.56 ±0.64 min and 1.48 ±0.58 min
`respectively (p < 0.001). The IN group had a signi-
`ficantly longer time to response to naloxone than
`the IV group (p < 0.001).
`After naloxone administration there was a sig-
`nificant difference in heart rate between the IN
`and IV groups (p = 0.003). However, blood pressure
`and respiratory rate were not significantly differ-
`ent between the two groups (p = 0.18, p = 0.17)
`(Table III).
`The mean arterial O2 saturation before IN and
`IV naloxone administration was 71.4 ±8.3% and
`72.7 ±6.3% (p = 0.45) respectively. Arterial O2 sat-
`uration following naloxone administration was
`94.4 ±1.3 in the IN group and 94.6 ±1.5 (p = 0.32)
`in the IV group.
`The mean length of hospital stay was 1.53
`±0.16 days and 1.2 ±0.15 days in the IN and IV
`
`Table I. Comparison of demographic, opioid agent
`and route of exposure between two groups
`
`Groups
`Intra-
`venous
`naloxone
`
`Intra-
`nasal
`naloxone
`
`Value
`of p
`
`29.9 ±8.4
`
`33.2 ±21.1
`
`0.11*
`
`Variables
`
`Age, mean ± SD
`[year]
`Males, n (%)
`
`Opioid agent, n (%)
`
`groups respectively (p = 0.15). Agitation after nal-
`oxone administration was observed in 12 patients
`in the IV group. No patient in the IN group were
`observed to become agitated.
`
`Discussion
`
`Intranasal administration of naloxone has been
`shown to have many advantages [7–13].
`Given the necessity for the rapid administra-
`tion of naloxone in opioid overdose emergencies,
`the nasal route can offer immediate safe access
`and can circumvent the difficulties of having to re-
`move clothing to cannulate. This method has been
`underutilized to date.
`This study showed that among opioid overdose
`patients, IN naloxone is as effective as IV nalox-
`one at reversing the depressive effects on the cen-
`tral nervous system caused by opioids. Although
`our results showed no significant clinical differ-
`ence between the two groups after naloxone ad-
`ministration, level of consciousness was higher in
`patients administered IN naloxone than those in
`the IV group. This finding may be because of direct
`transportation of naloxone to the central nervous
`system across the olfactory mucosa [7]. Although
`Dowling et al. [21] in an open-label crossover vol-
`unteer study evaluated the pharmacokinetics of
`intranasal naloxone and reported that the IN route
`is the least useful due to its poor bioavailability,
`major differences existed between their subjects
`and opioid poisoned patients. They administered
`IN naloxone to alert healthy volunteers who invol-
`untarily swallowed a significant percentage of the
`administered drug that pooled in the nasophar-
`ynx. Due to the high first pass metabolism of na-
`loxone this may have resulted in the very low bio-
`availability observed. In patients unconscious due
`
`39 (78)
`
`37 (74)
`
`0.64**
`
`Table II. Level of consciousness in opioid overdose
`patients before and after naloxone administration
`
`0.06**
`
`Level of consciousness
`
`Before
`nalox-
`one
`
`After
`nalox-
`one
`
`12 (24)
`
`24 (48)
`
`14 (28)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`28 (56)
`
`22 (44)
`
`10 (20)
`
`28 (56)
`
`0
`
`0
`
`12 (24)
`
`20 (40)
`
`0
`
`0
`
`18 (36)
`
`12 (24)
`
`Diphenoxylate
`
`Crack***
`
`Buprenorphine
`
`0
`
`2 (4)
`
`4 (8)
`
`4 (8)
`
`0
`
`0
`
`Methadone
`
`8 (16)
`
`10 (20)
`
`Heroin
`
`Opium
`
`14 (28)
`
`12 (24)
`
`22 (44)
`
`24 (48)
`
`Opioid exposure route, n (%)
`
`0.68**
`
`Intravenous
`
`13 (26)
`
`10 (20)
`
`Oral
`
`Sniffing
`
`26 (52)
`
`26 (52)
`
`11 (22)
`
`14 (28)
`
`*Independent t-test, **(cid:70)2 test, ***Crack in Iran contains heroin
`combined with other opioid agents
`
`Intranasal administration, n (%)
`Coma
`
`Stupor
`
`Obtundation
`
`Lethargic
`
`Conscious
`Intravenous administration, n (%):
`Coma
`
`Stupor
`
`Obtundation
`
`Lethargic
`
`Conscious
`
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`Ali Mohammad Sabzghabaee, Nastaran Eizadi-Mood, Ahmad Yaraghi, Samaneh Zandifar
`
`Table III. Vital signs, arterial O2 saturation and GCS (Glasgow Coma Scale) in opioid overdose patients before and
`after naloxone administration between two groups
`
`Variable
`
`Before naloxone
`administration
`
`After naloxone
`administration
`
`Value of p
`
`Systolic blood pressure [mm Hg]:
`
`Intranasal naloxone
`
`Intravenous naloxone
`Value of p
`Diastolic blood pressure [mm Hg]:
`
`Intranasal naloxone
`
`Intravenous naloxone
`Value of p
`Heart rate (per min):
`
`Intranasal naloxone
`
`Intravenous naloxone
`Value of p
`Respiratory rate (per min):
`
`Intranasal naloxone
`
`Intravenous naloxone
`Value of p
`Arterial O2 saturation:
`Intranasal naloxone
`
`Intravenous naloxone
`Value of p
`Glasgow Coma Scale (range: 1–15):
`
`Intranasal naloxone
`
`Intravenous naloxone
`Value of p
`*P value < 0.05, NS – not significant
`
`99 ±16
`
`97 ±21
`
`0.68
`
`63 ±8.9
`
`66 ±11
`
`0.11
`
`90 ±22
`
`89 ±25
`
`0.78
`
`13 ±5.9
`
`11 ±2.5
`
`0.06
`
`71.4 ±8.3
`
`72.7 ±6.3
`
`0.25
`
`9.7 ±1.6
`
`9.4 ±1.3
`
`0.22
`
`106 ±14.7
`
`112 ±9.6
`
`0.18
`
`78 ±7.1
`
`77 ±4.5
`
`0.18
`
`90 ±8.3
`
`97 ±12.9
`
`0.003
`
`18 ±2.4
`
`19 ±2.8
`
`0.17
`
`94.4 ±1.3
`
`94.6 ±1.5
`
`0.32
`
`14.3 ±0.73
`
`13.2 ±1.5
`
`< 0.001
`
`*
`
`*
`
`NS
`
`*
`
`*
`
`*
`
`*
`
`to opioid overdose with consequent depressed
`oropharyngeal reflexes, less nasally administered
`naloxone may be swallowed, thus increasing the
`IN absorption and bioavailability.
`Merlin et al. [22] reported that the route of ad-
`ministration (IV or IN) of naloxone made no signif-
`icant difference to its effect on level of conscious-
`ness (using GCS). Our findings were incompatible
`with these results. Previous studies have been
`criticized for using GCS to quantify the change
`in level of consciousness following naloxone ad-
`ministration in cases of opioid intoxication [23]
`but the GCS has previously been used to evaluate
`non-trauma patients [24–26]. Therefore, in our
`study we used both descriptive and GCS scores to
`evaluate the level of consciousness. There is dis-
`agreement between physicians over the clinical
`usefulness of the GCS [27, 28]. The inter-observer
`variability is high when the scoring systems are
`not used on a regular basis, thus affecting the ac-
`curacy and reproducibility of the data [29–32]. This
`is potentially relevant in our study, as GCS determi-
`nation was performed by several different physi-
`
`cians and had not formed a routine part of patient
`assessment before the study period. We tried to
`minimize variability by having one person to coor-
`dinate the process of data collection and had our
`anaesthesiologist or toxicologist formally train our
`emergency physicians in the assessment of GCS
`prior to the study. All GCS assessments were sub-
`sequently made by this group of physicians.
`Merlin et al. [22] also reported that the route of
`naloxone administration (IN or IV) made no differ-
`ence to the effect on respiratory rate. Our findings
`supported this conclusion. Our study also showed
`that there was no difference between the two
`groups in normalization of blood pressure and ar-
`terial O2 saturation after naloxone administration.
`There was a difference in the rates of agitation
`after naloxone treatment between the two study
`groups, with patients who received IV treatment
`showing higher rates (n = 12) than those who re-
`ceived IN treatment (n = 0). This may be explained
`by the difference in rates of naloxone absorption
`between the two methods of naloxone adminis-
`tration [9] and may be seen as an advantage of
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`Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial
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`the IN route. However, the higher rate of agitation
`in the IV group may be due to the higher number
`of addicted patients in this group.
`Since opioid abusers frequently have incom-
`plete, inaccessible or non-existent medical histo-
`ries, it is impossible to establish how many pa-
`tients in each group were addicted to opioids (and
`therefore subject to withdrawal with the adminis-
`tration of naloxone).
`Whilst the randomization method used in the
`study should result in an approximately equal ad-
`diction rate between the two groups, it remains
`impossible to state definitely that IN administra-
`tion results in a lower likelihood of agitation. To
`further investigate this area, a limited study of
`patients with a documented history of addiction
`would be required.
`In a review article Kerr et al. [33] demonstrated
`that there is not enough evidence to support IN na-
`loxone as a first-line intervention by paramedics for
`the treatment of heroin overdose in the pre-hospi-
`tal setting. In contrast, in a short-cut review Ashton
`and Hassan [34] screened 596 papers and conclud-
`ed that intranasal naloxone is a safe and effective
`first line, pre-hospital intervention, both in revers-
`ing the effects of an opioid overdose and helping to
`reduce the risk of needle stick injury.
`There are also some limitations to our study.
`Our results should not be extrapolated to other
`institutions. It is a single-centre study, and may
`not be representative of all patients. Since not
`all of the subjects became completely alert after
`naloxone administration, it remains possible that
`other toxic agents were present in some patients.
`However, no toxicological screening was carried
`out to establish the presence and type of other
`agents which may have affected the level of con-
`sciousness. Alternatively, an insufficient naloxone
`dosage may have resulted in some of the patients
`failing to return to full consciousness. In the pre-
`sented work there was a predominance of male
`patients – 78% and 74% in the IN and IV groups
`respectively. Therefore the described results may
`not be extrapolated to a female population.
`In conclusion, IN naloxone is as effective as IV
`naloxone in reversing both respiratory depression
`and the depressive effects on the central nervous
`system caused by opioid overdose. We may there-
`fore suggest using the IN route for administration
`of naloxone in opioid overdose patients to reverse
`clinical manifestations with less severe withdraw-
`al, especially in patients with a history of previous
`addiction.
`
`Acknowledgments
`
`We would like to thank all the staff nurses of
`the Poisoning Emergency Department of Noor and
`Ali Asghar (PBUH) University Hospital for their in-
`
`valuable help. The help and support of academ-
`ic faculty members of the Anaesthesiology and
`Intensive Care Department and members of the
`Research Committee of Isfahan University of Med-
`ical Sciences is greatly appreciated. This research
`is a result of a medical internship project and was
`financially supported by the vice-chancellery of re-
`search at the Isfahan University of Medical Scienc-
`es (Project Registration Number 386083, 2008).
`
`R e f e r e n c e s
`1. Goodman & Gilman’s the pharmacological basis of
`therapeutics. McGraw-Hill, Health Professions Division,
`New York 1996; 549-51.
`2. Dore GJ, Thomas DL. Management and treatment of in-
`jection drug users with hepatitis C virus (HCV) infection
`and HCV/human immunodeficiency virus coinfection.
`Semin Liver Dis 2005; 25: 18-32.
`3. Barton ED, Ramos J, Colwell C, Benson J, Baily J, Dunn W.
`Intranasal administration of naloxone by paramedics.
`Prehosp Emerg Care 2002; 6: 54-8.
`4. Barton ED, Colwell CB, Wolfe T, et al. Efficacy of intrana-
`sal naloxone as a needleless alternative for treatment
`of opioid overdose in the prehospital setting. J Emerg
`Med 2005; 29: 265-71.
`5. Dale O, Hjortkjaer R, Kharasch ED. Nasal administration
`of opioids for pain management in adults. Acta Anaes-
`thesiol Scand 2002; 46: 759-70.
`6. Lahat E, Goldman M, Barr J, Eshel G, Berkovitch M. Intra-
`nasal midazolam for childhood seizures. Lancet 1998;
`352: 620.
`7. Hussain AA, Kimura R, Huang CH. Nasal absorption of
`testosterone in rats. J Pharm Sci 1984; 73: 1300-1.
`8. Loimer N, Hofmann P, Chaudhry HR. Nasal administra-
`tion of naloxone is as effective as the intravenous route
`in opiate addicts. Int J Addict 1994; 29: 819-27.
`9. Loimer N, Hofmann P, Chaudhry HR. Nasal administra-
`tion of naloxone for detection of opiate dependence.
`J Psychiatr Res 1992; 26: 39-43.
`10. Ugwoke MI, Exaud S, Van Den Mooter G, Verbeke N, Kin-
`get R. Bioavailability of apomorphine following intrana-
`sal administration of mucoadhesive drug delivery sys-
`tems in rabbits. Eur J Pharm Sci 1999; 9: 213-9.
`11. Wermeling DP. Opioid harm reduction strategies: focus
`on expanded access to intranasal naloxone. Pharmaco-
`therapy 2010; 30: 627-31.
`12. Scaglione F, Scanni A, Tomirotti M, Dimaiuta M, Ferrari P,
`Fraschini F. Pharmacokinetics and bioavailability of
`metoclopramide nasal spray versus metoclopramide
`intravenous in healthy volunteers and cancer patients.
`Arzneimittelforschung 1993; 43: 986-8.
`13. Dobryakova YV, Dubynin VA, Ivleva YA, Belyaeva YA,
`Kamenskii AA. Effect of opioid antagonist naloxone on
`maternal motivation in albino rats. Bull Exp Biol Med
`2005; 140: 10-2.
`14. Glaser A, Arakaki D, Chan GM, Hoffman RS. Randomised
`trial of intranasal versus intramuscular naloxone in pre-
`hospital treatment for suspected opioid overdose. Med
`J Aust 2005; 182: 427.
`15. Kerr D, Kelly AM, Dietze P, Jolley D, Barger B. Randomized
`controlled trial comparing the effectiveness and safety
`of intranasal and intramuscular naloxone for the treat-
`ment of suspected heroin overdose. Addiction 2009;
`104: 2067-74.
`
`Arch Med Sci 2, April / 2014
`
`313
`
`Nalox1051
`Nalox-1 Pharmaceuticals, LLC
`Page 5 of 6
`
`
`
`Ali Mohammad Sabzghabaee, Nastaran Eizadi-Mood, Ahmad Yaraghi, Samaneh Zandifar
`
`16. Kelly AM, Koutsogiannis Z. Intranasal naloxone for life
`threatening opioid toxicity. Emerg Med J 2002; 19: 375.
`17. Wolfe TR, Bernstone T. Intranasal drug delivery: an alter-
`native to intravenous administration in selected emer-
`gency cases. J Emerg Nurs 2004; 30: 141-7.
`18. Kelly AM, Kerr D, Dietze P, Patrick I, Walker T, Koutsogi-
`annis Z. Randomised trial of intranasal versus intramus-
`cular naloxone in prehospital treatment for suspected
`opioid overdose. Med J Aust 2005; 182: 24-7.
`19. Shannon MW, Borron SW, Burns MJ (eds.). Haddad and
`Winchester’s clinical management of poisoning and
`drug overdose. Saunders/Elsevier, Philadelphia 2007.
`20. Barsic B, Marton E, Himbele J, Ravlić Z. Evaluation of the
`Glasgow Coma Scale score in critically ill infectious dis-
`ease patients. Infection 1996; 24: 297-300.
`21. Dowling J, Isbister GK, Kirkpatrick CM, Naidoo D, Grau-
`dins A. Population pharmacokinetics of intravenous,
`intramuscular, and intranasal naloxone in human vol-
`unteers. Ther Drug Monit 2008; 30: 490-6.
`22. Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal
`naloxone delivery is an alternative to intravenous nal-
`oxone for opioid overdoses. Am J Emerg Med 2010; 28:
`296-303.
`23. Duchěne D, Ponchel G. Nasal administration: a tool for
`tomorrow’s systemic administration of drugs. Drug De-
`velopment and Industrial Pharmacy 1993; 19: 101-22.
`24. Fulton JA, Greller HA, Hoffman RS. GCS and AVPU: the
`alphabet soup doesn’t spell “C-O-M-A” in toxicology.
`Ann Emerg Med 2005; 45: 224-5.
`25. Walther SM, Jonasson U, Gill H. Comparison of the
`Glasgow Coma Scale and the Reaction Level Scale for
`assessment of cerebral responsiveness in the critically
`ill. Intensive Care Med 2003; 29: 933-8.
`26. Weir CJ, Bradford AP, Lees KR. The prognostic value of
`the components of the Glasgow Coma Scale following
`acute stroke. QJM 2003; 96: 67-74.
`27. Holdgate A, Ching N, Angonese L. Variability in agree-
`ment between physicians and nurses when measuring
`the Glasgow Coma Scale in the emergency department
`limits its clinical usefulness. Emerg Med Australas 2006;
`18: 379-84.
`28. Gill MR, Reiley DG, Green SM. Interrater reliability of
`Glasgow Coma Scale scores in the emergency depart-
`ment. Ann Emerg Med 2004; 43: 215-23.
`29. Eizadi-Mood N, Saghaei M, Alfred S, et al. Comparative
`evaluation of Glasgow Coma Score and gag reflex in
`predicting aspiration pneumonitis in acute poisoning.
`J Crit Care 2009; 24: 470 e9-15.
`30. Polderman KH, Jorna EM, Girbes AR. Inter-observer vari-
`ability in APACHE II scoring: effect of strict guidelines
`and training. Intensive Care Med 2001; 27: 1365-9.
`31. Polderman KH, Thijs LG, Girbes AR. Interobserver vari-
`ability in the use of APACHE II scores. Lancet 1999; 353:
`380.
`32. Sabzghabaee AM, Eizadi-Mood N, Gheshlaghi F, Adib N,
`Safaeian L. Is there a relationship between admission
`blood glucose level following acute poisoning and clini-
`cal outcome? Arch Med Sci 2011; 7: 81-6.
`33. Kerr D, Dietze P, Kelly AM. Intranasal naloxone for the
`treatment of suspected heroin overdose. Addiction
`2008; 103: 379-86.
`34. Ashton H, Hassan Z. Best evidence topic report. Intrana-
`sal naloxone in suspected opioid overdose. Emerg Med J
`2006; 23: 221-3.
`
`314
`
`Arch Med Sci 2, April / 2014
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