Analgesia in Patients with Trauma in Emergency Medicine
A systematic review and meta-analysis
; ; ; ; ; ; ; ; ; ; ; ;
Background: Suitable analgesic drugs and techniques are needed for the acute care of the approximately 18 200—18 400 seriously injured patients in Germany each year.
Methods: This systematic review and meta-analysis of analgesia in trauma patients was carried out on the basis of randomized, controlled trials and observational studies. A systematic search of the literature over the 10-year period ending in February 2016 was carried out in the PubMed, Google Scholar, and Springer Link Library databases. Some of the considered trials and studies were included in a meta-analysis. Mean differences (MD) of pain reduction or pain outcome as measured on the Numeric Rating Scale were taken as a summarizing measure of treatment efficacy.
Results: Out of 685 studies, 41 studies were considered and 10 studies were included in the meta-analysis. Among the drugs and drug combinations studied, none was clearly superior to another with respect to pain relief. Neither fentanyl versus morphine (MD –0.10 with a 95% confidence interval of [−0.58; 0.39], p = 0.70) nor ketamine versus morphine (MD −1.27 [−3.71; 1.16], p = 0.31), or the combination of ketamine and morphine versus morphine alone (MD −1.23 [−2.29; −0.18], p = 0.02) showed clear superiority regarding analgesia.
Conclusion: Ketamine, fentanyl, and morphine are suitable for analgesia in spontaneously breathing trauma patients. Fentanyl and ketamine have a rapid onset of action and a strong analgesic effect. Our quantitative meta-analysis revealed no evidence for the superiority of any of the three substances over the others. Suitable monitoring equipment, and expertise in emergency procedures are prerequisites for safe and effective analgesia by healthcare professionals..
Each year 18 200–18 400 patients require treatment for severe injuries in Germany (1). In 2016, ca. 396 700 persons were injured in road traffic accidents (2). Adequate analgesia following trauma is a central aspect of emergency medical treatment before and after hospital admission (3–5). Although relief of pain is a fundamental human right (6), studies suggest that many trauma patients are undertreated in this respect (7). One of the tasks of the group convened to revise the German S3 guideline on treatment of multiple trauma and severe injuries in 2016 was to take steps towards the development of national recommendations on the treatment of pain in trauma patients (8).
The goals of this systematic analysis of the published literature were to compare the effects of various analgesics, alone and in combination, in (severely) injured but spontaneously breathing patients with no need for airway management; to review safety and adverse effects; and to formulate recommendations. To this end, we performed qualitative and quantitative analysis of the data from randomized controlled trials (RCTs) and observational studies.
This study adhered to the principles of the PRISMA statement for systematic reviews and followed the PICO scheme (population, interventions, comparison, outcome). The protocol, search strategy, and search terms were entered in the PROSPERO registry of systematic reviews and have been published (www.crd.york.ac.uk/PROSPERO, ID: CRD42016046110). Details of the study’s methods can be found in eBox 1. The endpoints of the meta-analysis were pain reduction (difference in pain rating before and after administration of analgesics) and the post-treatment score on the numeric rating scale (NRS).
Selection of studies
The initial literature survey turned up 665 relevant publications. A further 20 items were identified by an additional hand search. Of these 685 publications, 624 were excluded after perusal of titles and abstracts. Full-text inspection eliminated a further 20 publications, leaving 41 for analysis (Figure 1).
Twenty-three of the 41 studies were of the emergency rescue services, covering a total of 67 269 patients (10, 16, 21, 22, 27–32, 37–40, e1–e9), and the remaining 18 studies, comprising 1899 patients, were carried out in hospital emergency departments (9, 11–15, 17– 20, 23–26, 33–36). Overall, the substances most commonly used for analgesia were the opiates fentanyl and morphine, the NMDA receptor antagonist ketamine, and combinations of ketamine with opiates, followed by methoxyflurane, nitrous oxide, paracetamol, pentazocine, and sufentanil or combinations thereof. An overview of the studies can be found in eTable 1. Ten studies were included in a meta-analysis of pain reduction but were highly heterogeneous.
One RCT with 300 patients compared intravenous and inhaled morphine (10 or 20 mg). Inhalation of morphine was found to have efficacy comparable with that of intravenous administration, together with high safety (19). Observational studies showed that the intravenous administration of morphine can be safe and effective (30, 32).
Retrospective studies showed safe analgesia with ketamine (alone or in combination with midazolam) (33, e1, e2, e4, e9). Only in one of the included studies was S-ketamine used (e10). Administration of ketamine in a dosage <2 mg/kg was followed by a decrease in pulse-oximetric oxygen saturation (SpO2) in 0.7% of cases, but no ventilation was required (e9); assisted ventilation was needed, however, in 6% of cases after high-dose ketamine (2 mg/kg) (34). The adverse effects reported as being associated with ketamine included dysphoria (4%), hypersalivation (1%), and vomiting (5%) (e9). In one single case, laryngospasm lasting for 1 min was reported (34). Intranasal ketamine seems to be safe and effective in children (36).
Intravenous administration of fentanyl by paramedics and emergency physicians was safe and effective with no significant adverse effects (31, 37, 38, e3, e5). Two observational studies showed that intranasal fentanyl in a dose of 50 to 100 μg or 2 μg/kg was safe, effective, and associated with no or only few adverse effects in adults and children (31, 35).
Fentanyl versus morphine
Data from four RCTs (9, 15, 16, 27) and one cohort study (28) permitted comparison of analgesia with fentanyl and with morphine in terms of post-treatment NRS score and pain reduction (RCTs: fentanyl pre-NRS 6.8 to 8.4/post-NRS 3.5 to 6.6, morphine pre-NRS 7.0 to 8.3/post-NRS 4.0 to 6.2; cohort study: fentanyl pre-NRS 8.0/post-NRS 5.5, morphine pre-NRS 8.0/post-NRS 5.8). The post-treatment NRS score showed no clear-cut advantage of fentanyl over morphine (mean difference: −0.10, 95% confidence interval [−0.58; 0.39], p = 0.70) (Figure 2), but all medications investigated brought about a marked reduction in pain.
One cohort study that was not included in the meta-analysis showed greater pain reduction with fentanyl i.v. than with morphine i.v. (fentanyl pre-NRS 8.5/post-NRS 4.4, morphine pre-NRS 8.2/post-NRS 5.9) (38). Both RCTs and retrospective studies compared intranasal/inhaled fentanyl with morphine i.v. The RCTs found that intranasal/inhaled fentanyl was equivalent to morphine i.v. for pain reduction (fentanyl pre-NRS 6.8 to 8.4/post-NRS 3.0 to 6.6, morphine pre-NRS 7.0 to 8.7/post-NRS 3.0 to 6.2) (9, 13, 15, 27, 40). Retrospective analysis also showed that morphine i.v. was comparable in efficacy with intranasal fentanyl (pre-NRS: fentanyl 8.4, morphine 8.3; pain difference: fentanyl −4.5, morphine −4.5) (e8).
Ketamine versus morphine
Analgesia with ketamine or ketamine/morphine and analgesia with morphine could be compared in terms of post-treatment NRS score and pain reduction using the data from four RCTs (ketamine: pre-NRS 7.1 to 8.6/post-NRS 3.2 to 3.4, pain reduction 4.9 to 5.6; morphine: pre-NRS 7.0 to 8.5/post-NRS 3.9 to 4.2, pain reduction 3.2 to 5.0) (17, 21, 24, 25) and one cohort study (39). Ketamine and ketamine combinations were more effective analgesics than morphine alone (post-NRS: mean difference −1.23 [−2.29; −0.18], p = 0.02 [Figure 3]; pain reduction: mean difference −1.27 [−3.71; 1.16], p = 0.31 [Figure 4]). Analgesia with morphine and ketamine took effect significantly more rapidly than morphine alone (17, 21, 39). However, two of the RCTs showed that pain reduction was comparable after 30 min (24, 25).
One cluster-randomized study that was not included in the meta-analysis showed comparable pain reduction with morphine i.v. (3.1) and with ketamine i.v. (3.5); however, airway problems and vomiting were reported more frequently in the morphine group (29).
Fentanyl versus ketamine
Two RCTs compared ketamine/midazolam i. v. with fentanyl/midazolam i. v. In one study the results were comparable (20), while the other found swifter pain reduction with a lower risk of hypoxia in the ketamine group (11) (fentanyl: pre-NRS 7 to 8/post-NRS 1 to 2; ketamine: pre-NRS 7 to 9/post-NRS 1 to 3). Owing to high heterogeneity, however, no meta-analysis could be performed. One RCT compared ketamine/propofol i.v. with fentanyl/midazolam i. v. for short anesthesia in the emergency department (post-NRS: median = 0, interquartile ratio [IQR] 0 to 1 versus median = 3, IQR 1 to 6; p <0.001). In the course of treatment, better pain reduction was described in the ketamine group and a higher incidence of SpO2 decrease in the fentanyl group (26). One RCT in children compared intranasal fentanyl with intranasal ketamine and found comparable pain reduction (fentanyl: pre-NRS 8, post-NRS 3; ketamine: pre-NRS 8, post-NRS 3) (18).
Sufentanil versus morphine
One RCT compared sufentanil i.v. with morphine i.v. in trauma-related pain (10). Sufentanil acted more rapidly than morphine, but was not superior with regard to pain reduction after 15 min (sufentanil: pre-NRS ≥ 6, post-NRS 3.0; morphine pre-NRS ≥ 6, post-NRS 4.0).
Onset and course of pain reduction by fentanyl, ketamine, and morphine
One cohort study reported that fentanyl and morphine were equally effective (28), but it seems that analgesia can usually be achieved more quickly with fentanyl than with morphine (16, 38). With regard to the onset of pain reduction, inhaled fentanyl and morphine i.v. were described as equivalent (9, 27, 40), but sometimes fentanyl was faster acting (13, 15). One RCT reported that morphine and ketamine were equally effective, while in other studies ketamine, alone or in combination with other substances, was more effective or quicker-acting than morphine alone (17, 21, 24, 25). Compared with fentanyl, ketamine was faster (11) or equally fast (18, 20) to take effect. The duration of effect that can be expected was given as 10 to 15 min for ketamine, 20 to 40 min for fentanyl, and up to 4 h for morphine (4, e11).
Two RCTs compared the effect of N2O with that of ketamine or fentanyl (22, 23) and described equivalent analgesia. Similar results were reported for pentazocine (e6). A prehospital observational study in which paracetamol i.v. was administered to patients who predominantly had trauma of the extremities found pain reduction of NRS <5 in 50% of cases. The analgesia was described as mostly insufficient to manage severe pain (e7). One RCT compared paracetamol i.v. and morphine i.v.: the pain reduction was comparable, but morphine was quicker to take effect than paracetamol (12). Another RCT comparing paracetamol with ibuprofen described similar pain reduction in the two groups (14).
Adverse effects of the most commonly used analgesics
The documented adverse effects of fentanyl, ketamine, and morphine, the most commonly used analgesics, are summarized in eTable 2. Ketamine or combinations including ketamine led to (desired) reduced vigilance in 1.5 to 18% of cases (17, 18, 21, 36). Agitation may occur with ketamine. Decreases in SpO2 were found in all studies for fentanyl (mean 0.6%, maximum 16.1% ), ketamine (mean 0.4%, maximum 11.5% ), and morphine (mean 0.6%, maximum 4.8% ). Overall, assisted ventilation was necessary for 0.05% of patients with ketamine, 0.02% with fentanyl, and 0% with morphine (eTable 2). Hypersalivation was reported in 0.5 to 3% of cases, predominantly in children, but was clinically irrelevant and required no intervention (e9, 29, 33). Nausea and vomiting were the principal adverse effects of morphine (4.8%), fentanyl (1.5%), and ketamine (0.5%). Hypotension was described in 1.6% of cases for fentanyl and in 0.5% of cases for morphine (eTable 2).
Despite the variously defined endpoints, all the analgesics used in the identified studies and the meta-analyses seem to be similar in efficacy; nevertheless, fentanyl, ketamine, and combinations of fentanyl or ketamine with other substances take effect more rapidly than morphine (1 to 3 min versus 5 to 15 min after i.v. administration). Morphine is the oldest of the analgesics investigated in this systematic review. It has a very wide field of application, and its adverse effects are nausea, vomiting, decreased SpO2, and reduced vigilance (e12). Fentanyl is described as very effective with a swift onset of action (e12) and a low risk of adverse effects (e.g., hypotension and hypoxemia) (e13). International guidelines recommend morphine, fentanyl, and ketamine, administered by trained personnel, for pre-hospital analgesia (e14, e15). There are no data on the pre-hospital use of piritramide.
Numerous studies in Germany and other countries have shown that ketamine, alone or in combination with an opioid, is safe and effective when used not just by physicians but also by appropriately trained paramedics and nurses (20, 21, 24, 25, 29, 33, 36, 39, e1, e2, e4, e9, e16, e17). Analgosedation with ketamine can lead to dysphoria and vivid hallucinations or even to agitation (e18). For this reason, accompanying administration of a low-dose benzodiazepine is recommended (e19). Ketamine has the advantage that the patient is sufficiently protected from pain and shielded from external stimuli during the rescue process or invasive procedures (e.g., repositioning or splinting). Moreover, ketamine is particularly well-suited for analgesia of hemodynamically unstable patients (e20–e22). Several reviews have shown that ketamine does not differ from other substances in respect of intracranial pressure (ICP), cerebral perfusion pressure (CPP), neurological outcome, mortality, or length of stay in the intensive care unit (e23, e24); in fact, it is especially suitable for use in patients with head injuries (e25). In ventilated patients with elevated ICP, ketamine is effective in lowering the ICP and prevents undesired increases in ICP with stable blood pressure and CPP (e26). Steps must be taken to avoid hypercapnia. Nonpharmacological pain treatment and the embryotoxological aspects of the analgesics reviewed here are discussed in eBoxes 2 and 3.
Alternative routes of administration
Analgesics should be administered intravenously in the context of emergency medicine (5). All analgesics approved for i.v. administration can also be given by the intraosseous (i.o.) route (e27). Intranasal administration is an alternative in both children and adults. Most analgesics have not been approved for intranasal use, but clinical experience with ketamine and fentanyl has been reported (18, 31, e10, e28, e29).
Safety and monitoring
The prerequisites for safe analgesia are knowledge of the pharmacological characteristics of the substances involved, training in their administration, and presence of emergency equipment for treatment of any complications, independent of the user (e.g., nurse, paramedic, or emergency physician) or the situation (prehospital or in the hospital). The monitoring measures and the emergency equipment needed at hand depend on the expected complications and adverse effects. Monitoring of a spontaneously breathing patient under analgesia comprises ECG, blood pressure, breathing rate, heart rate, and SpO2, together with capnography if required (e30–e32). Patients under analgesia should regularly receive oxygen. The equipment for mask ventilation and suction must be available, and every user must be in the position to keep the airway free and perform ventilation. An intravenous access is recommended for treatment of hypotension or administration of naloxone as an opioid antagonist (e22, e23). Titrated administration is advised to avoid respiratory depression.
Pain has direct physiological effects (blood pressure, breathing rate, heart rate, oxygen consumption, inflammatory reaction) and is a risk factor for post-traumatic stress disorder (e34). From the patient’s point of view, adequate analgesia is an important goal of emergency medical care (5, e35). However, only half of trauma patients receive analgesics at all, and in most of those cases the analgesia achieved is insufficient (4, 7, e36–e40); this is independent of the professional role of the person administering the analgesic (e41– e44). The principal reasons for inadequate analgesia are concern about adverse effects and uncertainty regarding dosage. Proper training in analgesia is therefore essential and the corresponding steps must be taken (5).
The perception of pain is subjective, and pain is rated differently by patients and professionals (e45). Not all patients want analgesia, so every patient should be asked (e46). The NRS cannot be used in all patients; an alternative is to ask patients whether they are suffering severe or unbearable pain (e47).
In most cases, however, the NRS is useful in assessing the success of analgesia. The aim is to achieve an NRS score ≤ 4 (e19, e48, e49). The vital signs (e.g., breathing rate) may also serve to indicate whether adults are in pain (e50), and for children one can use pain evaluation scales adapted to the pediatric age group (e51–e53). Geriatric patients often have more and worse comorbidities, are frequently accustomed to pain, and are less liable to complain of pain; they must therefore be questioned in greater depth (e19).
This review and meta-analysis focuses on the analgesics most commonly used in Germany. The selected study design, with several endpoints (e.g., safety, efficacy, and adverse effects), led to a wide-ranging survey of the literature. However, the high degree of heterogeneity among the studies with regard to endpoints, study quality, and study characteristics represents a crucial limitation. For example, not all controlled studies recorded the time of onset of pain reduction. Many of the studies included did not report adverse effects uniformly. These limitations have to be borne in mind when interpreting the results. Only a small number of studies assessed the trauma by means of the Injury Severity Score (ISS), and very few of them investigated analgesia in seriously injured patients (ISS >15).
Healthcare professionals must be in the position to carry out safe and effective analgesia. The basis is formed by physical measures for pain relief. The preferred means of administration of analgesic drugs is the intravenous route; however, other routes are possible. The recommended analgesics are fentanyl, ketamine, and morphine, with comparable efficacy. Our quantitative meta-analysis shows that there are very few comparable studies of acceptable quality. The current state of knowledge permits no evidence-based statement of superiority of any one of these substances over the others for analgesia in trauma patients in emergency medicine. Analgesia must be carried out only by properly trained persons, the patient must be monitored without interruption, and emergency equipment for treatment of complications must be at hand.
We extend heartfelt thanks to Stefanie Hultzsch (Pharmacovigilance and Information Center for Embryonal Toxicology, Charité University Medicine, Berlin) for her opinions and advice on embryonal toxicology.
Conflict of interest statement
Prof. Böttiger has received lecture fees and/or reimbursement of travel costs from medupdate, Baxalta Deutschland, Bayer Vital, Boehringer Ingelheim Pharma, ZOLL Medical Deutschland, C.R. Bard, and Forum für medizinische Fortbildung.
The remaining authors declare that no conflict of interest exists.
Manuscript submitted on 29 November 2016, revised version accepted on
3 July 2017
Translated from the original German by David Roseveare
PD Dr. med. Michael Bernhard, MHBA
Zentrale Notaufnahme, Universitätsklinikum Leipzig
Liebigstr. 20, 04103 Leipzig, Germany
eTables, eFigure, eBoxes:
Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne: Prof. Böttiger
Department of Orthopedics, Trauma Surgery, and Sports Injuries, Cologne Hospitals, University of Witten/Herdecke: Prof. Bouillon, PD Dr. Wafaisade
Department of Anesthesiology, Surgical Intensive Care, Emergency Medicine, and Pain Therapy, Hospital am Eichert, ALB FILS Hospitals, Göppingen: Prof. Fischer
Department of Anesthesiology and Surgical Intensive Care, Hospital am Steinenberg, Reutlingen: Dr. Gaier
MegaMed GbR, Maikammer: Bernhard Gliwitzky
Department of Anaesthesiology and Intensive Care Medicine, Section Emergency Medicine, Federal Armed Forces Hospital, Ulm, Germany: Prof. Helm, Dr. Hossfeld
Department of Anesthesiology, Intensive Care, and Emergency Medicine, Bergmannstrost BG Hospital, Halle: Dr. Hilbert-Carius
Institute for Clinical Epidemiology and Applied Biometrics, University of Tübingen: Dr. Meisner, MA
Department of Medicine II – Cardiology, Angiology, Intensive Care, Hospital am Steinenberg, Reutlingen: Dr. Schempf
Central Emergency Department, Leipzig University Hospital: PD Dr. Bernhard, MHBA
|1.||Debus F, Lefering R, Frink M, et al.: Numbers of severely injured patients in Germany—a retrospective analysis from the DGU (German Society for Trauma Surgery) Trauma Registry. Dtsch Arztebl Int 2015; 112: 823–9 VOLLTEXT|
|2.||Statistisches Bundesamt: 7,1 % weniger Verkehrstote im Jahr 2016: Pressemitteilung Nr. 065 2017.|
|3.||Matthes G, Trentzsch H, Wölfl CG, et al.: Essential measures for prehospital treatment of severely injured patients: The trauma care bundle. Unfallchirurg 2015; 118: 652–6 CrossRef MEDLINE|
|4.||Stork B, Hofmann-Kiefer K: Analgesie in der Notfallmedizin. Anaesthesist 2009; 58: 639 CrossRef MEDLINE|
|5.||Kumle B, Wilke P, Koppert W, Kumle K, Gries A: Schmerztherapie in der Notfallmedizin. Fokus Notaufnahme. Anaesthesist 2013; 62: 902 CrossRef MEDLINE|
|6.||Brennan F, Carr DB, Cousins M: Pain management: a fundamental human right. Anesth Analg 2007; 105: 205–21 CrossRef MEDLINE|
|7.||Albrecht E, Taffe P, Yersin B, Schoettker P, Decosterd I, Hugli O: Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study. Br J Anaesth 2013; 110: 96–106 CrossRef MEDLINE|
|8.||DGU: S3-Leitlinie Polytrauma/Schwerverletzten-Behandlung: AWMF Register-Nr. 012/19. www.awmf.org/leitlinien/detail/ll/012–019.html (last accessed on 9 March 2017).|
|9.|| Borland M, Jacobs I, King B, O’Brien D: A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. |
Ann Emerg Med 2007; 49: 335–40 CrossRef MEDLINE
|10.||Bounes V, Barthelemy R, Diez O, Charpentier S, Montastruc JL, Ducasse JL: Sufentanil is not superior to morphine for the treatment of acute traumatic pain in an emergency setting: a randomized, double-blind, out-of-hospital trial. Ann Emerg Med 2010; 56: 509–16 CrossRef MEDLINE|
|11.|| Cevik E, Bilgic S, Kilic E, et al.: Comparison of ketamine-low-dose midozolam with midazolam-fentanyl for orthopedic emergencies: |
a double-blind randomized trial. Am J Emerg Med 2013; 31: 108–13 CrossRef MEDLINE
|12.||Craig M, Jeavons R, Probert J, Benger J: Randomised comparison of intravenous paracetamol and intravenous morphine for acute traumatic limb pain in the emergency department. Emerg Med J 2012; 29: 37–9 CrossRef MEDLINE|
|13.||Farahmand S, Shiralizadeh S, Talebian M-T, et al.: Nebulized fentanyl vs intravenous morphine for ED patients with acute limb pain: a randomized clinical trial. Am J Emerg Med 2014; 32: 1011–5 CrossRef MEDLINE|
|14.|| Friday JH, Kanegaye JT, McCaslin I, Zheng A, Harley JR: Ibuprofen provides analgesia equivalent to acetaminophen-codeine in the treatment of acute pain in children with extremity injuries: |
a randomized clinical trial. Acad Emerg Med 2009; 16: 711–6 CrossRef MEDLINE
|15.||Furyk JS, Grabowski WJ, Black LH: Nebulized fentanyl versus intravenous morphine in children with suspected limb fractures in the emergency department: a randomized controlled trial. Emerg Med Australas 2009; 21: 203–9 CrossRef MEDLINE|
|16.||Galinski M, Dolveck F, Borron SW, et al.: A randomized, double-blind study comparing morphine with fentanyl in prehospital analgesia. Am J Emerg Med 2005; 23: 114–9 CrossRef MEDLINE|
|17.||Galinski M, Dolveck F, Combes X, et al.: Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med 2007; 25: 385–90 CrossRef MEDLINE|
|18.||Graudins A, Meek R, Egerton-Warburton D, Oakley E, Seith R: The PICHFORK (Pain in Children Fentanyl or Ketamine) trial: a randomized controlled trial comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries. Ann Emerg Med 2015; 65: 248 CrossRef MEDLINE|
|19.||Grissa MH, Boubaker H, Zorgati A, et al.: Efficacy and safety of nebulized morphine given at 2 different doses compared to IV titrated morphine in trauma pain. Am J Emerg Med 2015; 33: 1557–61 CrossRef MEDLINE|
|20.||Jamal SM, Fathil SM, Nidzwani MM, Ismail AK, Yatim FM: Intravenous ketamine is as effective as midazolam/fentanyl for procedural sedation and analgesia in the emergency department. Med J Malaysia 2011; 66: 231–3 MEDLINE|
|21.||Jennings PA, Cameron P, Bernard S, et al.: Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: A randomized controlled trial. Ann Emerg Med 2012; 59: 497–503 CrossRef MEDLINE|
|22.||Kariman H, Majidi A, Amini A, et al.: Nitrous oxide/oxygen compared with fentanyl in reducing pain among adults with isolated extremity trauma: a randomized trial. Emerg Med Australas 2011; 23: 761–8 CrossRef MEDLINE|
|23.||Lee JH, Kim K, Kim TY, et al.: A randomized comparison of nitrous oxide versus intravenous ketamine for laceration repair in children. Pediatr Emerg Care 2012; 28: 1297–301 CrossRef MEDLINE|
|24.||Miller JP, Schauer SG, Ganem VJ, Bebarta VS: Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med 2015; 33: 402–8 CrossRef MEDLINE|
|25.||Motov S, Rockoff B, Cohen V, et al.: Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency department: A randomized controlled trial. Ann Emerg Med 2015; 66: 222 CrossRef MEDLINE|
|26.|| Nejati A, Moharari RS, Ashraf H, Labaf A, Golshani K: Ketamine/|
propofol versus midazolam/fentanyl for procedural sedation and analgesia in the emergency department: a randomized, prospective, double-blind trial. Acad Emerg Med 2011; 18: 800–6 CrossRef MEDLINE
|27.||Rickard C, O’Meara P, McGrail M, Garner D, McLean A, Le Lievre P: A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med 2007; 25: 911–7 CrossRef MEDLINE|
|28.||Smith MD, Wang Y, Cudnik M, Smith DA, Pakiela J, Emerman CL: The effectiveness and adverse events of morphine versus fentanyl on a physician-staffed helicopter. J Emerg Med 2012; 43: 69–75 CrossRef MEDLINE|
|29.|| Tran KP, Nguyen Q, Truong XN, et al.: A comparison of ketamine |
and morphine analgesia in prehospital trauma care: a cluster randomized clinical trial in rural Quang Tri province, Vietnam. Prehosp Emerg Care 2014; 18: 257–64 CrossRef MEDLINE
|30.||Greb I, Wranze E, Hartmann H, Wulf H, Kill C: Analgesie beim Extremitätentrauma durch Rettungsfachpersonal. Notfall Rettungsmed 2011; 14: 135–42 CrossRef|
|31.||Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS: Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study. Ann Emerg Med 2014; 63: 699–703 CrossRef MEDLINE|
|32.||Kill C, Greb I, Wranze E, et al.: Kompetenzentwicklung im Rettungsdienst. Ein Pilotprojekt zur erweiterten Notfalltherapie durch Rettungsassistenten. Notfall Rettungsmed 2007; 10: 266 CrossRef|
|33.||Bisanzo M, Nichols K, Hammerstedt H, et al.: Nurse-administered ketamine sedation in an emergency department in rural Uganda. Ann Emerg Med 2012; 59: 268–75 CrossRef MEDLINE|
|34.||Chudnofsky CR, Weber JE, Stoyanoff PJ, et al.: A combination of midazolam and ketamine for procedural sedation and analgesia in adult emergency department patients. Acad Emerg Med 2000; 7: 228–35 CrossRef MEDLINE|
|35.||Saunders M, Adelgais K, Nelson D: Use of intranasal fentanyl for the relief of pediatric orthopedic trauma pain. Acad Emerg Med 2010; 17: 1155–61 CrossRef MEDLINE|
|36.||Yeaman F, Oakley E, Meek R, Graudins A: Sub-dissociative dose intranasal ketamine for limb injury pain in children in the emergency department: a pilot study. Emerg Med Australas 2013; 25: 161–7 CrossRef MEDLINE|
|37.||Soriya GC, McVaney KE, Liao MM, et al.: Safety of prehospital intravenous fentanyl for adult trauma patients. J Trauma Acute Care Surg 2012; 72: 755–9 CrossRef MEDLINE|
|38.||Garrick JF, Kidane S, Pointer JE, Sugiyama W, van Luen C, Clark R: Analysis of the paramedic administration of fentanyl. J Opioid Manag 2011; 7: 229–34 CrossRef|
|39.||Johansson P, Kongstad P, Johansson A: The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scand J Trauma Resusc Emerg Med 2009; 17: 61 CrossRef MEDLINE PubMed Central|
|40.||Bendall JC, Simpson PM, Middleton PM: Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients. Prehosp Emerg Care 2011; 15: 158–65 CrossRef MEDLINE|
|e1.||Bredmose PP, Grier G, Davies GE, Lockey DJ: Pre-hospital use of ketamine in paediatric trauma. Acta Anaesthesiol Scand 2009; 53: 543–5 CrossRef MEDLINE|
|e2.||Bredmose PP, Lockey DJ, Grier G, Watts B, Davies G: Pre-hospital use of ketamine for analgesia and procedural sedation. Emerg Med J 2009; 26: 62–4 CrossRef MEDLINE|
|e3.||Friesgaard KD, Nikolajsen L, Giebner M, et al.: Efficacy and safety of intravenous fentanyl administered by ambulance personnel. Acta Anaesthesiol Scand 2016; 60: 537–43 CrossRef MEDLINE|
|e4.||Häske D, Schempf B, Gaier G, Niederberger C: Prähospitale Analgosedierung durch Rettungsassistenten: Effektivität und Prozessqualität unter ärztlicher Supervision [Prehospital analgesia performed by paramedics: quality in processes and effects under medical supervision]. Anaesthesist 2014; 63: 209–16 CrossRef MEDLINE|
|e5.||Kanowitz A, Dunn TM, Kanowitz EM, Dunn WW, Vanbuskirk K: Safety and effectiveness of fentanyl administration for prehospital pain management. Prehosp Emerg Care 2006; 10: 1–7 CrossRef MEDLINE|
|e6.||Losvik OK, Murad MK, Skjerve E, Husum H: Ketamine for prehospital trauma analgesia in a low-resource rural trauma system: a retrospective comparative study of ketamine and opioid analgesia in a ten-year cohort in Iraq. Scand J Trauma Resusc Emerg Med 2015; 23: 94 CrossRef MEDLINE PubMed Central|
|e7.||Luiz T, Scherer G, Wickenkamp A, et al.: Prähospitale Analgesie durch Rettungsassistenten in Rheinland-Pfalz: Praktikabilität, analgetische Wirkung und Sicherheit bei i. v.-verabreichtem Paracetamol [Prehospital analgesia by paramedics in Rhineland-Palatinate: Feasability, analgesic effectiveness and safety of intravenous paracetamol]. Anaesthesist 2015; 64: 927-36 CrossRef MEDLINE|
|e8.||Middleton PM, Simpson PM, Sinclair G, Dobbins TA, Math B, Bendall JC: Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care 2010; 14: 439–47 CrossRef CrossRef|
|e9.||Porter K: Ketamine in prehospital care. Emerg Med J 2004; 21: 351–4 CrossRef PubMed Central|
|e10.||Johansson J, Sjöberg J, Nordgren M, Sandström E, Sjöberg F, Zetterström H: Prehospital analgesia using nasal administration of S-ketamine—a case series. Scand J Trauma Resusc Emerg Med 2013; 21: 38 CrossRef MEDLINE PubMed Central|
|e11.||Adams HA, Flemming A: Analgesie, Sedierung und Anästhesie in der Notfallmedizin. Anästh Intensivmed 2015(56): 75–90.|
|e12.||Thomas SH, Shewakramani S: Prehospital trauma analgesia. J Emerg Med 2008; 35: 47–57 CrossRef MEDLINE|
|e13.||Krauss WC, Shah S, Shah S, Thomas SH: Fentanyl in the out-of-hospital setting: variables associated with hypotension and hypoxemia. J Emerg Med 2011; 40: 182–7 CrossRef MEDLINE|
|e14.||American College of Emergency Physicians ACEP: Out-of-hospital use of analgesia and sedation: approved by the Board of Directors June 2015. www.acep.org/Clinical---Practice-Management/Out-of-Hospital-Use-of-Analgesia-and-Sedation/ (last accessed on 24 May 2016).|
|e15.||Gausche-Hill M, Brown KM, Oliver ZJ, et al.: An evidence-based guideline for prehospital analgesia in trauma. Prehosp Emerg Care 2014; 18, Suppl 1: 25–34.|
|e16.||Höll M: Präklinische Analgosedierung mit Ketamin S und Midazolam durch Notfallsanitäter. Anästh Intensivmed 2017; 58: S108.|
|e17.||Schempf B, Casu S, Häske D: Prähospitale Analgosedierung durch Notärzte und Rettungsassistenten. Anaesthesist 2017; 66: 325–32 CrossRef MEDLINE|
|e18.||Moy RJ, Le Clerc S: Ketamine in prehospital analgesia and anaesthesia. Trends in Anaesthesia and Critical Care 2011; 1: 243–5 CrossRef|
|e19.||Hossfeld B, Holsträter S, Bernhard M, Lampl L, Helm M, Kulla M: Prähospitale Analgesie beim Erwachsenen. Notf.med. up2date 2015; 10: 269–84.|
|e20.||Morris C, Perris A, Klein J, Mahoney P: Anaesthesia in haemodynamically compromised emergency patients: does ketamine represent the best choice of induction agent? Anaesthesia 2009; 64: 532–9 CrossRef MEDLINE|
|e21.||Paal P, Herff H, Mitterlechner T, et al.: Anaesthesia in prehospital emergencies and in the emergency room. Resuscitation 2010; 81: 148–54 CrossRef MEDLINE|
|e22.||German Trauma Society (DGU): S3 – Guideline on Treatment of Patients with Severe and Multiple Injuries: AWMF-Registry No. 012/019. www.awmf.org/leitlinien/detail/ll/012-019.html.|
|e23.||Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM: The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review. Ann Emerg Med 2015; 65: 43 CrossRef MEDLINE|
|e24.||Roberts DJ, Hall RI, Kramer AH, Robertson HL, Gallagher CN, Zygun DA: Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials. Crit. Care Med. 2011; 39: 2743–51 CrossRef MEDLINE|
|e25.||Filanovsky Y, Miller P, Kao J: Myth: Ketamine should not be used as an induction agent for intubation in patients with head injury. CJEM 2010; 12: 154–7 CrossRef|
|e26.||Bar-Joseph G, Guilburd Y, Tamir A, Guilburd JN: Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension. J Neurosurg Pediatr 2009; 4: 40–6 CrossRef MEDLINE|
|e27.||Bernhard M, Gräsner J, Gries A, et al.: Die intraossäre Infusion in der Notfallmedizin. Anästh Intensivmed 2010; 51: s615–s620.|
|e28.||Riediger C, Haschke M, Bitter C, et al.: The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study. J Pain Res 2015; 8: 87–94.|
|e29.||Samuel N, Steiner IP, Shavit I: Prehospital pain management of injured children: a systematic review of current evidence. Am J Emerg Med 2015; 33: 451–4 CrossRef MEDLINE|
|e30.||Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin und Berufsverband Deutscher Anästhesisten: Analgosedierung bei Erwachsenen. Anästh Intensivmed 2010; 51: 598–602.|
|e31.||Godwin SA, Caro DA, Wolf SJ, et al.: Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med 2005; 45: 177–96 CrossRef MEDLINE|
|e32.||Dewdney C, MacDougall M, Blackburn R, Lloyd G, Gray A: Capnography for procedural sedation in the ED: a systematic review. Emerg Med J 2017; 34: 476–84 CrossRef MEDLINE|
|e33.||National Association of Emergency Medical Technicians (NAEMT): PHTLS: Prehospital trauma life support. Burlington, MA: Jones & Bartlett Learning 2016.|
|e34.||Norman SB, Stein MB, Dimsdale JE, Hoyt DB: Pain in the aftermath of trauma is a risk factor for post-traumatic stress disorder. Psychol. Med. 2008; 38; 533–42 MEDLINE|
|e35.||Cepeda MS, Africano JM, Polo R, Alcala R, Carr DB: What decline in pain intensity is meaningful to patients with acute pain? Pain 2003; 105: 151–7 CrossRef|
|e36.||Bakkelund KE, Sundland E, Moen S, Vangberg G, Mellesmo S, Klepstad P: Undertreatment of pain in the prehospital setting: a comparison between trauma patients and patients with chest pain. Eur J Emerg Med 2013; 20: 428–30 CrossRef MEDLINE|
|e37.||Stalnikowicz R, Mahamid R, Kaspi S, Brezis M: Undertreatment of acute pain in the emergency department: a challenge. Int J Qual Health Care 2005; 17: 173–6 CrossRef MEDLINE|
|e38.||Bounes V, Barniol C, Minville V, Houze-Cerfon C-H, Ducassé JL: Predictors of pain relief and adverse events in patients receiving opioids in a prehospital setting. Am J Emerg Med 2011; 29: 512–7 CrossRef MEDLINE|
|e39.||Schauer SG, Robinson JB, Mabry RL, Howard JT: Battlefield analgesia: TCCC guidelines are not being followed. J Spec Oper Med 2015; 15: 85–9 MEDLINE|
|e40.||Pierik, Jorien G J, IJzerman MJ, Gaakeer MI, et al.: Pain management in the emergency chain: the use and effectiveness of pain management in patients with acute musculoskeletal pain. Pain Med 2015; 16: 970–84 CrossRef MEDLINE|
|e41.||Ricard-Hibon A, Chollet C, Saada S, Loridant B, Marty J: A quality control program for acute pain management in out-of-hospital critical care medicine. Ann Emerg Med 1999; 34: 738–44 CrossRef|
|e42.||Moller JC, Ballnus S, Kohl M, et al.: Evaluation of the performance of general emergency physicians in pediatric emergencies: Obstructive airway diseases, seizures, and trauma. Pediatr Emerg Care 2002; 18: 424–8 CrossRef MEDLINE|
|e43.||Stelle zur trägerübergreifenden Qualitätssicherung im Rettungsdienst Baden-Württemberg ( SQR-BW): Qualitätsbericht: Rettungsdienst Baden-Württemberg, Berichtsjahr 2014; www.sqrbw.de/de/sqr-bw/qualitaetsberichte (last accessed on 31 January 2016).|
|e44.||Vassiliadis J, Hitos K, Hill CT: Factors influencing prehospital and emergency department analgesia administration to patients with femoral neck fractures. Emerg Med (Fremantle) 2002; 14: 261–6.|
|e45.||van Dijk, Jacqueline F M, van Wijck, et al.: Postoperative pain assessment based on numeric ratings is not the same for patients and professionals: a cross-sectional study. Int J Nurs Stud 2012; 49: 65–71 CrossRef MEDLINE|
|e46.||Singer AJ, Garra G, Chohan JK, Dalmedo C, Thode HC: Triage pain scores and the desire for and use of analgesics. Ann Emerg Med 2008; 52: 689–95 CrossRef MEDLINE|
|e47.||Green SM, Krauss BS: The Numeric Scoring of Pain: This Practice Rates a Zero Out of Ten. Ann Emerg Med 2016; 67:573–5 CrossRef MEDLINE|
|e48.||Becker M, Pogatzki-Zahn EM: Postoperative Schmerztherapie: Pathophysiologie, Pharmakologie und Therapie ; 99 Tabellen. Stuttgart [u.a.]: Thieme 2008.|
|e49.||Maier C, Nestler N, Richter H, et al.: The quality of pain management in German hospitals. Dtsch Arztebl Int 2010; 107: 607–14.|
|e50.||Bendall JC, Simpson PM, Middleton PM: Prehospital vital signs can predict pain severity: analysis using ordinal logistic regression. Eur J Emerg Med 2011; 18: 334–9 CrossRef MEDLINE|
|e51.||Atkinson P, Chesters A, Heinz P: Pain management and sedation for children in the emergency department. BMJ 2009; 339: b4234 CrossRef MEDLINE|
|e52.||Jennings PA, Cameron P, Bernard S: Measuring acute pain in the prehospital setting. Emerg Med J 2009; 26: 552–5 CrossRef MEDLINE|
|e53.||McConahay T, Bryson M, Bulloch B: Defining mild, moderate, and severe pain by using the color analogue scale with children presenting to a pediatric emergency department. Acad Emerg Med 2006; 13: 341–4 CrossRef|
|e54.||Melamed E, Blumenfeld A, Kalmovich B, et al.: Prehospital Care of Orthopedic Injuries. Prehosp Disaster Med 2007; 22: 22–5 CrossRef MEDLINE|
|e55.||Worsing RA: Principles of prehospital care of musculoskeletal injuries. Emerg Med Clin North Am 1984; 2: 205–17 MEDLINE|
|e56.||Cuske J: The Lost Art of Splinting: How to properly immobilize extremities & manage pain. JEMS 2008; 33(7): 50–9 CrossRef|
|e57.||Perkins TJ: Fracture management. Effective prehospital splinting techniques. Emerg Med Serv 2007; 36: 35–7, 39 MEDLINE|
|e58.||Beck A, Gebhard F, Kinzl L, Strecker W: Principles and techniques of primary trauma surgery management at the site [Prinzipien und Techniken der unfallchirurgischen Erstversorgung am Einsatzort]. Unfallchirurg 2001; 104: 1082–96; quiz 1097, 1099.|
|e59.||Beck A, Gebhard F, Kinzl L: Notärztliche Versorgung des Traumapatienten. Notfall Rettungsmed 2002; 5: 57–71 CrossRef|
|e60.||Lee C, Porter KM: Prehospital management of lower limb fractures. Emerg Med J 2005; 22: 660–3 CrossRef MEDLINE PubMed Central|
|e61.||Probst C, Hildebrand F, Frink M, Mommsen P, Krettek C: [Prehospital treatment of severely injured patients in the field: an update]. Chirurg 2007; 78: 875–84 MEDLINE|
|e62.||Feilberg VL, Rosenborg D, Broen Christensen C, Mogensen JV: Excretion of morphine in human breast milk. Acta Anaesthesiol Scand 1989; 33: 426–8 CrossRef|
|e63.||Robieux I, Koren G, Vandenbergh H, Schneiderman J: Morphine excretion in breast milk and resultant exposure of a nursing infant. J Toxicol Clin Toxicol 1990; 28: 365–70 CrossRef|
|e64.||Wittels B, Scott DT, Sinatra RS: Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study. Anesthesiology 1990; 73: 864–9 CrossRef|
|e65.||Goma HM, Said RN, El-Ela AM: Study of the newborn feeding behaviors and fentanyl concentration in colostrum after an analgesic dose of epidural and intravenous fentanyl in cesarean section. Saudi Med J 2008; 29: 678–82 MEDLINE|
|e66.||Nitsun M, Szokol JW, Saleh HJ, et al.: Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk. Clin Pharmacol Ther 2006; 79: 549–57 CrossRef MEDLINE|
|e67.||Steer PL, Biddle CJ, Marley WS, Lantz RK, Sulik PL: Concentration of fentanyl in colostrum after an analgesic dose. Can J Anaesth 1992; 39: 231–5 CrossRef MEDLINE|
|e68.||Baraka A, Louis F, Dalleh R: Maternal awareness and neonatal outcome after ketamine induction of anaesthesia for Caesarean section. Can J Anaesth 1990; 37: 641–4 CrossRef MEDLINE|
|e69.||Reich DL, Silvay G: Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989; 36: 186–97 CrossRef MEDLINE|