Presented at the Society for Academic Emergency Medicine annual meeting, Boston, MA, June 2011.
Original Research Contribution
Nitrous Oxide for Early Analgesia in the Emergency Setting: A Randomized, Double-blind Multicenter Prehospital Trial
Article first published online: 13 FEB 2013
© 2013 by the Society for Academic Emergency Medicine
Academic Emergency Medicine
Volume 20, Issue 2, pages 178–184, February 2013
How to Cite
ACADEMIC EMERGENCY MEDICINE 2013; 20, 178–184 © 2013 by the Society for Academic Emergency Medicine
Support was institutional and was provided by the Toulouse University Hospital. None of the authors have any commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest.
ClinicalTrials.gov identifier: NCT01356745.
- Issue published online: 13 FEB 2013
- Article first published online: 13 FEB 2013
- Manuscript Accepted: 9 SEP 2012
- Manuscript Revised: 28 AUG 2012
- Manuscript Revised: 8 AUG 2012
- Manuscript Received: 22 MAY 2012
Although 50% nitrous oxide (N2O) and oxygen is a widely used treatment, its efficacy had never been evaluated in the prehospital setting. The objective of this study was to demonstrate the efficacy of premixed N2O and oxygen in patients with out-of-hospital moderate traumatic acute pain.
This prospective, randomized, multicenter, double-blind trial enrolled patients with acute moderate pain (numeric rating scale [NRS] score between 4 and 6 out of 10) caused by trauma. Patients were assigned to receive either 50/50 N2O and oxygen 9 L/min (N2O group) or medical air (MA) 9 L/min (MA group), in ambulances from two nurse-staffed fire department centers. After the first 15 minutes, every patient received N2O and oxygen. The primary endpoint was pain relief at 15 minutes (T15), defined as a NRS ≤ 3 of 10. The NRS was measured every 5 minutes. Secondary endpoints were treatment safety and adverse events, time to analgesia, and patient and investigator satisfaction with analgesia.
Sixty patients were included with no differences between groups in age (median = 34 years, interquartile range [IQR] = 23 to 53 years), sex (37 males, 66%), and initial median NRS of 6 (IQR = 5 to 6). At T15, 67% of the patients in the N2O group had an NRS score of 3 or lower versus 27% of those in the MA group (delta = 40%, 95% confidence interval [CI] = 17% to 63%; p < 0.001). The median pain scores were lower in the N2O group at T15, 2 (IQR = 1 to 4) versus 5 (IQR = 3 to 6). There was a difference at 5 minutes that persisted at all subsequent time points. Four patients (one in the N2O group) experienced adverse events (nausea) during the protocol.
This study demonstrates the efficacy of N2O for the treatment of pain from acute trauma in adults in the prehospital setting.
Óxido Nitroso para la Analgesia Precoz en el Escenario de Emergencias: Un Ensayo Clínico Prehospitalario con Asignación Aleatoria, Doble Ciego y Multicéntrico
Aunque el óxido nitroso (N2O) y el oxígeno al 50% es un tratamiento ampliamente utilizado, su eficacia no ha sido evaluada en el escenario prehospitalario. El objetivo fue demostrar la eficacia del N2O y el oxígeno premezclado en los pacientes con dolor agudo traumático moderado fuera del hospital.
Ensayo clínica prospectivo, con asignación aleatoria, doble ciego y multicéntrico que incluyó pacientes con dolor agudo moderado (puntuación entre 4 y 6 sobre un máximo de 10 en una escala numérica [NRS]) secundario a traumatismo. Los pacientes fueron asignados a recibir bien N20 y oxígeno 50/50 a 9 L/min (grupo N2O), o aire medicinal (AM) a 9 L/min (grupo AM), en ambulancias de los centros de bomberos supervisadas por dos enfermeros. Tras los primeros 15 minutos, cada paciente recibió N2O y oxígeno. El resultado principal fue el alivio del dolor a los 15 minutos (T15), definido como un NRS ≤ 3 sobre 10. El NRS se midió cada 5 minutos. Los resultados secundarios fueron la seguridad y los eventos adversos del tratamiento, el tiempo hasta la analgesia y la satisfacción del paciente y del investigador con la analgesia.
Se incluyeron sesenta pacientes sin diferencias concernientes a la edad (mediana 34 años, rango intercuartil [RIC 23 a 53 años]), el sexo, (37 varones, 66%) y la mediana inicial de NRS de 6 (RIC 5 a 6). Al T15, el 67% de los pacientes del grupo N2O tuvo una puntuación de NRS de 3 o menos vs. el 27% de aquéllos del grupo AM, (delta 40%; IC95% = 17% a 63%, p < 0,001). La puntuación mediana de dolor fue menor en el grupo N2O al T15, 2 (RIC 1 a 4) vs. 5 (RIC 3 a 6). Hubo una diferencia a los cinco minutos que persistió en todos los puntos de tiempo consecutivos. Cuatro pacientes experimentaron un evento adverso (náusea) durante el protocolo (uno era del grupo N2O).
Este estudio demuestra la eficacia del N2O para el tratamiento del dolor del traumatismo agudo en los adultos en el escenario prehospitalario.
A safe, noninvasive, and effective form of pain relief would represent an advantage in the prehospital treatment of patients experiencing pain. The use of intravenous (IV) analgesics (such as opioids) can be limited by concerns about the adverse effects of these drugs in this setting. For a number of years, many rescue organizations throughout the world, including some employing caregivers not trained as emergency medical technicians, have made use of 50% nitrous oxide (N2O) and oxygen analgesia. There has been limited clinical evidence for the efficacy of this form of analgesia. N2O has a low solubility in blood and is not bound to blood proteins. It acts rapidly and is quickly reversible after inhalation is discontinued. A search of the literature identified 12 randomized controlled trials investigating the use of 50% N2O (compared with placebo or conventional analgesic regimens) in a range of conditions.2 Children were well represented, but we could not identify studies comparing the treatments in an adult prehospital emergency setting. Some older cohort studies had been performed in adult prehospital patients (all causes of pain), but none had proven the efficacy of inhaled analgesia.[3-6] Thal et al.3 evaluated self-administered analgesia using a 50/50 mixture of N2O and oxygen in 47 patients, Amey et al. in 88 patients, Donen et al. in 240 patients, and Johnson and Atherton in 200 patients. In these studies, 65% to 93.4% of patients experienced either complete or partial relief from acute pain. More recently, in an emergency setting, a study compared N2O and fentanyl, but the study had multiple limitations (unblinded design, analgesia delayed until after x-ray diagnosis, and nonconsecutive patients).
The goal of this investigation was to evaluate the efficacy of N2O and oxygen compared to medical air (MA) for prehospital treatment of adult patients with moderate traumatic acute pain. The primary outcome variable was the percentage of patients experiencing analgesia (defined by a numeric rating scale [NRS] score of 3 of 10 or lower) at 15 minutes. Secondary objectives were time to analgesia, treatment safety, and patient and caregiver satisfaction concerning analgesia.
This was a prospective, randomized, double-blind, multicenter, controlled trial registered at ClinicalTrials.gov (identifier NCT01356745). Enrollment began in February 2010 and finished when the desired number of patients was reached in March 2011. The regional ethics committee (CPP, Toulouse II, France) approved this study.
Study Setting and Population
France has a sophisticated and modern system of out-of-hospital emergency care. It is two-tiered, with basic life support ambulances staffed by firefighters or emergency medical technicians whose skills include oxygen administration, bandaging, splinting, and immobilization and physician or nurse-staffed ambulances. Some of the firefighter teams include an emergency nurse, whose skills consist of drugs administration according to local protocols. This study took place in Midi-Pyrénées district (1,156,000 inhabitants, 6,300 km2 [2,400 square miles]). All inclusions were performed in two out-of hospital Firefighter Emergency Services (Centre de Colomiers, Centre de Massat, Service de Santé et de Secours Médical [SSSM], Service départemental d'incendie et de secours de la Haute Garonne [SDIS 31]) under the scientific supervision of the Toulouse University Hospital SAMU (Purpan Hospital, Toulouse, France). French law makes no provision for anyone other than physicians to perform medical research, except for nurses under direct or indirect physician supervision. The nurse identified each patient and verified the eligibility criteria. The SAMU dispatching physician, informed by phone, controlled the inclusion and exclusion criteria and part of his responsibility was to decide to include or not the patient in the study. Patients meeting eligibility criteria received standardized written and oral information by the nurse, and if they (or any family members present) did not refuse participation, they were enrolled. Full informed consent was obtained from patients by the Purpan Hospital emergency department (ED) physician as soon as was feasible, but at least 30 minutes after any gas inhalation, to avoid suggestibility. A total of 20 nurses and 34 physicians participated in subject recruitment. Before the study, physicians and fire service nurses underwent separately a standardized comprehensive education program given by three instructors (the fire service pharmacist of the study, the principal investigator, and the sponsor representative) concerning the ethical conduct of research (information and collection of informed consent form) and the study protocol. The training for fire service nurses was longer and more specific on the trial intervention and the treatment of acute traumatic pain. Then, e-learning short refresher sessions (in the form of monthly newsletters and quizzes) were incorporated into the physicians' and nurses' usual ongoing training throughout the study period.
Patients were eligible for inclusion if aged 18 years or older, with moderate acute pain (defined as a numeric rating scale score of 4, 5, or 6 out of 10) caused by trauma. The score was determined by the nurse before any care was done. The exclusion criteria were contraindications of premixed 50% N2O and oxygen (intracranial hypertension, unconsciousness, pneumothorax, recent eye surgery, and other disorders involving accumulation of gas in closed body spaces, such as emphysema, intestinal ileus, sinusitis, or facial trauma). Other exclusion criteria were lack of a nurse in the fire service team, previous use of analgesic medication within 6 hours, pregnancy, or inclusion in another clinical trial. Due to ethical considerations (full informed consent obtained by the ED physicians of one hospital), patients not transported to the reference hospital (Purpan Hospital) were not included. The patients within the area concerned usually go to this Level I trauma center referral hospital, but some of them prefer going to other out-of-zone hospitals (not participating in the study), so these patients were not included. Consecutive patients, 24 hours a day, 7 days a week, with any trauma with moderate pain were screened and enrolled. Eligible patients were randomly assigned in a 1:1 ratio to receive premixed 50% N2O and oxygen inhalation (N2O group) or MA inhalation (MA group).
A table of random numbers determined the randomization sequence, using a restricted randomization scheme equilibrated by blocks of 12 to ensure roughly equal numbers in each group. The randomization schedule was kept safe in an independent research office; no investigator was aware of the allocation of the data. Only the pharmacist responsible for gas allocation had consulting access to this information. For each patient screened by the nurse, the SAMU medical dispatcher made the final decision to include and to randomize him or her. Group assignments were sealed in opaque envelopes and opened sequentially by the medical dispatcher who then assigned the patients to the groups. All the gas cylinders were identical and identified only with a letter. This letter was changed regularly by the independent pharmacist to ensure the blinding of nurses who had already enrolled another subject. Fifteen minutes after the beginning of inhalation, the blinded gas was stopped and all patients received premixed 50% N2O and oxygen from another unblinded cylinder until arrival at the ED. The emergency physician (EP) collected the written consent of the patient at least 30 minutes after any gas inhalation. All gas administration was stopped on arrival at the ED, and all patients were subsequently treated at the discretion of the attending admitting physician, including the continuation of analgesic medication if indicated.
The fire service nurse recorded the following characteristics at enrollment in the study: age, sex, height, weight, type of traumatic injury, baseline pain score, blood pressure, pulse rate, respiratory rate, and oxygen saturation. Pain assessment was obtained by asking patients to rate their pain with an integer between 0 and 10, 0 being “pain-free” and 10 being “worst pain ever.” The following physiologic parameters were recorded: noninvasive monitoring of blood pressure, pulse rate, respiratory rate, pulse oximetry, sedation level with a sedation scale[8-10] (Table 1), and adverse events. Pain assessment and safety evaluation were conducted at baseline, every 5 minutes for 30 minutes, and then every 15 minutes until arrival at the ED. Overall patient and investigator satisfaction with analgesia (pain relief classified as excellent, good, mild, or weak) was recorded on arrival at the ED. The ED physician asked both patient and nurse their satisfaction and reported the results on a separate case report form. Adverse events were also prospectively recorded during the first 30 minutes of the hospital stay by the EP (nausea, emesis, dizziness, excitement, numbness, drowsiness) on separate case report forms. The adverse events were classified as severe if death, any life-threatening situation, prolongation of length of stay, lifelong bodily or psychological injury, or increased susceptibility to disease occurred. The data for each patient were collected by the fire service nurses in case report forms, identified by the randomization number and initials of patients, and coded by experienced research associates.
|Description||Patient is awake||Patient has intermittent sleeping||Patient is sleeping, awakened by verbal stimulation||Patient is sleeping, awakened by tactile stimulation||Patient is not aroused by stimulation|
The primary endpoint was the percentage of patients with pain relief (with a numerical rating scale of 3 or lower) 15 minutes after the time of initiation of the study drug. This value has been chosen in other studies as the cutoff for pain relief.[8-11] Secondary endpoints were treatment safety and adverse events, time to analgesia, and patient and investigator satisfaction with analgesia.
Descriptive statistics are reported as means with standard deviations, medians with interquartile ranges (IQR), and proportions with exact binomial 95% confidence intervals (CIs). Proportions were compared by using chi-square tests or Fisher's exact test when appropriate. Means were compared using a t-test for normally distributed data or the nonparametric two-sample Mann-Whitney rank sum test for data not fitting the assumptions of parametric testing.
All participants who underwent random assignment were analyzed according to group assignment in an intention-to-treat fashion. For the missing values, we used the last evaluation available, assuming no further improvement after the dropout, whereas all randomized patients were included in the safety analyses.
For sample size calculation, we used preliminary observational data on 53 patients obtained in one center. Those preliminary data were consistent with the literature.[3, 4] We found that 60% of the patients receiving N2O and oxygen experienced pain relief at 15 minutes versus 20% of patients receiving MA. The approach for the study design was a superiority design, so a sample size of 52 was therefore calculated with a two-sided test with a 0.05 type I error and a power of 90%. We decided to include 60 patients to account for those lost to follow-up. SAS statistical software (version 9.1, SAS Institute, Cary, NC) was used for data analysis. A p value < 0.05 was considered significant.
Between February 2, 2010, and March 23, 2011, there were 648 patients screened for inclusion and 60 patients were randomly assigned to treatment (Figure 1). There were no statistically significant differences between groups concerning age (median = 34 years; IQR = 23 to 53 years), sex (37 males, 66%), initial pain scores (median = 6, IQR = 5 to 6), or other characteristics (Table 2).
|Group||Nitrous Oxide and Oxygen (n = 30)||MA (n = 30)|
|Age (years)||37 (26–66)||29 (23–50)|
|Males||20 (67)||19 (63)|
|Body mass index (kg/m2)||24.5 (22–29.6)||24.2 (20.7–26.9)|
|Localization of pain|
|Upper limb||11 (37)||8 (27)|
|Lower limb||12 (40)||15 (50)|
|Back trauma||6 (20)||7 (23)|
|Thoracic trauma||1 (3)||0|
|Pain rating on NRS at time 0||6 (5–6)||6 (5–6)|
|Physiology time 0|
|Heart rate (min−1)||83 (72–88)||84 (69–96)|
|Respiratory rate (min−1)||18 (16–20)||18 (16–20)|
|Systolic pulse pressure (mm Hg)||135 (120–146)||134 (117–155)|
|Diastolic pulse pressure (mm Hg)||83 (73–90)||81 (70–98)|
|SpO2 (%)||99 (98–100)||99 (98–99)|
Fifteen minutes after the inhalation, 67% of the patients in the N2O group had an NRS score of 3 or lower versus 27% of those in the MA group (delta = 40%, 95% CI = 17% to 63%, p < 0.001; Figure 2). The median pain scores were significantly lower in the N2O group at T15: 2 (IQR = 1 to 4) versus 5 (IQR = 3 to 6; p < 0.0001). This difference was significant after 5 minutes of administration (Figure 3).
Analysis at other times of assessment shows earlier pain relief with N2O at 5 and 10 minutes, with no difference 5 minutes after T15 when every patient received N2O (Figure 2). All the patients (except one in the N2O group) and all the fire service nurses (except one in each group) were either satisfied or very satisfied with the results of the analgesic treatment.
Table 3 shows the number and type of adverse events reported between randomization and T30, all mild in seriousness. All these adverse effects were fully reversible with no other complication 5 minutes after the end of inhalation. No adverse event occurred within the first 30 minutes of hospital stay.
|Group||Nitrous Oxide and Oxygen (n = 30)||MA (n = 30)|
|Adverse events from T0 to T15||0||0|
|Adverse events from T15 to T30 Nausea||1 (3)||3 (10)|
|Sedation score = 1||5 (17)||4 (13)|
|Physiology at T15|
|Heart rate (min−1)||76 (72–83)||81 (67–92)|
|Respiratory rate (min−1)||17 (15–20)||18 (16–20)|
|Systolic blood pressure (mm Hg)||131 (120–148)||129 (117–136)|
|Diastolic blood pressure (mm Hg)||79 (71–85)||81 (69–85)|
|SpO2 (%)||99 (99–100)||99 (98–100)|
To the best of our knowledge, this was the first randomized, double-blind, multicenter study of N2O for adult patients in an emergency setting. N2O and oxygen inhalation appeared to be clinically superior to placebo for the treatment of moderate traumatic acute pain in a prehospital setting. In addition, we found a low incidence of adverse effects with no severe complications. Patients and caregivers were satisfied with the results of the analgesic treatment in both groups, probably due to the fact that all patients received premixed 50% N2O and oxygen after 15 minutes.
For a number of years, 50% N2O analgesia has been widely used by many rescue organizations, without clear demonstration of its efficacy in this setting. Some cohort studies have been performed, but none have proven the efficacy of inhaled analgesia.[4-6, 12] Faddy and Garlick2 identified through a search of the literature 12 randomized controlled trials investigating the use of 50% N2O. Randomized studies included in this review included a variety of patient populations and a broad spectrum of pain sources,[12-22] but most of them had a poor methodologic quality. Children were well represented, but none of these studies compared the treatments in an adult emergency setting. Application of the findings of this review to emergency adult care seemed not appropriate. Reproduction is always an important part of science, and our study employs more rigorous methods than earlier studies. The novelty of our study is important, as no prior study has compared N2O and placebo in a prehospital setting in such a rigorous way.
Adverse effects were rare and mild and could not definitively be attributed to N2O. In our study, four patients (7%) experienced nausea, all fully reversible with no other complication 5 minutes after the end of inhalation. In other studies, no patients experienced clinically deleterious side effects. In the study by Amey et al., 48% of patients (41 of 85) reported side effects, of which 90% were mild. In a large prehospital cohort study, N2O and oxygen was provided to 1,243 patients over a period of 18 months. Of the 1,201 patients evaluated, 20.6% reported minor side effects consisting of nausea or vomiting (5.7%), dizziness or lightheadedness (10.3%), excitement (3.7%), and numbness (0.3%). Ninety-one (7.6%) patients became drowsy or fell into a light sleep but all were readily aroused by verbal command. All retained the ability to cough or swallow on command. No consistent or clinically adverse changes were found in blood pressure or pulse rates.
Several strategies have been proposed to improve management of pain. Aggressive opioid titration protocols, strict IV analgesia protocols, or changing from morphine to another opioid have been proposed to overcome poor response to morphine for treatment of acute pain.[10, 24] On the other hand, groups such as lifeguards, marine rescue, and other rescue teams provide the initial care to a variety of patients. These organizations do not provide a standard of training that allows their members to administer IV analgesics. For members of these groups to effectively treat patients in extreme pain, they need to have a safe and effective alternative form of pain relief at their disposal. The National Association of EMS Physicians position statement on the use of N2O in prehospital emergency care states that N2O is within the scope of practice of EMS medical directors and can be used by EMS field personnel following appropriate education and training. To our knowledge, N2O is not widely used in United States and European prehospital emergency medicine. This study reinforces the ongoing use of 50% N2O by all these groups thorough a clear protocol, supervised and regularly revised by a medical director.
The inferences that can be drawn from these data are limited in several respects. Our study was conducted with prehospital trauma patients, and the results may not be generalizable to other emergency or patient settings. Our study was designed to assess the efficacy of N2O and oxygen, not the safety. In our study, the incidence of adverse effects was low, and there were no severe adverse effects, hospitalizations, or subject dropout due to adverse events, but we cannot definitely assess the absolute safety of the N2O, as our study may be underpowered. Some of the patients were not included because they wanted to be referred to another hospital (not participating in the study) than the reference hospital. Nevertheless, this number of patients was low and may not affect our results. Satisfaction was measured after both groups had received N2O, and not after the first 15 minutes, so we did not record the satisfaction of the difference in treatments. Finally, it is always possible that factors affecting analgesia may be more or less prevalent in treatment groups despite randomization. Although we rely on randomization to balance baseline differences that are measured and unmeasured and thus reduce confounders known and unknown, it is still possible that the groups differ on these characteristics.
This study demonstrates the efficacy of nitrous oxide for the treatment of moderate pain from trauma in adult patients in the prehospital setting. We found a difference in pain relief at 5 minutes and at all subsequent time points. Early analgesia in a prehospital setting can be obtained with the use of 50% nitrous oxide and oxygen.
The authors thank Colonel Patrick Toufflet, CEO of SDIS 31, Vanessa Houze-Cerfon, MPH, and Beatrice Appiah, MPH, for their help in conducting this study. The authors also thank the firefighters, nurses, and SAMU physicians who enrolled the patients and made this study possible and all the enrolled patients for their kindness and comprehension.
- 1Predictors of pain relief and adverse events in patients receiving opioids in a prehospital setting. Am J Emerg Med. 2011; 29:512–7., , , , .
- 10Sufentanil 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., , , , , .
- 17A controlled oximetric evaluation of inhalational, opioid and epidural analgesia in labour. Anaesth Intensive Care. 1989; 17:418–21., , .
- 20Patient-administered nitrous oxide/oxygen provides safe and effective analgesia for percutaneous liver biopsy: a randomized placebo-controlled trial. Am J Gastroentol. 2001; 96:1553–7., , , .
- 25National Association of EMS Physicians. Prehospital Pain Management. Available at: http://www.naemsp.org/Documents/POSITION%20PrehospitalPainMgmt.pdf. Accessed Jan 8, 2013., . Position paper.