Fármacos para el tratamiento de las náuseas y vómitos en adultos en los servicios de urgencias
Resumen
Antecedentes
Las náuseas y vómitos son una afección frecuente y angustiante en los servicios de urgencias (SU). La etiología de las náuseas y vómitos en los SU es diversa y a menudo se prescriben fármacos. Actualmente no existe consenso en cuanto a la farmacoterapia óptima de las náuseas y vómitos en el contexto del SU de adultos.
Objetivos
Proporcionar pruebas de la eficacia y la seguridad de los fármacos antieméticos para el tratamiento de las náuseas y vómitos en el contexto del SU de adultos.
Métodos de búsqueda
Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; 2014, número 8), MEDLINE (OvidSP) (enero 1966 hasta agosto 2014), EMBASE (OvidSP) (enero 1980 hasta agosto 2014) y en ISI Web of Science (enero 1955 hasta agosto 2014). También se buscó en los registros de ensayos clínicos relevantes y en actas de congresos.
Criterios de selección
Se incluyeron ensayos controlados aleatorios (ECA) de cualquier fármaco para el tratamiento de las náuseas y vómitos en el tratamiento de los adultos en el SU. La elegibilidad de los estudios no estuvo limitada por el idioma o el estado de publicación.
Obtención y análisis de los datos
Dos autores de la revisión de forma independiente realizaron la selección de los estudios, la extracción de los datos y la evaluación del riesgo de sesgo de los estudios incluidos. Se estableció contacto con los autores de los estudios para obtener la información faltante, si era necesario.
Resultados principales
Se incluyeron ocho ensayos, con 952 participantes, de los cuales el 64% eran mujeres. Los ensayos incluidos fueron generalmente de calidad adecuada; seis ensayos presentaban bajo riesgo de sesgo y dos ensayos un alto riesgo de sesgo. Tres ensayos con 518 participantes compararon cinco fármacos diferentes con placebo; todos informaron el resultado primario como cambio medio en la escala analógica visual (EAV) (0 a 100) para la gravedad de las náuseas desde el inicio hasta los 30 minutos. Los ensayos no informaron de manera sistemática otros resultados primarios del cambio en las náuseas en la EAV a los 60 minutos o el número de episodios de vómitos. Las diferencias en el cambio medio en la EAV desde el inicio hasta los 30 minutos entre placebo y los fármacos evaluados fueron: metoclopramida (tres ensayos, 301 participantes; diferencia de medias [DM] ‐5,27; intervalo de confianza [IC] del 95%: ‐11,33 a 0,80), ondansetrón (dos ensayos, 250 participantes; DM ‐4,32; IC del 95%: ‐11,20 a 2,56), proclorperazina (un ensayo, 50 participantes; DM ‐1,80; IC del 95%: ‐14,40 a 10,80), prometazina (un ensayo, 82 participantes; DM ‐8,47; IC del 95%: ‐19,79 a 2,85) y droperidol (un ensayo, 48 participantes; DM ‐15,8; IC del 95%: ‐26,98 a ‐4,62). El único cambio estadísticamente significativo en la EAV desde el inicio hasta los 30 minutos fue para droperidol, en un único ensayo con 48 participantes. Ningún otro fármaco fue significativamente superior a placebo desde el punto de vista estadístico. Otros ensayos incluidos evaluaron un fármaco comparado con "controles activos" (antiemético alternativo). No hubo pruebas convincentes de la superioridad de ningún fármaco en concreto comparado con un control activo. Todos los ensayos incluidos en esta revisión informaron los eventos adversos, pero se informaron de manera variable, lo que impidió el agrupamiento significativo de los resultados. Los eventos adversos fueron generalmente leves, no se informaron eventos adversos graves. En general, la calidad de las pruebas fue baja, sobre todo porque no había suficientes datos.
Conclusiones de los autores
En la población del SU, no existen pruebas definitivas para apoyar la superioridad de ningún fármaco sobre otro, ni la superioridad de ningún fármaco sobre placebo. Los participantes que recibieron placebo a menudo informaron una mejoría clínicamente significativa de las náuseas, lo que implica que el tratamiento de apoyo general como los líquidos intravenosos puede ser suficiente para la mayoría de los pacientes. Si se considera necesario utilizar un fármaco, su elección se puede hacer sobre la base de otras consideraciones como la preferencia del paciente, el perfil de efectos adversos y el costo. La revisión estuvo limitada por la escasez de ensayos clínicos en este contexto. Los estudios de investigación futuros deben incluir el uso de placebo y considerar la posibilidad de centrarse en grupos con diagnósticos específicos y controlar factores como el líquido intravenoso administrado.
PICO
Resumen en términos sencillos
Fármacos para el tratamiento de las náuseas y vómitos en los servicios de urgencias
Pregunta de la revisión
Se examinaron los efectos de los fármacos para el tratamiento de las náuseas y vómitos en adultos en el servicio de urgencias.
Antecedentes
Las náuseas (sentirse enfermo) y vómitos (estar enfermo) son un síntoma frecuente en los pacientes en los servicios de urgencias y pueden ser resultado de varias causas diferentes. Además de ser angustiantes, pueden dar lugar a otros problemas como la deshidratación (cuando el cuerpo pierde más líquidos que los que recibe). Los fármacos para tratar las náuseas han sido útiles en otros contextos, como después de las operaciones, aunque no se sabe cuál es el mejor fármaco para los pacientes en los servicios de urgencias.
Características de los estudios
Las pruebas están actualizadas hasta agosto 2014. Se incluyeron ocho ensayos clínicos con 952 participantes. Los ensayos evaluaron muchos fármacos diferentes a diferentes dosis, pero solamente tres ensayos incluyeron un grupo placebo (fármaco simulado). Seis de estos ensayos fueron de alta calidad, con bajo riesgo de error (es decir sesgo, cuando se exagera el efecto verdadero). En esta revisión se incluyeron los efectos de los fármacos sobre las náuseas y vómitos hasta una hora después de proporcionar el fármaco.
Resultados clave y calidad de las pruebas
Los resultados principales de interés fueron el efecto sobre las náuseas entre cero y 60 minutos después de administrar el fármaco, número de vómitos y efectos secundarios de los fármacos. De estos resultados, solamente se informaron en todos los ensayos las náuseas a los 30 minutos y los efectos secundarios. De todos los ensayos, solamente se informó que un fármaco fue mejor que placebo y otros fármacos. Ese fue el droperidol, que fue incluido en un ensayo pequeño con 97 participantes. Ningún otro fármaco único fue definitivamente mejor que otro, y ninguno de los otros ensayos que incluyeron un grupo placebo indicó que los fármacos activos funcionaran definitivamente mejor que placebo. Los efectos secundarios fueron leves.
Estos resultados indican que en los pacientes en el servicio de urgencias, las náuseas en general mejorarán, ya sea si se tratan con fármacos específicos o con placebo. Por lo tanto, el tratamiento de apoyo como los líquidos intravenosos (cuando los líquidos se administran directamente en un vaso sanguíneo) puede ser suficiente para muchos pacientes. En general, la calidad de las pruebas fue baja, principalmente porque no había datos suficientes.
Conclusiones de los autores
Summary of findings
| Metoclopramide for nausea and vomiting in the emergency department | ||||||
| Patient or population: people with nausea and vomiting Settings: emergency department Comparisons: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Metoclopramide | |||||
| Change in nausea severity at 30 minutes | The mean nausea severity decrease ‐ metoclopramide vs. placebo ranged across control groups from | The mean nausea severity decrease ‐ metoclopramide vs. placebo in the intervention groups was | ‐ | 301 | ⊕⊕⊝⊝ | A larger decrease in nausea severity score indicates better control of symptoms. A difference of > 15 mm is thought to be the 'minimum clinically significant difference' |
| Number of vomiting episodes | See comment | See comment | Not estimable | 301 (3 studies) | See comment | This outcome was not reported in any of the included studies |
| Adverse reactions | See comment | See comment | Not estimable | 301 (3 studies) | See comment | No pooling of results was possible, due to variations in reporting. No studies reported any serious adverse reactions or significant difference in adverse reactions |
| Proportion of participants requiring rescue medication | Study population | OR 0.3 | 299 | ⊕⊕⊝⊝ | An OR < 1 means less need for the medication with metoclopramide | |
| 381 per 1000 | 156 per 1000 | |||||
| Moderate | ||||||
| 363 per 1000 | 146 per 1000 | |||||
| Participant satisfaction with intervention | Study population | OR 1.07 | 216 | ⊕⊕⊝⊝ | An OR < 1 implies better satisfaction with metoclopramide | |
| 657 per 1000 | 672 per 1000 | |||||
| Moderate | ||||||
| 721 per 1000 | 734 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded for imprecision (wide confidence interval and not achieving optimal information size). | ||||||
Antecedentes
Descripción de la afección
Las náuseas y vómitos son una afección frecuente y angustiante en los servicios de urgencias (SU), con más de 8 000 000 de presentaciones anualmente en los EE.UU. (LaValley 2003). Las náuseas describen la sensación desagradable de la necesidad inminente de vomitar, mientras que los vómitos se refieren a la expulsión oral vigorosa de los contenidos gástricos asociada con la contracción de la musculatura de la pared abdominal y torácica(Quigley 2001). Por lo tanto, mientras las náuseas son una experiencia subjetiva, los vómitos representan un evento físico.
Las náuseas y vómitos pueden ser muy angustiantes y las complicaciones pueden variar desde triviales a graves, por ejemplo, deshidratación, trastornos de los electrólitos, aspiración, síndrome de Mallory‐Weiss (desgarros de la mucosa gástrica y esofágica) y rotura esofágica(Bork 2011; Zun 2010). La causa más frecuente de las náuseas y vómitos en el SU es la gastroenteritis aguda (inflamación del sistema gastrointestinal); sin embargo, la etiología de las náuseas y vómitos en el contexto de los SU es diversa y puede incluir respuestas fisiológicas y patológicas del sistema digestivo, trastornos del sistema nervioso central, problemas endocrinos o metabólicos y toxinas o fármacos, entre otros (Zun 2010). Las náuseas y vómitos en el SU pueden coexistir con otros trastornos médicos (p.ej. infarto de miocardio u obstrucción del intestino delgado) o ser resultado de otros tratamientos prescritos en el SU (p.ej. analgesia con opiáceos)
Descripción de la intervención
El tratamiento de un paciente en el SU a menudo incluye la identificación de la causa de las náuseas y vómitos, así como el reconocimiento y la corrección de las consecuencias y complicaciones(AGA 2001; Quigley 2001). Los antieméticos se prescriben habitualmente para las náuseas y vómitos sin diferenciar en el contexto del SU, aunque hay poco consenso en cuanto al tratamiento óptimo. El tratamiento a menudo se dirige a la presunta causa fisiopatológica o se extrapola de las pruebas en otros contextos.
De qué manera podría funcionar la intervención
La fisiopatología de las náuseas y vómitos es un proceso complejo. El aspecto físico del vómito está coordinado por el centro del vómito en el cerebro, localizado funcionalmente en la formación reticular lateral de la médula. Las vías eferentes del centro del vómito se establecen principalmente a través de los nervios vago, frénico y espinales (Zun 2010). El centro del vómito recibe la información de diversas fuentes incluida la zona desencadenante del quimiorreceptor (ZDQ) localizada en el área postrema en el piso del cuarto ventrículo, los nervios vago y simpático, así como impulsos directamente del sistema digestivo y otras fuentes(Bork 2011; Carpenter 1990). La ZDQ también es activada por los mediadores en la circulación, que pueden incluir hormonas, péptidos, fármacos o toxinas (Zun 2010).
Debido a la naturaleza compleja del proceso de las náuseas y vómitos, los antieméticos consisten en un grupo diverso de productos químicos con mecanismos y sitios de acción variables. Los objetivos de su acción incluyen la ZDQ entre los receptores de dopamina, los receptores de serotonina en el área postrema y el núcleo del tracto solitario y los receptores colinérgicos y de histamina. Otros agentes ejercen su acción periféricamente en el sistema digestivo, y en otros el mecanismo de acción no está completamente dilucidado.
Por qué es importante realizar esta revisión
Pruebas de alto nivel apoyan la administración de antieméticos en el tratamiento de las náuseas y vómitos en muchos contextos y poblaciones; sin embargo, hay poca orientación o consenso en las recomendaciones para el tratamiento de las náuseas y vómitos en el contexto de los SU de adultos. Las recomendaciones son inconsistentes y rara vez se basan en la evidencia. Los agentes farmacológicos de preferencia difieren significativamente entre los países y regiones (LaValley 2003; Mee 2011). Las náuseas y vómitos postoperatorios(Carlisle 2006),y las náuseas y vómitos inducidos por quimioterapia (Billio 2010; Jordan 2007), y radioterapia(Kris 2006; Maranzano 2005), en particular, se han investigado ampliamente y se han publicado revisiones sistemáticas y guías. También se han publicado revisiones sistemáticas Cochrane sobre el uso de antieméticos en pacientes que reciben cuidados paliativos (Dorman 2010; Perkins 2009), en la gastroenteritis pediátrica y de los adolescentes(Fedorowicz 2011), las náuseas y vómitos asociados con el primer trimestre del embarazo (Mathews 2010), y el uso de puntos de presión de acupuntura (Ezzo 2006; Lee 2009). Sin embargo, la extrapolación de las pruebas de estos contextos a la población del SU no es directa debido a las diferencias en las etiologías, las poblaciones de pacientes y otros factores. Esta revisión es importante para ayudar a establecer las pruebas actuales para el tratamiento de las náuseas y vómitos en este contexto clínicamente diverso, y para ayudar a determinar las prioridades de los estudios de investigación futuros.
Objetivos
Proporcionar pruebas de la eficacia y la seguridad de los fármacos antieméticos para el tratamiento de las náuseas y vómitos en el contexto del SU de adultos.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Se incluyeron ensayos controlados aleatorios (ECA) de cualquier fármaco para el tratamiento de las náuseas y vómitos en el contexto del SU. No se restringió la elegibilidad de los estudios por el idioma o el estado de publicación. Se excluyeron los estudios de cohorte prospectivos y los estudios cuasialeatorios.
Tipos de participantes
Se incluyeron participantes en el SU de adultos, con 16 años de edad o más con náuseas y vómitos. Los ensayos solamente se incluyeron si los participantes del estudio se identificaron como "adultos", o si más del 80% de los participantes tenía 16 años de edad o más. Se estableció contacto con los autores de los estudios si los datos de la edad no estaban disponibles, y los estudios no se incluyeron en esta revisión si las edades de los participantes no estaban claras. Se identificó claramente el contexto como SU.
Tipos de intervenciones
Las intervenciones incluyeron cualquier agente farmacológico prescrito para el tratamiento de las náuseas y vómitos. Se consideró cualquier dosis, formulación o vía de administración. Los comparadores apropiados incluyeron placebo, ningún tratamiento o "control activo" (antiemético alternativo).
Tipos de medida de resultado
Gravedad de las náuseas, evaluada mediante el uso de cualquier escala o puntuación y el número de episodios de vómitos.
Resultados primarios
-
Gravedad de las náuseas. Las náuseas se evaluaron medidas con cualquier escala o puntuación utilizada por los autores de los estudios, y se transformaron de ser necesario a una puntuación entre 0 y 100. Se registraron como resolución completa de las náuseas (p.ej. inclusión de la puntuación 0 en una escala analógica visual [EAV] y el cambio a partir del valor inicial, con una diferencia mínima clínicamente significativa [DMCS] a partir del valor inicial definida como 15 mm en la EAV(Hendey 2005). Se incluyeron los puntos temporales entre cero y 60 minutos como relevantes para la práctica del fármaco de urgencia.
-
Número de episodios de vómitos, como resultados autoinformados e informados por el médico.
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Cualquier reacción adversa.
Resultados secundarios
-
Proporción de participantes que requirieron medicación de rescate.
-
Proporción de participantes que requirieron ingreso hospitalario.
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Estancia hospitalaria media o mediana en el SU.
-
Satisfacción del participante con la intervención.
Results
Description of studies
Results of the search
The electronic search identified 6799 studies with duplicates removed, consisting of 1389 from EMBASE, 3630 from MEDLINE, 320 from CENTRAL and 2507 from Web of Science. After screening titles and abstracts, we identified 13 studies for examination of the full text. We identified eight relevant studies from searching conference proceedings and clinical trial registries. Four of the studies appeared to report unique studies of relevance to our review, whereas four of the studies reported data subsequently published in journals and identified by the electronic database search. We contacted authors of the four other studies, but received no data from investigators, meaning information was only available in abstract form. Two of the authors of this Cochrane review were co‐authors of the Egerton‐Warburton 2014 study. Therefore, the search yielded 17 studies for consideration for inclusion. After evaluation of the full‐text articles, we included eight studies in the review (see Characteristics of included studies table), we excluded five studies (see Characteristics of excluded studies table), and we identified four studies that were available in abstract form, and had insufficient information to assess (see Characteristics of studies awaiting classification table). For a PRISMA flow diagram of search strategy, see Figure 1.
Study flow diagram.
Included studies
We included eight trials in this review (Barrett 2011; Braude 2006; Braude 2008; Chae 2011; Cham 2004; Egerton‐Warburton 2014; Ernst 2000; Patka 2011). Further details are available in the Characteristics of included studies table.
Design
The eight included trials were all parallel group, randomized trials. One trial was described as single blind (Cham 2004), the remainder were described as double blind. The included trials had two to four treatment arms, with only three trials including a placebo arm (Barrett 2011; Braude 2006; Egerton‐Warburton 2014), the other trials using an active control. One trial was described as a non‐inferiority trial (Braude 2008). The total sample size was 952 participants, consisting of 338 men and 614 women.
Participants and setting
The included trials were conducted in EDs in the US and Australia, mostly identified as university affiliated or teaching hospitals. All only included adults aged over 18 years. Most trials included nausea and vomiting from a variety of aetiologies, three trials excluded participants if their initial nausea VAS score was less than 40 mm (Barrett 2011; Braude 2006; Braude 2008). One trial specified the requirement for "uncomplicated gastritis and gastroenteritis" for eligibility (Ernst 2000). Women outnumbered men in all trials.
Intervention
The trials evaluated six different antiemetics. All trials included only intravenous antiemetics. Two trials had four arms (Barrett 2011; Braude 2006), and one trial had three arms (Egerton‐Warburton 2014). Only three trials included a placebo arm (Barrett 2011; Braude 2006; Egerton‐Warburton 2014). Five trials evaluated metoclopramide in doses of 10 mg, 20 mg and 0.4 mg/kg up to 32 mg. One trial compared two different doses of metoclopramide (Cham 2004). Five trials evaluated 5‐hydroxytryptamine‐3 (5‐HT3) blockers (Barrett 2011; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Patka 2011), four using ondansetron 4 mg (Barrett 2011; Braude 2008; Egerton‐Warburton 2014; Patka 2011), and one using tropisetron 0.5 mg (Chae 2011). Three trials included prochlorperazine 10 mg (Braude 2006; Ernst 2000; Patka 2011); three trials evaluated promethazine, one trial at 12.5 mg (Barrett 2011), and two trials at 25 mg (Braude 2008; Ernst 2000). All trials involved administration of a single stat dose as a bolus or over two to five minutes. Most trials included administration of varying amounts of intravenous fluid during the study period.
Outcomes
All included studies reported the primary outcome of severity of nausea reported on any scale or score. Seven of the studies reported nausea on a 100‐mm VAS (Barrett 2011; Braude 2006; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Ernst 2000; Patka 2011), and one study used a 0 to 10 numerical rating scale (NRS) (Cham 2004). All studies included the time point of 30 minutes; three trials also reported data at 60 minutes (Chae 2011; Ernst 2000; Patka 2011); two trials reported outcomes beyond 60 minutes that we did not consider relevant to this review (Chae 2011; Patka 2011).
Three trials reported the number of vomiting episodes (Chae 2011; Egerton‐Warburton 2014; Patka 2011). All trials reported adverse events, but the trials classified and reported them differently. All trials reported the outcome of requirement for rescue medication, but this was variably defined, or not defined in trials. Three trials reported the proportion of participants requiring hospital admission (Braude 2008; Ernst 2000; Patka 2011). No trials reported on ED length of stay, while three reported participant satisfaction (Braude 2006; Braude 2008; Egerton‐Warburton 2014).
Excluded studies
We excluded five studies; see Characteristics of excluded studies table for details. The study by Roy 1991 compared oral doses of metoclopramide and domperidone, three times a day over one week. The setting appeared to be in general practice and outcomes were measured beyond the time frame of relevance to this review. Another excluded trial, which evaluated one or two doses of intramuscular domperidone 10 mg versus placebo, measured outcomes beyond the relevant time frame and was not clearly identified as ED (Agorastos 1981). We excluded one report as it was not an RCT, but an uncontrolled prospective design with no appropriate comparator group (Ordog 1984). We excluded one large multicentre trial evaluating two different doses of ondansetron (8 mg and 16 mg) versus placebo for opiate‐associated nausea and vomiting (Sussman 1999). The setting was not clearly an ED, although it was stated that "many" participants were managed in EDs, and the primary outcome was resolution of symptoms at 24 hours, which was not relevant to this review. Finally, we excluded one single‐centre study from Israel because the setting was not an ED, but rather an outpatient setting, participants requiring intravenous treatment were excluded and time points of the outcome assessments were not of relevance to this review (Cohen 1999).
Awaiting classification
There are four trials awaiting classification (Friedland 2008; Haensel 2007; Thacker 2003; Thacker 2004; see Characteristics of studies awaiting classification table). These trials were available in abstract form only, with insufficient detail to allow inclusion in the review. We were unable to obtain further information from authors of these trials.
Ongoing studies
We found no ongoing studies.
Risk of bias in included studies
We assessed the risk of bias of each trial; see Characteristics of included studies table, Assessment of risk of bias in included studies and 'Risk of bias' summary (Figure 2; Figure 3).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
All included trials reported acceptable methods of random sequence generation. The report by Braude 2008 reported only that drugs were "randomized in blocks of 10" and the method of sequence generation was not explicitly stated. This was clarified with the authors as being generated by computer program and recorded as low risk of bias for the review. Allocation concealment was adequate in seven out of eight studies. One study did not elucidate any mechanism of allocation concealment in the report, and was, therefore, considered unclear risk of bias (Patka 2011).
Blinding
Blinding of participants and personnel was adequate in six trials (Barrett 2011; Braude 2006; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Ernst 2000), unclear in one trial (Patka 2011), and judged as high risk of bias in one trial (Cham 2004). Outcomes were self reported in all included trials. The trial judged to be high risk of bias was reported as single blind, with no further details provided, but made no attempt to blind clinical staff (Cham 2004). One other trial described preparation of the study drug by independent nurses from the usual ward stock, keeping the drug allocation concealed from the participant and treating doctor (Chae 2011). While we considered that this procedure could potentially compromise blinding, we thought this would have been unlikely to have occurred sufficiently to affect the outcome, and we, therefore, judged the trial to be low risk of bias for this domain. We assessed one trial as unclear risk of bias as the authors did not report any mechanism for blinding (Patka 2011).
With regards to detection bias, outcomes were all self reported, consequently the same trial was rated as high risk of bias (Cham 2004), and the same trial was reported as unclear risk of bias (Patka 2011) due to similar reasons as described above.
Incomplete outcome data
All trials were at low risk of attrition bias. Although two trials had some unexplained missing data (Chae 2011; Patka 2011), these appeared balanced between intervention groups, outside the time points considered most relevant to this review, and unlikely to have a significant impact on the intervention effect estimates.
Selective reporting
There was no evidence of selective reporting in any of the trials. Outcomes listed in methods sections were reflected in results reported. One trial listed two primary outcomes on a clinical trial registry, and reported the non‐significant outcome as a secondary outcome in the published report (Chae 2011). However, as all results were reported, we considered this to be low risk of bias.
Other potential sources of bias
We assessed two trials as 'unclear' with regards to other potential sources of bias. The Patka 2011 trial was generally poorly reported, with inconsistencies throughout the report, and no reason given for non‐recruitment of substantial numbers of potentially eligible participants. The trial by Barrett 2011 reported an unplanned interim analysis and post hoc power calculation. The trial was then stopped at just over one‐third of their planned recruitment target, because the likelihood of achieving a statistically significant result was remote, hence introducing the possibility of a type 2 error, which was acknowledged in the report. We judged that this may have introduced some bias.
Effects of interventions
See summary of findings Table for the main comparison for the comparison of metoclopramide, the drug most commonly evaluated, versus placebo.
This section included results from all eight trials. The three trials that included a placebo arm evaluated five different drugs: metoclopramide, ondansetron, prochlorperazine, promethazine and droperidol (Barrett 2011; Braude 2006; Egerton‐Warburton 2014). The five non‐placebo trials evaluated the same five drugs (Braude 2008; Chae 2011; Cham 2004; Ernst 2000; Patka 2011), with one trial including the 5‐HT3 blocker tropisetron (Chae 2011).
To address the aims of this review, we combined the trials to allow comparisons of drugs versus placebo and each drug versus active control. Despite a degree of heterogeneity, this did allow for some pooling of results. We also presented the results of each drug studied versus each other drug. Some of these comparisons involved small numbers from one or two trials only, so caution is advised in interpretation of these findings.
Comparison of drug versus placebo
Three trials, with 518 participants, compared five different drugs with placebo (Barrett 2011; Braude 2006; Egerton‐Warburton 2014).
Primary outcomes
Severity of nausea
All three trials reported the primary outcome of mean VAS rating change for nausea severity from baseline to 30 minutes (Barrett 2011; Braude 2006; Egerton‐Warburton 2014).
All three trials evaluated metoclopramide and involved 301 participants. From pooled results, the MD in VAS rating change at 30 minutes between metoclopramide and placebo was ‐5.27 (95% CI ‐11.33 to 0.80) (Figure 4).
Forest plot of comparison: 1 Metoclopramide versus placebo, outcome: 1.1 Change in nausea severity at 30 minutes.
Two trials evaluated ondansetron and involved 250 participants (Barrett 2011; Egerton‐Warburton 2014). From pooled results, the MD in nausea VAS rating change at 30 minutes between ondansetron and placebo was ‐4.32 (95% CI ‐11.20 to 2.56) (Analysis 2.1).
One trial each evaluated prochlorperazine (50 participants; Braude 2006), promethazine (82 participants; Barrett 2011), and droperidol (48 participants; Braude 2006). The MD in VAS rating change at 30 minutes between prochlorperazine and placebo was ‐1.80 (95% CI ‐14.40 to 10.80) (Table 1). Between promethazine and placebo the MD was ‐8.47 (95% CI ‐19.79 to 2.85) (Table 2), and between droperidol and placebo the MD was ‐15.80 (95% CI ‐26.98 to ‐4.62) (Table 3).
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 50 | Mean Difference (IV, Random, 95% CI [mm]) | ‐1.80 [‐14.40, 10.80] |
| Proportion of participants requiring rescue medication | 50 | Odds Ratio (M‐H, Random, 95% CI) | 1.83 [0.45, 7.51] |
| Participant satisfaction | 50 | Odds Ratio (M‐H, Random, 95% CI) | 0.91 [0.20, 4.13] |
Data from single trial comparing prochlorperazine versus placebo (Braude 2006).
CI: confidence interval.
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 82 | Mean Difference (IV, Random, 95% CI [mm]) | ‐8.47 [‐19.79, 2.85] |
| Proportion of participants requiring rescue medication | 86 | Odds Ratio (M‐H, Random, 95% CI) | 0.57 [0.24, 1.34] |
Data from single trial comparing promethazine versus placebo (Barrett 2011).
CI: confidence interval.
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 48 | Mean Difference (IV, Random, 95% CI [mm]) | ‐15.80 [‐26.98, ‐4.62] |
| Proportion of participants requiring rescue medication | 48 | Odds Ratio (M‐H, Random, 95% CI) | 0.26 [0.03, 2.54] |
| Participant satisfaction | 48 | Odds Ratio (M‐H, Random, 95% CI) | 1.82 [0.30, 11.02] |
Data from single trial comparing droperidol versus placebo (Braude 2006).
CI: confidence interval.
Only the result for droperidol favoured drug over placebo (Braude 2006; Table 3).
Number of vomiting episodes
One trial reported the reduction in number of vomiting episodes, which were similar for ondansetron (median 0, interquartile range (IQR) 0 to 1), metoclopramide (median 0, IQR 0 to 2) and placebo (median 0, IQR 0 to 1) (Egerton‐Warburton 2014). The other two trials did not report the number of vomiting episodes (Barrett 2011; Braude 2006).
Adverse reactions
All three trials reported adverse reactions (Barrett 2011; Braude 2006; Egerton‐Warburton 2014); however, differences in reporting precluded pooling of results. None of the trials reported any serious adverse events.
Barrett 2011, evaluating ondansetron, metoclopramide and promethazine versus placebo, separately reported the proportion of participants with akathisia, headache and sedation at baseline and 30 minutes (characterized as none, mild, moderate and severe). These symptoms were commonly reported at baseline making interpretation of 30‐minute data problematic. At 30 minutes, akathisia was more common with each drug compared with placebo (4/38 (11%) with ondansetron, 11/41 (27%) with metoclopramide, 2/43 (5%) with promethazine, 1/38 with placebo). Headache was reported by 11/39 (28%) participants with ondansetron, 8/41 (20%) with metoclopramide and 12/43 (28%) with promethazine, compared with 6/38 (16%) with placebo. Sedation was reported by 16/39 (41%) participants with ondansetron, 21/40 (53%) with metoclopramide and 25/43 (58%) with promethazine, compared with 13/38 (34%) with placebo.
Braude 2006 reported mean and SD change in anxiety and sedation on a VAS from baseline to 30 minutes. For anxiety, the mean change for droperidol was ‐25.9 (SD 30.2), metoclopramide ‐25.4 (SD 24.3), prochlorperazine ‐21.9 (SD 38.8) and placebo ‐31.7 (SD 31.6); these differences were not significant (P value = 0.79). For sedation, the mean change for droperidol was 13.5 (SD 32.2), metoclopramide 0.4 (SD 30.1), prochlorperazine 5.1 (SD 26.5) and placebo ‐4.8 (SD 25.0); these differences were not significant (P value = 0.75).
Egerton‐Warburton 2014 reported adverse events in 9/258 (3.5%) participants: six in participants who received metoclopramide (two akathisia, two restlessness, one sweatiness and one muscle twitching), two in participants who received ondansetron (one dizziness and one stinging at injection site) and one in a participant who received placebo (shaking and restlessness).
The only significant result was a higher rate of akathisia for the "any drug" group compared with placebo (Barrett 2011).
Secondary outcomes
Proportion of participants requiring rescue medication
All three trials reported the proportion the participants requiring rescue medication, with 510 participants (Barrett 2011; Braude 2006; Egerton‐Warburton 2014).
All three trials evaluated metoclopramide and included 299 participants (Barrett 2011; Braude 2006; Egerton‐Warburton 2014). The pooled outcome versus placebo favoured metoclopramide (OR 0.3, 95% CI 0.17 to 0.53) (Analysis 1.2).
Two trials evaluated ondansetron and included 247 participants (Barrett 2011; Egerton‐Warburton 2014). There was no difference in pooled outcome versus placebo for this outcome (OR 0.82, 95% CI 0.49 to 1.37) (Analysis 2.2).
One trial each evaluated prochlorperazine (50 participants; Braude 2006), promethazine (82 participants; Barrett 2011), and droperidol (48 participants; Braude 2006). There was no difference in outcome between any drug versus placebo (prochlorperazine: OR 1.83, 95% CI 0.45 to 7.51; Table 1; promethazine: OR 0.57, 95% CI 0.24 to 1.34; Table 2 droperidol: OR 0.26, 95% CI 0.03 to 2.54; Table 3).
The only result favouring a drug over placebo was for metoclopramide (Analysis 1.2).
Proportion of participants who required hospital admission
None of the three trials including a placebo arm reported the proportion of participants who required hospital admission (Barrett 2011; Braude 2006; Egerton‐Warburton 2014).
Mean or median emergency department length of stay
None of the three trials including a placebo arm reported the mean or median ED length of stay (Barrett 2011; Braude 2006; Egerton‐Warburton 2014).
Participant satisfaction with intervention
Two trials reported participant satisfaction with intervention (Braude 2006; Egerton‐Warburton 2014). Both trials evaluated metoclopramide, involving 216 participants. From pooled results, there was no difference in participant satisfaction between metoclopramide and placebo (OR 1.07, 95% CI 0.60 to 1.91) (Analysis 1.3).
One trial each evaluated ondansetron (164 participants; Egerton‐Warburton 2014), droperidol (48 participants; Braude 2006) and prochlorperazine (50 participants; Braude 2006). There was no difference in satisfaction for ondansetron, droperidol or prochlorperazine versus placebo (ondansetron: OR 0.80, 95% CI 0.43 to 1.49; Table 4 droperidol: OR 1.82, 95% CI 0.30 to 11.02; Table 3 prochlorperazine: OR 0.91, 95% CI 0.20 to 4.13; Table 1).
| Outcome | Participants | Statistical methods | Effect estimate |
| Participant satisfaction | 164 | Odds Ratio (M‐H, Random, 95% CI) | 0.80 [0.43, 1.49] |
Data from single trials comparing drug versus placebo.
CI: confidence interval.
Comparison of metoclopramide versus active control
Five trials with 528 participants evaluated metoclopramide against an active control (Barrett 2011; Braude 2006; Chae 2011; Cham 2004; Egerton‐Warburton 2014).
Primary outcomes
Severity of nausea
One trial, involving 58 participants, compared metoclopramide 0.4 mg/kg (up to 32 mg) with a standard 10‐mg dose (Cham 2004). The outcome was reported as change in severity on a NRS of nausea 0 to 10. The median reduction in nausea was 5 (95% CI 4 to 6) in the 0.4‐mg/kg group compared with 4 (95% CI 3 to 5) in the 10‐mg group. This difference was not statistically significant (P value = 0.63).
The other four trials, involving 470 participants, included comparisons of metoclopramide with other active control, all reporting change in nausea severity on the VAS (mm) at 30 minutes (Barrett 2011; Braude 2006; Chae 2011; Egerton‐Warburton 2014). From pooled results, the MD in VAS rating at 30 minutes between metoclopramide and any active control was ‐0.00 (95% CI ‐4.50 to 4.49) (Analysis 3.1).
Three trials, involving 356 participants, compared metoclopramide with a 5‐HT3 antagonist (Barrett 2011; Chae 2011; Egerton‐Warburton 2014). From pooled results, the MD in VAS rating at 30 minutes between metoclopramide and 5‐HT3 antagonist was ‐1.74 (95% CI ‐6.88 to 3.40) (Analysis 4.1). Two of these trials, involving 256 participants, compared metoclopramide with ondansetron (Barrett 2011; Egerton‐Warburton 2014), while the other trial, involving 100 participants, compared metoclopramide with tropisetron (Chae 2011). Separately for this outcome, the MDs were ‐2.00 (95% CI ‐8.30 to 4.29) (Analysis 5.1) for metoclopramide versus ondansetron and ‐1.20 (95% CI ‐10.11 to 7.71) (Table 5) for metoclopramide versus tropisetron. One trial, involving 83 participants, compared metoclopramide with promethazine (Barrett 2011). The change in VAS rating at 30 minutes between metoclopramide and promethazine was 0.10 (95% CI ‐10.06 to 10.26) (Table 6). One trial compared metoclopramide with prochlorperazine (49 participants) and droperidol (47 participants) (Braude 2006). The change in VAS rating at 30 minutes (MD) between metoclopramide and prochlorperazine was 0.30 (95% CI ‐13.12 to 13.72) (Table 7), and between metoclopramide and droperidol was 14.30 (95% CI 2.21 to 26.39) (Table 8).
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 100 | Mean Difference (IV, Random, 95% CI [mm]) | ‐1.20 [‐10.11, 7.71] |
| Proportion of participants requiring rescue medication | 100 | Odds Ratio (M‐H, Random, 95% CI) | 3.16 [1.03, 9.69] |
Data from single trials comparing metoclopramide versus active control.
CI: confidence interval.
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 83 | Mean Difference (IV, Random, 95% CI [mm]) | 0.10 [‐10.06, 10.26] |
| Proportion of participants requiring rescue medication | 88 | Odds Ratio (M‐H, Random, 95% CI) | 0.36 [0.14, 0.93] |
Data from single trials comparing metoclopramide versus active control.
CI: confidence interval.
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 49 | Mean Difference (IV, Random, 95% CI [mm]) | 0.30 [‐13.12, 13.72] |
| Proportion of participants requiring rescue medication | 49 | Odds Ratio (M‐H, Random, 95% CI) | 0.13 [0.01, 1.13] |
| Participant satisfaction | 49 | Odds Ratio (M‐H, Random, 95% CI) | 1.05 [0.23, 4.78] |
Data from single trials comparing metoclopramide versus active control.
CI: confidence interval.
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 47 | Mean Difference (IV, Random, 95% CI [mm]) | 14.30 [2.21, 26.39] |
| Proportion of participants requiring rescue medication | 47 | Odds Ratio (M‐H, Random, 95% CI) | 0.88 [0.05, 14.87] |
| Participant satisfaction | 47 | Odds Ratio (M‐H, Random, 95% CI) | 0.53 [0.09, 3.19] |
Data from single trials comparing metoclopramide versus active control.
CI: confidence interval.
The only statistically significant result between metoclopramide and any active control was that favouring droperidol over metoclopramide (Table 8) (Braude 2006).
Number of vomiting episodes
Four of the trials did not report the number of vomiting episodes within the time frame of interest to this review (Barrett 2011; Braude 2006; Chae 2011; Cham 2004). The related findings of Egerton‐Warburton 2014 have been previously described (see 'Comparison of drug versus placebo: Primary outcomes: Number of vomiting episodes').
Adverse reactions
All five trials reported adverse events; however, differences in reporting precluded pooling of results. None of the trials reported any serious adverse events. The most commonly reported adverse events were akathisia and headache.
Cham 2004, evaluating a weight‐based dose of metoclopramide with standard dose, reported similar adverse event rates (weight‐based dose: 2/24 (8%); standard dose: 0/34 (0%); P value = 0.33).
Adverse events in three of the five trials have previously been described (see 'Comparison of drug versus placebo: Primary outcomes: Adverse reactions'), and there were no differences between metoclopramide and active control (Barrett 2011; Braude 2006; Egerton‐Warburton 2014).
Chae 2011 comparing metoclopramide with tropisetron reported higher rates of akathisia (scored from 0 to 17) in the metoclopramide group at both 30 and 60 minutes (at 30 minutes: MD 1.1, 95% CI 0.1 to 22; at 60 minutes: 1.2, 95% CI 1.01 to 2.5). Baseline akathisia scores were also higher in the metoclopramide group (MD 0.3, 95% CI ‐0.22 to 0.8). Headache was reported by 5/50 (10%) participants in the metoclopramide group and 11/50 (22%) participants in the tropisetron group (difference 12%, 95% CI ‐4.2% to 28.2%, P value = 0.17). Dizziness was reported by 3/50 (6%) participants in the metoclopramide group and 5/50 (10%) participants in the tropisetron group (difference 4.0%, 95% CI ‐8.6% to 16.6%, P value = 0.71).
The only significant result was of more frequent akathisia for metoclopramide in comparison with tropisetron (Chae 2011).
Secondary outcomes
Proportion of participants requiring rescue medication
All five trials reported proportion of participants requiring rescue medication (Barrett 2011; Braude 2006; Chae 2011; Cham 2004; Egerton‐Warburton 2014).
Cham 2004, comparing the different doses of metoclopramide, reported no difference in proportions requiring rescue medication (OR 0.83, 95% CI 0.18 to 3.86).
Four trials compared metoclopramide with any other active control on the outcome of rescue medication requirement in 469 participants (Barrett 2011; Braude 2006; Chae 2011; Egerton‐Warburton 2014). The pooled results showed no difference in requirement for rescue medication between metoclopramide and any active control (OR 0.61, 95% CI 0.21 to 1.73) (Analysis 3.2). Three trials, involving 353 participants, compared metoclopramide with 5‐HT3 blockers (Barrett 2011; Chae 2011; Egerton‐Warburton 2014). The pooled results showed no difference in the requirement for rescue medication (OR 0.71, 95% CI 0.20 to 2.50) (Analysis 4.2). However, pooled results from the two trials comparing metoclopramide and ondansetron, involving 253 participants, found that fewer participants receiving metoclopramide required rescue medication (OR 0.39, 95% CI 0.22 to 0.68) (Analysis 5.2) (Barrett 2011; Egerton‐Warburton 2014). One study comparing metoclopramide with tropisetron, involving 100 participants, found that more participants receiving metoclopramide required rescue medication (OR 3.16, 95% CI 1.03 to 9.69) (Table 5) (Chae 2011).
One trial compared metoclopramide with promethazine with fewer participants requiring rescue medication for metoclopramide (9/43 (22%) with metoclopramide versus 19/45 (44%) with promethazine; OR 0.36, 95% CI 0.14 to 0.93) (Table 6) (Barrett 2011). One trial compared metoclopramide with prochlorperazine or droperidol (Braude 2006). It found no difference in requirement for rescue medication (1/25 (4%) with metoclopramide versus 6/24 (25%) prochlorperazine; OR 0.13, 95% CI 0.01 to 1.13) (Table 7); 1/25 (4%) with metoclopramide versus 1/22 (4.5%) with droperidol; OR 0.88, 95% CI 0.05 to 14.87) (Table 8).
Proportion of participants who required hospital admission
None of the five trials evaluating metoclopramide reported proportion of participants who required hospital admission (Barrett 2011; Braude 2006; Chae 2011; Cham 2004; Egerton‐Warburton 2014).
Mean or median emergency department length of stay
None of the five trials evaluating metoclopramide reported mean or median ED length of stay (Barrett 2011; Braude 2006; Chae 2011; Cham 2004; Egerton‐Warburton 2014).
Participant satisfaction with intervention
Two trials, involving 242 participants, reported participant satisfaction (Braude 2006; Egerton‐Warburton 2014). From pooled results, there was no difference in participant satisfaction between metoclopramide and active control (OR 1.24, 95% CI 0.71 to 2.17) (Analysis 3.3).
Braude 2006 reported satisfaction as 21/25 (84%) with metoclopramide and 20/24 (83%) with prochlorperazine (OR 1.05, 95% CI 0.23 to 4.78) (Table 7) and 20/22 (95%) with droperidol (OR 0.53, 95% CI 0.09 to 3.19) (Table 8).
Egerton‐Warburton 2014 reported satisfaction as 53/86 (61%) with metoclopramide and 46/85 (54.1%) with ondansetron (OR 1.36, 95% CI 0.74 to 2.50) (Table 9).
| Outcome | Participants | Statistical method | Effect estimate |
| Participant satisfaction | 171 | Odds Ratio (M‐H, Random, 95% CI) | 1.36 [0.74, 2.50] |
Data from single trials comparing metoclopramide versus active control.
CI: confidence interval.
Comparison of 5‐HT3 blockers versus active control
Five studies, involving 583 participants, compared 5‐HT3 blockers against an active control (Barrett 2011; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Patka 2011). Four trials evaluated ondansetron (Barrett 2011; Braude 2008; Egerton‐Warburton 2014; Patka 2011), and one trial evaluated tropisetron (Chae 2011).
Primary outcomes
Severity of nausea
All five trials reported the primary outcome of mean VAS rating change for nausea severity from baseline to 30 minutes (Barrett 2011; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Patka 2011). From pooled results, the difference in mean VAS rating change (MD) at 30 minutes between 5‐HT3 blockers and any active control was 2.88 (95% CI ‐2.03 to 6.59) (Figure 5). The results were not affected by exclusion of the study with high risk of bias (Patka 2011), or by including studies only evaluating ondansetron (Analysis 7.1).
Forest plot of comparison: 3 5HT‐3 Antagonists versus active control, outcome: 6.1 Change in nausea severity at 30 minutes.
Three trials, involving 356 participants, compared 5‐HT3 blockers with metoclopramide (Barrett 2011; Chae 2011; Egerton‐Warburton 2014). From pooled results, the difference in mean VAS rating change (MD) at 30 minutes between metoclopramide and 5‐HT3 antagonist was ‐1.74 (95% CI ‐6.88 to 3.40) (Analysis 4.1). Separately, two trials, involving 256 participants, compared ondansetron with metoclopramide (Barrett 2011; Egerton‐Warburton 2014), while the other trial, involving 100 participants, compared tropisetron with metoclopramide (Chae 2011). From pooled results, the difference in mean VAS rating change (MD) at 30 minutes between metoclopramide and ondansetron was ‐2.00 (95% CI ‐8.30 to 4.29) (Analysis 5.1), while for tropisetron it was ‐1.20 (95% CI ‐10.11 to 7.71) (Table 5).
Two trials, involving 204 participants, compared ondansetron with promethazine (Barrett 2011; Braude 2008). From pooled results, the difference in mean VAS rating change (MD) at 30 minutes was 3.16 (95% CI ‐4.29 to 10.60) (Analysis 8.1).
One trial, involving 64 participants, compared ondansetron with prochlorperazine (Patka 2011). The difference in mean VAS rating change (MD) at 30 minutes between ondansetron and prochlorperazine was 6.50 (95% CI ‐8.70 to 21.70) (Table 10). We deemed this trial at high risk of bias (Risk of bias in included studies).
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 64 | Mean Difference (IV, Random, 95% CI [mm]) | 6.50 [‐8.70, 21.70] |
| Proportion of participants requiring rescue medication | 64 | Odds Ratio (M‐H, Random, 95% CI) | 5.74 [0.63, 52.23] |
| Proportion of participants who required hospital admission | 64 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.00 [0.97, 25.77] |
Data from single trial comparing ondansetron versus prochlorperazine (Patka 2011).
CI: confidence interval.
Number of vomiting episodes
Three of the five trials evaluating 5‐HT3 antagonists did not report the number of vomiting episodes within the time frame of interest to this review (Barrett 2011; Braude 2008; Chae 2011). The related findings from Egerton‐Warburton 2014 have been previously described (see 'Comparison of drug versus placebo: Primary outcomes: Number of vomiting episodes'). Patka 2011 reported the proportion of participants vomiting from 0 to 30 minutes and 31 to 60 minutes. This was low for both ondansetron and prochlorperazine (0 to 30 minutes: 2/32 (6%) with ondansetron and 0/32 (0%) with prochlorperazine; 31 to 60 minutes: 0/32 (0%) with ondansetron and 1/32 (3%) with prochlorperazine).
Adverse reactions
All five trials reported adverse events (Barrett 2011; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Patka 2011); however, variability in reporting precluded meaningful pooling of results.
Adverse events from the trials of Barrett 2011; Chae 2011; Egerton‐Warburton 2014 were described in preceding sections (see 'Comparison of drug versus placebo: Primary outcomes: Adverse reactions'). Braude 2008 reported mean change in anxiety and sedation on a VAS from baseline to 30 minutes. For anxiety, the mean changes for ondansetron and promethazine were ‐13 (SD 27) with ondansetron and ‐14 (SD 26) with promethazine (MD ‐1, 95% CI ‐10 to 10). For sedation, the mean changes were less for ondansetron compared with promethazine (5 (SD 25) with ondansetron versus 19 (SD 30) with promethazine; MD 14, 95% CI 5 to 24). Patka 2011 reported no difference in akathisia rates between ondansetron and prochlorperazine (1/32 (3%) with ondansetron versus 3/32 (9%) with prochlorperazine). Sedation scores were also reported to be similar between groups (no details given), while headache scores were reported to be "significantly lower" (P value < 0.05) for prochlorperazine at all time points, but no data were provided.
The result favouring ondansetron over active control was a lower rate of sedation (Braude 2008). The result favouring an active control over ondansetron was a lower headache score for prochlorperazine (Patka 2011).
Secondary outcomes
Proportion of participants requiring rescue medication
Five trials, involving 582 participants, reported the proportion of participants requiring rescue medication (Barrett 2011; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Patka 2011). From pooled results, there was no difference in requirement for rescue medication between 5‐HT3 blockers and any active control (OR 1.47, 95% CI 0.72 to 3.01) (Analysis 6.2).
From the four trials, involving 482 participants, which evaluated ondansetron against any active control, the pooled analysis found a higher requirement for rescue medication for ondansetron than for active control (OR 2.00, 95% CI 1.29 to 3.09) (Analysis 7.2) (Barrett 2011; Braude 2008; Egerton‐Warburton 2014; Patka 2011). This result did not change with exclusion of the study at high risk of bias (Patka 2011).
Three of the trials, involving 353 participants, compared 5‐HT3 blockers with metoclopramide (Barrett 2011; Chae 2011; Egerton‐Warburton 2014). From pooled results, there was no difference in requirement for rescue medication between metoclopramide and 5‐HT3 blockers (OR 0.71, 95% CI 0.20 to 2.50) (Analysis 4.2). Two of these trials, involving 254 participants, compared ondansetron with metoclopramide (Barrett 2011; Egerton‐Warburton 2014). Pooled results showed that more participants in the ondansetron group required rescue medication (OR 0.39, 95% CI 0.22 to 0.68) (Analysis 5.2).
Two trials, involving 207 participants, compared ondansetron with promethazine (Barrett 2011; Braude 2008). Pooled results showed no difference in requirement for rescue medication (OR 1.29, 95% CI 0.70 to 2.37) (Analysis 8.2).
One trial, involving 64 participants, which compared ondansetron with prochlorperazine, reported no difference in requirement for rescue medication (OR 5.74, 95% CI 0.63 to 52.23) (Table 10) (Patka 2011).
Pooled results favoured any active control over ondansetron for requirement for rescue medication (Analysis 7.2). For individual drugs, the only significant result was that favouring metoclopramide over ondansetron (Analysis 5.2).
Proportion of participants who required hospital admission
Two trials, involving 184 participants, compared need for admission between 5‐HT3 blockers and active control (Braude 2008; Patka 2011). Pooled results showed no difference between 5‐HT3 blockers and active control (OR 1.84, 95% CI 0.35 to 9.60) (Analysis 6.3). The result did not change with the exclusion of the trial at high risk of bias (Patka 2011). Separately, Braude 2008 reported the admission rates to be 13/60 (22%) with ondansetron versus 14/60 (23%) with promethazine (OR 0.91, 95% CI 0.39 to 2.14) (Table 11), while Patka 2011 reported admission rates to be 8/32 (25%) with ondansetron versus 2/32 (6%) with prochlorperazine (OR 5.00, 95% CI 0.97 to 25.77) (Table 10).
| Outcome | Participants | Statistical methods | Effect estimate |
| Proportion of participants who required hospital admission | 120 | Odds Ratio (M‐H, Random, 95% CI) | 0.91 [0.39, 2.14] |
| Participant satisfaction | 92 | Odds Ratio (M‐H, Random, 95% CI) | 2.63 [0.76, 9.11] |
Data from single trials comparing ondansetron versus active control.
CI: confidence interval.
Mean or median emergency department length of stay
None of the trials reported the mean or median ED length of stay (Barrett 2011; Braude 2008; Chae 2011; Egerton‐Warburton 2014; Patka 2011).
Participant satisfaction with intervention
Two trials, involving 263 participants, reported participant satisfaction with intervention (Braude 2008; Egerton‐Warburton 2014). Pooled results showed no difference in satisfaction between ondansetron and any active control (OR 1.23, 95% CI 0.36 to 4.22) (Analysis 7.3). Separately, Braude 2008 reported satisfaction to be 40/44 (91%) with ondansetron versus 38/48 (79%) with promethazine (OR 2.63, 95% CI 0.76 to 9.11) (Table 11), while Egerton‐Warburton 2014 reported satisfaction to be 53/86 (61.6%) with metoclopramide versus 46/85 (54.1%) with ondansetron (OR 1.36, 95% CI 0.74 to 2.50) (Table 9).
Comparison of prochlorperazine versus active control
Three trials, involving 219 participants, evaluated prochlorperazine against an active control (Braude 2006; Ernst 2000; Patka 2011).
Primary outcomes
Severity of nausea
Two trials, involving 135 participants, reported the primary outcome of mean VAS rating change for nausea severity from baseline to 30 minutes (Braude 2006; Patka 2011). From pooled results, the difference in mean VAS rating change (MD) at 30 minutes between prochlorperazine and active control was 0.93 (95% CI ‐11.57 to 13.42) (Analysis 9.1).
One trial, involving 84 participants, reported median VAS rating change at 30 and 60 minutes (Ernst 2000). These were 45 with prochlorperazine and 27 with promethazine at 30 minutes, and 60.5 with prochlorperazine and 47 with promethazine at 60 minutes. No variances were reported, but the difference was reported to be statistically significant in favour of prochlorperazine (P value = 0.004 at 30 minutes, and P value < 0.001 at 60 minutes).
One trial compared prochlorperazine with droperidol (46 participants), and metoclopramide (49 participants) (Braude 2006). Results favoured droperidol over prochlorperazine, with a difference in mean VAS rating change (MD) at 30 minutes of 14.00 (95% CI 1.67 to 26.33) (Table 12), but there was no difference between metoclopramide and prochlorperazine (MD 0.30, 95% CI ‐13.12 to 13.72) (Table 7).
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 46 | Mean Difference (IV, Random, 95% CI [mm]) | 14.00 [1.67, 26.33] |
| Proportion of participants requiring rescue medication | 46 | Odds Ratio (M‐H, Random, 95% CI) | 1.91 [0.16, 22.66] |
| Participant satisfaction | 46 | Odds Ratio (M‐H, Random, 95% CI) | 0.50 [0.08, 3.05] |
Data from single trials comparing prochlorperazine versus droperidol.
CI: confidence interval.
One trial, involving 64 participants, compared prochlorperazine with ondansetron (Patka 2011). The difference in mean VAS rating change (MD) at 30 minutes was 6.50 (95% CI ‐8.70 to 21.70) (Table 10).
One result favoured prochlorperazine over promethazine (Ernst 2000). One result favoured droperidol over prochlorperazine (Table 12) (Braude 2006).
Number of vomiting episodes
None of the trials evaluating prochlorperazine reported the number of vomiting episodes. The related findings from Patka 2011 have been previously described (see 'Comparison of 5‐HT3 blockers versus active control: Primary outcomes: Number of vomiting episodes').
Adverse reactions
All three trials reported adverse events (Braude 2006; Ernst 2000; Patka 2011); however, variations in reporting precluded pooling of data. There were no serious adverse events in any of the trials.
Adverse events from Braude 2006 and Patka 2011 have been described in previous sections (see 'Comparison of 5‐HT3 blockers versus active control: Primary outcomes: Adverse reactions'). Ernst 2000 reported identical akathisia rates at 6/42 (14%) with prochlorperazine and promethazine, and drowsiness at 38% with prochlorperazine and 71% with promethazine (difference 33%, 95% CI 13% to 53%; P value = 0.02).
The significant result was of a lower rate of drowsiness for prochlorperazine compared with promethazine (Ernst 2000).
Secondary outcomes
Proportion of participants requiring rescue medication
All three trials, involving 219 participants, reported proportion of participants requiring rescue medication (Braude 2006; Ernst 2000; Patka 2011). From pooled results, there was no difference between prochlorperazine and active control (OR 0.77, 95% CI 0.07 to 8.74) (Analysis 9.2). Exclusion of results from the trial at high risk of bias did not change the result (Patka 2011).
Braude 2006 reported requirement for rescue medication in 1/25 (4%) with metoclopramide compared with 6/24 (25%) with prochlorperazine (OR 0.13, 95% CI 0.01, 1.13) (Table 7), and 1/22 (4%) with droperidol (OR 1.91, 95% CI 0.16 to 22.66) (Table 12). Patka 2011 reported requirement for rescue medication in 5/32 (16%) with ondansetron and 1/32 (3%) with prochlorperazine (OR 5.74, 95% CI 0.63 to 52.23) (Table 10). Ernst 2000 reported requirement for rescue medication in 3/42 (7%) with prochlorperazine and 12/42 (29%) with promethazine (OR 0.19, 95% CI 0.05 to 0.74) (Table 13).
| Outcome | Participants | Statistical method | Effect estimate |
| Proportion of participants requiring rescue medication | 84 | Odds Ratio (M‐H, Random, 95% CI) | 0.19 [0.05, 0.74] |
| Proportion of participants who required hospital admission | 84 | Odds Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 8.22] |
Data from single trials comparing prochlorperazine versus promethazine.
CI: confidence interval.
The only significant result was that fewer participants required rescue medication with prochlorperazine compared with promethazine (Table 13) (Ernst 2000).
Proportion of participants who required hospital admission
Two trials, involving 148 participants, reported proportion of participants who required hospital admission (Ernst 2000; Patka 2011). From pooled results, the difference favoured prochlorperazine versus active control (OR 0.22, 95% CI 0.05 to 0.95) (Analysis 9.3). Exclusion of the trial at high risk of bias did change the result (Patka 2011), since Ernst 2000 reported the difference in proportions requiring admission as OR 0.33 (95% CI 0.01 to 8.22) (Table 13).
Mean or median emergency department length of stay
None of the trials evaluating prochlorperazine reported mean or median ED length of stay (Braude 2006; Ernst 2000; Patka 2011).
Participant satisfaction with intervention
Only one trial reported participant satisfaction (Braude 2006). There was no difference between the groups (20/24 (83%) with prochlorperazine versus 41/47 (87%) with active control; OR 0.73, 95% CI 0.19 to 2.89) (Table 14), or separately between prochlorperazine and droperidol (20/24 (83%) with prochlorperazine versus 20/22 (95%) with droperidol; OR 0.50, 95% CI 0.08 to 3.05) (Table 12), or prochlorperazine and metoclopramide (20/24 (83%) with prochlorperazine versus 21/25 (84%) with metoclopramide; OR 1.05, 95% CI 0.23 to 4.78) (Table 7).
| Outcome | Participants | Statistical method | Effect estimate |
| Participant satisfaction | 71 | Odds Ratio (M‐H, Random, 95% CI) | 0.73 [0.19, 2.89] |
Data from single trials comparing prochlorperazine versus active control.
CI: confidence interval.
Comparison of promethazine versus active control
Three trials, involving 328 participants, evaluated promethazine versus active control (Barrett 2011; Braude 2008; Ernst 2000).
Primary outcomes
Severity of nausea
Two trials, involving 244 participants, reported the primary outcome of mean VAS rating change for nausea severity from baseline to 30 minutes (Barrett 2011; Braude 2008). From pooled results, the difference in mean VAS rating change (MD) at 30 minutes between promethazine and active control was ‐2.17 (95% CI ‐8.99 to 4.66) (Analysis 10.1).
One trial, involving 84 participants, reported median VAS rating change at 30 and 60 minutes (Ernst 2000). These were 45 mm with prochlorperazine and 27 mm with promethazine at 30 minutes, and 60.5 mm with prochlorperazine and 47 mm with promethazine at 60 minutes. No variances were reported, but the difference was reported as being statistically significant in favour of prochlorperazine (P value = 0.004 at 30 minutes, and P value < 0.001 at 60 minutes).
Two trials, involving 204 participants, compared promethazine with ondansetron (Barrett 2011; Braude 2008). From pooled results, difference in mean VAS rating change (MD) to 30 minutes between ondansetron and promethazine was 3.16 (95% CI ‐4.29 to 10.60) (Analysis 8.1).
One trial, involving 83 participants, compared promethazine with metoclopramide (Barrett 2011). The difference in mean VAS rating change (MD) at 30 minutes was 0.10 (95% CI ‐10.06 to 10.26) (Table 6).
The only significant result was that favouring prochlorperazine over promethazine (Ernst 2000).
Number of vomiting episodes
None of the trials reported number of vomiting episodes.
Adverse reactions
All three trials reported adverse events, but variable reporting precluded pooling of results (Barrett 2011; Braude 2008; Ernst 2000). These have been described in detail in previous sections (see 'Comparison of drug versus placebo: Primary outcomes: Adverse reactions' and 'Comparison of prochlorperazine versus active control: Primary outcomes: Adverse reactions'). In brief, Ernst 2000 reported more drowsiness for promethazine versus prochlorperazine (71% with promethazine versus 38% with prochlorperazine; difference 33%, 95% CI 13% to 53%; P value = 0.02), while rates of akathisia were similar at 14% in both groups. Braude 2008 reported more sedation for promethazine versus ondansetron (difference in mean VAS rating at 30 minutes 14, 95% CI 5 to 24). Barrett 2011 reported no difference in sedation at 30 minutes between promethazine and any active control (OR 1.58, 95% CI 0.74 to 3.34).
Secondary outcomes
Proportion of participants requiring rescue medication
Three trials, involving 334 participants, reported proportion of participants requiring rescue medication (Barrett 2011; Braude 2008; Ernst 2000). From pooled results, there was no difference in need for rescue medication between promethazine and active control (OR 1.55, 95% CI 0.58 to 4.14) (Analysis 10.2).
Two trials, involving 207 participants, found no difference between ondansetron and promethazine (OR 1.29, 95% CI 0.70 to 2.37) (Analysis 8.2) (Barrett 2011; Braude 2008).
One trial, involving 88 participants, reported less need for rescue medication with metoclopramide versus promethazine (19/43 (22%) with metoclopramide versus 9/45 (44%) with promethazine (OR 0.36, 95% CI 0.14 to 0.93) (Table 6) (Barrett 2011).
One trial, involving 84 participants, reported less need for rescue medication with prochlorperazine versus promethazine (3/42 (7%) with prochlorperazine versus 12/42 (29%) with promethazine; OR 0.19, 95% CI 0.05 to 0.74) (Table 13) (Ernst 2000).
There was a greater requirement for rescue medication for promethazine in comparison with both metoclopramide (Table 6) (Barrett 2011) and prochlorperazine (Table 13) (Ernst 2000).
Proportion of participants who required hospital admission
Two trials, involving 204 participants, reported proportion of participants who required hospital admission (Braude 2008; Ernst 2000). From pooled results, there was no difference in admission requirement between promethazine and active control (OR 1.18, 95% CI 0.51 to 2.70) (Analysis 10.3). One trial, involving 120 participants, reported no difference in admission requirement between ondansetron and promethazine (13/60 (22%) with ondansetron versus 14/60 (23%) with promethazine; OR 0.91, 95% CI 0.39 to 2.14) (Table 11) (Braude 2008). One trial, involving 84 participants, reported no difference in admission requirement between prochlorperazine and promethazine (0/42 (0%) with prochlorperazine versus 1/42 (2.4%) with promethazine; OR 0.33, 95% CI 0.01 to 8.22) (Table 13) (Ernst 2000).
Mean or median emergency department length of stay
None of the three trials reported mean or median ED length of stay.
Participant satisfaction with intervention
One trial, involving 92 participants, reported participant satisfaction with intervention (Braude 2008). There was no difference between ondansetron and promethazine (40/44 (91%) with ondansetron versus 38/48 (79%) with promethazine; OR 2.63, 95% CI 0.76 to 9.11) (Table 11).
Comparison of droperidol versus active control
One trial, involving 71 participants, evaluated droperidol against active control (Braude 2006).
Primary outcomes
Severity of nausea
Braude 2006 reported the primary outcome of mean VAS rating change for nausea severity from baseline to 30 minutes. From pooled results, the difference in mean VAS rating change (MD) at 30 minutes between droperidol and active control was ‐14.10 (95% CI ‐24.26 to ‐3.94) (Table 15). Separately, the differences in mean VAS rating changes at 30 minutes also favoured droperidol in comparison with metoclopramide (MD 14.30, 95% CI 2.21 to 26.39) (Table 8), and with prochlorperazine (MD 14.00, 95% CI 1.67 to 26.33) (Table 12).
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 71 | Mean Difference (IV, Random, 95% CI [mm]) | ‐14.10 [‐24.26, ‐3.94] |
| Proportion of participants requiring rescue medication | 71 | Odds Ratio (M‐H, Random, 95% CI) | 0.29 [0.03, 2.48] |
| Participant satisfaction | 69 | Odds Ratio (M‐H, Random, 95% CI) | 3.41 [0.39, 29.68] |
Data from single trial by Braude 2006.
CI: confidence interval.
Number of vomiting episodes
The trial did not evaluated number of vomiting episodes.
Adverse reactions
Adverse events for this trial have been previously described (see 'Comparison of drug versus placebo: Primary outcomes: Adverse reactions') (Braude 2006). There were no serious adverse events reported. In brief, the mean changes for anxiety ratings were droperidol ‐25.9 (SD 30.2), metoclopramide ‐25.4 (SD 24.3) and prochlorperazine ‐21.9 (SD 38.8); and for sedation were droperidol 13.5 (SD 32.2), metoclopramide 0.4 (SD 30.1) and prochlorperazine 5.1 (SD 26.5).
Secondary outcomes
Proportion of participants requiring rescue medication
Braude 2006 reported requirement for rescue medication, which was similar for droperidol and active control (1/22 (4.5%) with droperidol versus 7/49 (14%) with active control; OR 0.29, 95% CI 0.03 to 2.48) (Table 15). Separately, 1/22 (4.5%) with droperidol was compared with the 1/25 (4%) with metoclopramide (OR 0.88, 95% CI 0.05 to 14.87) (Table 8) and 6/24 (25%) with prochlorperazine (OR 1.91, 95% CI 0.16 to 22.66) (Table 12).
Proportion of participants who required hospital admission
The trial did not report proportion of participants who required hospital admission.
Mean or median emergency department length of stay
The trial did not report mean or median ED length of stay.
Participant satisfaction with intervention
The trial reported participant satisfaction with intervention (Braude 2006). From pooled results, this was similar between droperidol and active control (20/21 (95%) with droperidol versus 41/48 (85%) with active control; OR 3.41, 95% CI 0.39 to 29.68) (Table 15). Separately, the 20/21 (95%) with droperidol was compared with 21/25 (84%) with metoclopramide (OR 0.53, 95% CI 0.09 to 3.19) (Table 8) and 20/24 (83%) with prochlorperazine (OR 0.50, 95% CI 0.08 to 3.05) (Table 12).
Discusión
Resumen de los resultados principales
Las náuseas y vómitos están presentes con frecuencia en los pacientes en los SU con muchas afecciones diferentes. La administración temprana de fármacos antieméticos es normal, independientemente de la causa subyacente, debido a la naturaleza angustiante de los síntomas y la posibilidad de complicaciones secundarias. Sin embargo, a pesar de la frecuencia del problema clínico, el número limitado de estudios elegibles para inclusión en esta revisión sistemática fue sorprendente. Lo anterior limitó la posibilidad de agrupar los resultados y no fue posible considerar los factores de confusión potenciales como los grupos de diagnóstico primario o la cantidad de líquidos intravenosos administrados.
Luego de aceptar estas limitaciones, esta revisión Cochrane no encontró pruebas convincentes de que ningún fármaco tuviera un efecto clínicamente más significativo que otro fármaco, o que ninguno de los diferentes fármacos fuera superior a placebo. Los tres ensayos con un brazo placebo, individualmente y al agrupar los resultados cuando fue posible, encontraron que no hubo diferencias significativas en las reducciones de la EAV entre placebo y metoclopramida, ondansetrón, proclorperazina o prometazina (Barrett 2011; Braude 2006; Egerton‐Warburton 2014). Para los fármacos individuales versus otro fármaco (control activo), cuando fue posible agrupar los resultados de tres ensayos, junto con los otros cuatro estudios que compararon diferentes fármacos antieméticos(Braude 2008; Chae 2011; Ernst 2000; Patka 2011), las diferencias en las reducciones de la EAV entre los grupos no fueron significativas.
Solamente dos ensayos establecieron conclusiones de superioridad para un fármaco particular (Braude 2006; (Braude 2006; Braude 2006 informó que la reducción en la EAV para droperidol fue significativamente mayor que para metoclopramida, proclorperazina y placebo yErnst 2000 concluyó que la reducción en la EAV para proclorperazina fue significativamente mayor que para prometazina, pero como las reducciones en todos los grupos excedieron la DMCS, la importancia clínica de esta superioridad no está clara. De manera similar, dos de los ensayos que incluyeron un brazo placebo informaron una tendencia estadísticamente no significativa hacia la superioridad para ondansetrón, metoclopramida y prometazina en comparación con placebo(Barrett 2011; Egerton‐Warburton 2014), pero en ambos ensayos el límite inferior del IC del 95% de la reducción de la EAV para placebo todavía excedió la DMCS, por lo que nuevamente la importancia clínica de estas tendencias estadísticas también es dudosa. Aunque puede parecer intuitivo que reducciones estadísticamente mayores se equipararían con mayores beneficios clínicos, no hay bibliografía hasta la fecha que apoye este planteamiento.
En otros contextos se utiliza la reducción del número de episodios de vómitos después del tratamiento (Carlisle 2006), como la medida de resultado primaria, por lo que se incluyó en esta revisión. Este resultado probó no ser una medida útil, ya que en su mayoría los participantes incluidos en los ensayos en el SU solamente presentaron náuseas, y en los tres ensayos que informaron el número de vómitos (Chae 2011; Egerton‐Warburton 2014; Patka 2011), la frecuencia fue tan baja que no fue posible demostrar una reducción significativa en el transcurso de un período de 30 minutos.
La medida de resultado primaria final de eventos adversos mostró resultados variables, pero en general fueron bastante leves y no requirieron tratamientos específicos. No hubo eventos adversos graves en ninguno de los ensayos incluidos. La prometazina se asoció con más sedación o somnolencia en dos ensayos (Braude 2008; Ernst 2000), el ondansetrón con cefaleas (Patka 2011), y la metoclopramida y la proclorperazina con alguna acatisia (Chae 2011; Egerton‐Warburton 2014; Patka 2011), aunque estos efectos fueron relativamente poco habituales y leves. Una revisión sistemática grande sobre fármacos para prevenir las náuseas y vómitos postoperatorios, que informó los efectos adversos de 380 ensayos, encontró que droperidol aumentó el riesgo de somnolencia, a la vez que disminuyó el riesgo de cefalea, y que ondansetrón aumentó el riesgo de cefalea, pero no encontró pruebas de una diferencia en el riesgo de otros efectos adversos (Carlisle 2006).
De las medidas de resultado secundarias consideradas, solamente la administración de fármacos de rescate adicionales se incluyó en todos los ensayos. El número pequeño de ensayos, junto con los resultados variables e inconsistentes, hizo que este resultado fuera de utilidad limitada. Lo anterior puede provenir de una falta de definición en cuanto a lo que se consideró necesidad de fármacos de rescate, ya que en todos los estudios se dejó a la discreción del médico de atención del SU. Es de señalar que el tratamiento con prometazina se asoció con una mayor necesidad de medicación de rescate, y curiosamente los participantes tratados con ondansetrón tuvieron mayores probabilidades de necesitar fármacos de rescate en comparación con control activo o metoclopramida. Pocos ensayos informaron la satisfacción del paciente o las tasas de ingreso hospitalario, y las tasas de ingreso hospitalario no se incluyeron en ninguno de los ensayos con control con placebo. La satisfacción del paciente fue similar con todos los fármacos incluidos en la revisión. Ninguno de los ensayos informó la duración de la estancia hospitalaria en el SU. Es digno de mención que no se demostró la superioridad de los antagonistas 5HT3 en comparación con otras clases en ninguno de los resultados evaluados, lo que quizás contradice la percepción anecdótica frecuente de su efectividad.
Compleción y aplicabilidad general de las pruebas
En general, hubo escasez de ensayos clínicos que evaluaran la efectividad de los fármacos antieméticos para las náuseas y vómitos en el contexto del SU. Menos de 1000 participantes se han evaluado en este contexto. Lo anterior es de cierta manera sorprendente, debido a la frecuencia de los síntomas en el SU y, aunque el tratamiento de la afección con antieméticos en la práctica clínica es muy frecuente, hay poco consenso sobre el tratamiento más apropiado. La interpretación de las pruebas disponibles está obstaculizada por la heterogeneidad clínica, específicamente por la variedad de los diferentes fármacos evaluados en los estudios hasta la fecha, las diferencias en la gravedad inicial y los criterios de inclusión, y la amplia variedad de enfermedades subyacentes que provocan el síntoma náuseas en el contexto del SU. En su mayoría los ensayos incluidos en esta revisión Cochrane tuvieron criterios de inclusión bastante amplios por lo que, aunque se podrían establecer conclusiones generales, la aplicabilidad de los resultados a todos los pacientes con náuseas en el SU, o a subgrupos particulares, aún es incierta. Debido a la escasez relativa de ensayos en el contexto del SU, en ciertas circunstancias puede ser apropiado extrapolar las pruebas de las revisiones sistemáticas en otros contextos (p.ej. náuseas y vómitos en el primer trimestre del embarazo) (Mathews 2010). Los fármacos evaluados en los ocho ensayos incluidos reflejaron la práctica habitual; la metoclopramida se incluyó en cinco ensayos, los antagonistas 5‐HT3 en cuatro, la prometazina en tres, la proclorperazina en dos y el droperidol en uno, pero hay otros agentes y no se estudió la administración de los fármacos en combinación.
También podría debatirse el uso del cambio en la EAV, en el que se basan principalmente las conclusiones de esta revisión. La EAV se ha validado para medir y monitorizar el cambio en la gravedad de las náuseas. Se ha demostrado la alta correlación entre los descriptores adjetivales de la gravedad y los rangos de medición de la EAV, y la DMCS se ha definido como el cambio medio en la EAV cuando los pacientes informan la gravedad del síntoma como "un poco menos". Sin embargo, la investigación sobre la DMCS es algo limitada, pero al parecer la DMCS es mayor en los pacientes con náuseas graves al inicio que en los pacientes con gravedad moderada o leve. En consecuencia, las cifras informadas han variado entre 12 y 30 mm, y al parecer dependen de la gravedad mixta de una población particular. En esta revisión, se señaló que mientras las diferencias en las reducciones de la EAV entre los grupos fueron similares, las reducciones en la EAV informadas para los mismos fármacos en diferentes estudios variaron mucho. En general ocurrió que cuando las calificaciones iniciales de la EAV fueron mayores, las reducciones informadas después del tratamiento, incluso para placebo, fueron mayores. Este resultado parece consistente con los informes de variabilidad en la DMCS en diferentes subgrupos de gravedad y destaca la dificultad de predefinir una única DMCS en poblaciones múltiples. Se estableció un rango medio de DMCS de 15 mm para utilizar en esta revisión que es obviamente problemático, pero como las reducciones en la EAV para todos los tratamientos de todos los estudios excedieron cómodamente esta cifra, parece razonable concluir que los niveles informados de mejoría del paciente fueron clínicamente significativos.
Calidad de la evidencia
En general, la metodología de los ensayos incluidos en la revisión pareció ser adecuada y se informa adicionalmente en la sección Evaluación del riesgo de sesgo en los estudios incluidos. Se consideró que dos ensayos tuvieron alto riesgo de sesgo porque la ocultación fue inadecuada o no informaron adecuadamente ciertos dominios que no fue posible aclarar con los autores (Cham 2004; Patka 2011). Se consideró que los otros ensayos incluidos tuvieron bajo riesgo de sesgo en general, aunque preocupan algunos aspectos metodológicos secundarios.
Sesgos potenciales en el proceso de revisión
Los sesgos potenciales se redujeron al mínimo al realizar una búsqueda exhaustiva de los estudios potencialmente elegibles. No fue posible obtener informes de los ensayos, ni datos suficientes sobre cuatro estudios no publicados identificados mediante la búsqueda en los registros de ensayos clínicos, que pueden introducir alguna posibilidad de sesgo (Friedland 2008; Haensel 2007; Thacker 2003; Thacker 2004).
La heterogeneidad clínica entre los ensayos hizo difícil agrupar los datos de algunos resultados para el metanálisis. La heterogeneidad clínica se debió a que los ensayos incluidos evaluaron diferentes agentes, diferentes dosis y utilizaron diferentes grupos control activos, y solamente tres ensayos incluyeron un brazo control placebo (Barrett 2011; Braude 2006; Egerton‐Warburton 2014). Se presentaron los resultados y el análisis con el modelo de efectos aleatorios de los resultados que compararon fármacos individuales y combinados con controles activos. Hubo falta de datos exhaustivos que compararan diversas dosis de los fármacos incluidos en la revisión, y se consideró que fue poco probable que lo anterior afectara significativamente los resultados. Se considera que las comparaciones presentadas aquí son válidas e informativas.
Dos autores de esta revisión también fueron autores de uno de los estudios incluidos (Egerton‐Warburton 2014). Se redujo al mínimo el sesgo porque la extracción de los datos y la evaluación de la calidad fueron realizadas por un autor no relacionado con el estudio (JF). No hubo desacuerdos con este ensayo en cuanto a la evaluación de la calidad o la extracción de los datos, por lo que no fue necesario que una persona independiente decidiera al respecto.
Acuerdos y desacuerdos con otros estudios o revisiones
No se conoce de alguna otra revisión sistemática anterior sobre el tratamiento de las náuseas y vómitos en el contexto del SU.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 Metoclopramide versus placebo, outcome: 1.1 Change in nausea severity at 30 minutes.
Forest plot of comparison: 3 5HT‐3 Antagonists versus active control, outcome: 6.1 Change in nausea severity at 30 minutes.
Comparison 1 Metoclopramide versus placebo, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 1 Metoclopramide versus placebo, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 1 Metoclopramide versus placebo, Outcome 3 Participant satisfaction.
Comparison 2 Ondansetron versus placebo, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 2 Ondansetron versus placebo, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 3 Metoclopramide versus active control, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 3 Metoclopramide versus active control, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 3 Metoclopramide versus active control, Outcome 3 Participant satisfaction.
Comparison 4 Metoclopramide versus 5HT3 antagonist, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 4 Metoclopramide versus 5HT3 antagonist, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 5 Metoclopramide versus ondansetron, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 5 Metoclopramide versus ondansetron, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 6 5HT3 Antagonists versus active control, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 6 5HT3 Antagonists versus active control, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 6 5HT3 Antagonists versus active control, Outcome 3 Proportion of participants who required hospital admission.
Comparison 7 Ondansetron versus active control, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 7 Ondansetron versus active control, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 7 Ondansetron versus active control, Outcome 3 Participant satisfaction.
Comparison 8 Ondansetron versus promethazine, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 8 Ondansetron versus promethazine, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 9 Prochlorperazine versus active control, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 9 Prochlorperazine versus active control, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 9 Prochlorperazine versus active control, Outcome 3 Proportion of participants who required hospital admission.
Comparison 10 Promethazine versus active control, Outcome 1 Change in nausea severity at 30 minutes.
Comparison 10 Promethazine versus active control, Outcome 2 Proportion of participants requiring rescue medication.
Comparison 10 Promethazine versus active control, Outcome 3 Proportion of participants who required hospital admission.
| Metoclopramide for nausea and vomiting in the emergency department | ||||||
| Patient or population: people with nausea and vomiting Settings: emergency department Comparisons: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Metoclopramide | |||||
| Change in nausea severity at 30 minutes | The mean nausea severity decrease ‐ metoclopramide vs. placebo ranged across control groups from | The mean nausea severity decrease ‐ metoclopramide vs. placebo in the intervention groups was | ‐ | 301 | ⊕⊕⊝⊝ | A larger decrease in nausea severity score indicates better control of symptoms. A difference of > 15 mm is thought to be the 'minimum clinically significant difference' |
| Number of vomiting episodes | See comment | See comment | Not estimable | 301 (3 studies) | See comment | This outcome was not reported in any of the included studies |
| Adverse reactions | See comment | See comment | Not estimable | 301 (3 studies) | See comment | No pooling of results was possible, due to variations in reporting. No studies reported any serious adverse reactions or significant difference in adverse reactions |
| Proportion of participants requiring rescue medication | Study population | OR 0.3 | 299 | ⊕⊕⊝⊝ | An OR < 1 means less need for the medication with metoclopramide | |
| 381 per 1000 | 156 per 1000 | |||||
| Moderate | ||||||
| 363 per 1000 | 146 per 1000 | |||||
| Participant satisfaction with intervention | Study population | OR 1.07 | 216 | ⊕⊕⊝⊝ | An OR < 1 implies better satisfaction with metoclopramide | |
| 657 per 1000 | 672 per 1000 | |||||
| Moderate | ||||||
| 721 per 1000 | 734 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded for imprecision (wide confidence interval and not achieving optimal information size). | ||||||
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 50 | Mean Difference (IV, Random, 95% CI [mm]) | ‐1.80 [‐14.40, 10.80] |
| Proportion of participants requiring rescue medication | 50 | Odds Ratio (M‐H, Random, 95% CI) | 1.83 [0.45, 7.51] |
| Participant satisfaction | 50 | Odds Ratio (M‐H, Random, 95% CI) | 0.91 [0.20, 4.13] |
| Data from single trial comparing prochlorperazine versus placebo (Braude 2006). CI: confidence interval. | |||
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 82 | Mean Difference (IV, Random, 95% CI [mm]) | ‐8.47 [‐19.79, 2.85] |
| Proportion of participants requiring rescue medication | 86 | Odds Ratio (M‐H, Random, 95% CI) | 0.57 [0.24, 1.34] |
| Data from single trial comparing promethazine versus placebo (Barrett 2011). CI: confidence interval. | |||
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 48 | Mean Difference (IV, Random, 95% CI [mm]) | ‐15.80 [‐26.98, ‐4.62] |
| Proportion of participants requiring rescue medication | 48 | Odds Ratio (M‐H, Random, 95% CI) | 0.26 [0.03, 2.54] |
| Participant satisfaction | 48 | Odds Ratio (M‐H, Random, 95% CI) | 1.82 [0.30, 11.02] |
| Data from single trial comparing droperidol versus placebo (Braude 2006). CI: confidence interval. | |||
| Outcome | Participants | Statistical methods | Effect estimate |
| Participant satisfaction | 164 | Odds Ratio (M‐H, Random, 95% CI) | 0.80 [0.43, 1.49] |
| Data from single trials comparing drug versus placebo. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 100 | Mean Difference (IV, Random, 95% CI [mm]) | ‐1.20 [‐10.11, 7.71] |
| Proportion of participants requiring rescue medication | 100 | Odds Ratio (M‐H, Random, 95% CI) | 3.16 [1.03, 9.69] |
| Data from single trials comparing metoclopramide versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 83 | Mean Difference (IV, Random, 95% CI [mm]) | 0.10 [‐10.06, 10.26] |
| Proportion of participants requiring rescue medication | 88 | Odds Ratio (M‐H, Random, 95% CI) | 0.36 [0.14, 0.93] |
| Data from single trials comparing metoclopramide versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 49 | Mean Difference (IV, Random, 95% CI [mm]) | 0.30 [‐13.12, 13.72] |
| Proportion of participants requiring rescue medication | 49 | Odds Ratio (M‐H, Random, 95% CI) | 0.13 [0.01, 1.13] |
| Participant satisfaction | 49 | Odds Ratio (M‐H, Random, 95% CI) | 1.05 [0.23, 4.78] |
| Data from single trials comparing metoclopramide versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 47 | Mean Difference (IV, Random, 95% CI [mm]) | 14.30 [2.21, 26.39] |
| Proportion of participants requiring rescue medication | 47 | Odds Ratio (M‐H, Random, 95% CI) | 0.88 [0.05, 14.87] |
| Participant satisfaction | 47 | Odds Ratio (M‐H, Random, 95% CI) | 0.53 [0.09, 3.19] |
| Data from single trials comparing metoclopramide versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Participant satisfaction | 171 | Odds Ratio (M‐H, Random, 95% CI) | 1.36 [0.74, 2.50] |
| Data from single trials comparing metoclopramide versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 64 | Mean Difference (IV, Random, 95% CI [mm]) | 6.50 [‐8.70, 21.70] |
| Proportion of participants requiring rescue medication | 64 | Odds Ratio (M‐H, Random, 95% CI) | 5.74 [0.63, 52.23] |
| Proportion of participants who required hospital admission | 64 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.00 [0.97, 25.77] |
| Data from single trial comparing ondansetron versus prochlorperazine (Patka 2011). CI: confidence interval. | |||
| Outcome | Participants | Statistical methods | Effect estimate |
| Proportion of participants who required hospital admission | 120 | Odds Ratio (M‐H, Random, 95% CI) | 0.91 [0.39, 2.14] |
| Participant satisfaction | 92 | Odds Ratio (M‐H, Random, 95% CI) | 2.63 [0.76, 9.11] |
| Data from single trials comparing ondansetron versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical methods | Effect estimate |
| Change in nausea severity at 30 minutes | 46 | Mean Difference (IV, Random, 95% CI [mm]) | 14.00 [1.67, 26.33] |
| Proportion of participants requiring rescue medication | 46 | Odds Ratio (M‐H, Random, 95% CI) | 1.91 [0.16, 22.66] |
| Participant satisfaction | 46 | Odds Ratio (M‐H, Random, 95% CI) | 0.50 [0.08, 3.05] |
| Data from single trials comparing prochlorperazine versus droperidol. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Proportion of participants requiring rescue medication | 84 | Odds Ratio (M‐H, Random, 95% CI) | 0.19 [0.05, 0.74] |
| Proportion of participants who required hospital admission | 84 | Odds Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 8.22] |
| Data from single trials comparing prochlorperazine versus promethazine. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Participant satisfaction | 71 | Odds Ratio (M‐H, Random, 95% CI) | 0.73 [0.19, 2.89] |
| Data from single trials comparing prochlorperazine versus active control. CI: confidence interval. | |||
| Outcome | Participants | Statistical method | Effect estimate |
| Change in nausea severity at 30 minutes | 71 | Mean Difference (IV, Random, 95% CI [mm]) | ‐14.10 [‐24.26, ‐3.94] |
| Proportion of participants requiring rescue medication | 71 | Odds Ratio (M‐H, Random, 95% CI) | 0.29 [0.03, 2.48] |
| Participant satisfaction | 69 | Odds Ratio (M‐H, Random, 95% CI) | 3.41 [0.39, 29.68] |
| Data from single trial by Braude 2006. CI: confidence interval. | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 3 | 301 | Mean Difference (IV, Random, 95% CI) | ‐5.27 [‐11.33, 0.80] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 3 | 299 | Odds Ratio (M‐H, Random, 95% CI) | 0.30 [0.17, 0.53] |
| 3 Participant satisfaction Show forest plot | 2 | 216 | Odds Ratio (M‐H, Random, 95% CI) | 1.07 [0.60, 1.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 2 | 250 | Mean Difference (IV, Random, 95% CI) | ‐4.32 [‐11.20, 2.56] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 2 | 247 | Odds Ratio (M‐H, Random, 95% CI) | 0.82 [0.49, 1.37] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 4 | 470 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐4.50, 4.49] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 4 | 469 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.21, 1.73] |
| 3 Participant satisfaction Show forest plot | 2 | 242 | Odds Ratio (M‐H, Random, 95% CI) | 1.24 [0.71, 2.17] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 3 | 356 | Mean Difference (IV, Random, 95% CI) | ‐1.74 [‐6.88, 3.40] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 3 | 353 | Odds Ratio (M‐H, Random, 95% CI) | 0.71 [0.20, 2.50] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 2 | 256 | Mean Difference (IV, Random, 95% CI) | ‐2.00 [‐8.30, 4.29] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 2 | 253 | Odds Ratio (M‐H, Random, 95% CI) | 0.39 [0.22, 0.68] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 5 | 583 | Mean Difference (IV, Fixed, 95% CI) | 2.28 [‐2.03, 6.59] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 5 | 582 | Odds Ratio (M‐H, Random, 95% CI) | 1.47 [0.72, 3.01] |
| 3 Proportion of participants who required hospital admission Show forest plot | 2 | 184 | Odds Ratio (M‐H, Random, 95% CI) | 1.84 [0.35, 9.60] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 4 | 483 | Mean Difference (IV, Random, 95% CI) | 2.61 [‐2.31, 7.53] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 4 | 482 | Odds Ratio (M‐H, Random, 95% CI) | 2.00 [1.29, 3.09] |
| 3 Participant satisfaction Show forest plot | 2 | 263 | Odds Ratio (M‐H, Random, 95% CI) | 1.23 [0.36, 4.22] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 2 | 204 | Mean Difference (IV, Random, 95% CI) | 3.16 [‐4.29, 10.60] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 2 | 207 | Odds Ratio (M‐H, Random, 95% CI) | 1.29 [0.70, 2.37] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 2 | 135 | Mean Difference (IV, Random, 95% CI) | 0.93 [‐11.57, 13.42] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 3 | 219 | Odds Ratio (M‐H, Random, 95% CI) | 0.77 [0.07, 8.74] |
| 3 Proportion of participants who required hospital admission Show forest plot | 2 | 148 | Odds Ratio (M‐H, Random, 95% CI) | 0.22 [0.05, 0.95] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Change in nausea severity at 30 minutes Show forest plot | 2 | 244 | Mean Difference (IV, Random, 95% CI) | ‐2.17 [‐8.99, 4.66] |
| 2 Proportion of participants requiring rescue medication Show forest plot | 3 | 334 | Odds Ratio (M‐H, Random, 95% CI) | 1.55 [0.58, 4.14] |
| 3 Proportion of participants who required hospital admission Show forest plot | 2 | 204 | Odds Ratio (M‐H, Random, 95% CI) | 1.18 [0.51, 2.70] |
