FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000924331> ?p ?o ?g. }

• W2000924331 endingPage "337" @default.
• W2000924331 startingPage "330" @default.
• W2000924331 abstract "The objective was to assess the effect on stress biomarkers of supplemental opioid to a standard propofol dosing protocol for emergency department (ED) procedural sedation (PS). The hypothesis was that there is no difference in the change in serum catecholamines between PS using propofol with or without supplemental alfentanil. This was a randomized, nonblinded pilot study of adult patients undergoing PS in the ED for the reduction of fractures and dislocations. Patients with pain before the procedure were treated with intravenous (IV) morphine sulfate until their pain was adequately treated for at least 20 minutes before starting the procedure. Patients were randomized to receive either 10 μg/kg alfentanil followed by 1 mg/kg propofol, followed by 0.5 mg/kg every 3 minutes as needed, or propofol only, dosed in similar fashion without supplemental alfentanil. Doses, vital signs, nasal end-tidal CO2 (ETCO2), pulse oximetry, and bispectral electroencephalogram (EEG) analysis scores were recorded. Subclinical respiratory depression was defined as a change in ETCO2 > 10 mm Hg, an oxygen saturation of < 92% at any time, or an absent ETCO2 waveform at any time. Clinical events related to respiratory depression were noted during the procedure, including the addition of or increase in the flow rate of supplemental oxygen, the use of a bag–valve–mask apparatus, airway repositioning, or stimulation to induce breathing. Blood was drawn 1 minute prior to the administration of the medications for PS and again 1 minute after completion of the procedure for which the patient was sedated. Serum was tested for total catecholamines, epinephrine, norepinephrine, and dopamine. Postprocedure, patients were asked to report any pain perceived during the procedure. Data were analyzed using descriptive statistics, Wilcoxon rank sum tests, and chi-square tests, as appropriate. Twenty patients were enrolled; 10 received propofol and 10 received propofol with alfentanil. No clinically significant complications were noted. Subclinical respiratory depression was seen in four of 10 (40%) patients in the propofol group and five of 10 (50%) patients in the propofol/alfentanil group (effect size = −10%, 95% confidence interval [CI] = −53% to 33%). There was no difference in the rate of clinical signs of respiratory depression between the two groups. Pain during the procedure was reported by two of 10 (20%) patients in the propofol group and five of 10 (50%) patients in the propofol/alfentanil group (effect size = −30%, 95% CI = −70% to 10%). Recall of some part of the procedure was reported by 0 of 10 (0%) patients in the propofol group and five of 10 (50%) of patients in the propofol/alfentanil group (effect size = −50%, 95% CI = −81% to −19%). There was no difference in the baseline or postprocedure catecholamine levels between the groups. No difference in serum catecholamines was detected immediately after PS between patients who receive propofol with and without supplemental opioid in this small pilot study. PS using propofol only without supplemental opioid did not appear to induce markers of physiologic stress in this small pilot study. Valorar el efecto que, sobre los biomarcadores de estrés, tiene el suplemento de los opioides a un protocolo de propofol con dosis estándar para los procedimientos de sedación (PS) en el servicio de urgencias (SU). La hipótesis fue que no hay diferencias en el cambio de catecolaminas séricas en los PS entre el propofol con y sin suplemento de alfentanilo. Estudio piloto aleatorizado no enmascarado en pacientes adultos en los que se llevó a cabo un PS en el SU para la reducción de fracturas y luxaciones. Los pacientes con dolor antes del procedimiento se trataron con sulfato de morfina IV hasta que su dolor fue adecuadamente controlado al menos durante 20 minutos antes de iniciar el procedimiento. Los pacientes fueron asignados a recibir alfentanilo 10 μg/kg seguido de propofol 1 mg/kg, seguido de 0,5 mg/kg cada tres minutos si fuera necesario; o sólo propofol a dosis similar sin el suplemento de alfentanilo. Se recogieron las dosis, las constantes vitales, el CO2 espiratorio nasal (end-tidal CO2 –ETCO2-), la pulsioximetría y el análisis del electroencefalograma (EEG) biespectral. Se definió la depresión respiratoria subclínica como un cambio en el ETCO2 > 10 mmHg, una saturación de oxígeno < 92% en cualquier momento o una ausencia de la onda de ETCO2 en cualquier momento. Los eventos clínicos relacionados con la depresión respiratoria se anotaron durante el procedimiento, incluyendo la suma de o incremento en el porcentaje de suplemento de flujo de oxígeno, el uso de un dispositivo de ventilación bolsa-válvula-máscara, la reposición de la vía aérea o la estimulación para inducir la respiración. Se obtuvo la sangre un minuto antes de la administración de la medicación para el PS, y otra vez un minuto tras completar el procedimiento para el cual el paciente había sedado. Se midieron en el suero las catecolaminas, la adrenalina, la noradrenalina, y la dopamina. Posteriormente al procedimiento, se preguntó a los pacientes acerca de cualquier dolor percibido durante el procedimiento. Los datos se analizaron usando estadística descriptiva, el test de Wilcoxon y el de la ji-cuadrado, según fuera necesario. Se incluyeron 20 pacientes, 10 pacientes recibieron propofol y 10 recibieron propofol y alfentanilo. No se documentaron complicaciones clínicas significativas. Se vio depresión respiratoria subclínica en 4 de 10 (40%) pacientes en el grupo propofol y en 5 de 10 (50%) pacientes en el grupo propofol/alfentanilo (tamaño del efecto −10%, IC 95% = −53% a 33%). No hubo diferencias en el porcentaje de signos clínicos de depresión respiratoria entre los dos grupos. Se documentó dolor durante el procedimiento en 2 de 10 (20%) pacientes en el grupo propofol y en 5 de 10 (50%) pacientes en el grupo propofol/alfentanilo (tamaño efecto −30%, IC 95% = −70% a 10%). Se documentó recuerdo de alguna parte del procedimiento en 0 de 10 (0%) pacientes en el grupo propofol y 5 de 10 (50%) pacientes en el grupo propofol/alfentanilo (tamaño efecto −50%, IC 95% = −81% a −19%). No hubo diferencias en los niveles de catecolaminas entre el momento inicial y tras el procedimiento entre los grupos. No se detectaron diferencias en las catecolaminas séricas inmediatamente tras el PS entre los pacientes que recibieron propofol con y sin suplemento de opioides en este pequeño estudio piloto. Los PS que usan propofol sólo sin suplemento de opiáceos no parecieron inducir marcadores fisiológicos de estrés. CME Editor: Hal Thomas, MD Authors: James R. Miner, MD, Johanna C. Moore, MS, MD, David Plummer, MD, Richard O. Gray, MD, Sagar Patel, MD, and Jeffrey D. Ho, MD Article Title: Randomized Clinical Trial of the Effect of Supplemental Opioids in Procedural Sedation with Propofol on Serum Catecholamines If you wish to receive free CME credit for this activity, please refer to the website: http://www.wileyblackwellcme.com. Accreditation and Designation Statement: Blackwell Futura Media Services designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Educational Objectives After completing this exercise, the reader will be able to describe the risks and benefits of an opioid in conjunction with propofol for procedural sedation. Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Faculty Disclosures: CME editor – Hal Thomas, MD: No relevant financial relationships to disclose. Authors –James R. Miner, MD, Johanna C. Moore, MS, MD, David Plummer, MD, Richard O. Gray, MD, Sagar Patel, MD, and Jeffrey D. Ho, MD. This manuscript underwent peer review in line with the standards of editorial integrity and publication ethics maintained by Academic Emergency Medicine. The peer reviewers have no relevant financial relationships. The peer review process for Academic Emergency Medicine is double-blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services's Policy on Activity Disclosure and Conflict of Interest. No relevant financial relationships exist for any individual in control of the content and therefore there were no conflicts to resolve. Instructions on Receiving Free CME Credit For information on applicability and acceptance of CME credit for this activity, please consult your professional licensing board. This activity is designed to be completed within an hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Follow these steps to earn credit: This activity will be available for CME credit for twelve months following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months. Patients in the emergency department (ED) undergoing painful procedures, such as orthopedic manipulations, often require moderate or deep procedural sedation (PS) to successfully perform the procedure. This is achieved with the use of sedative agents such as propofol administered at doses that allow patients to maintain airway reflexes and have some response to verbal stimuli (moderate sedation) or to pain (deep sedation). Propofol has been well studied for this purpose and provides adequate sedation to perform procedures successfully with a minimum of cardiorespiratory side effects and a short duration of action.1-4 Propofol has sedative and amnestic properties, but is not thought to have any specific analgesic effect. The clinical significance of procedural pain that a patient experiences, but cannot later recall, is unclear.5 Previous studies have shown that amnesia from propofol lasts a mean of 15.7 minutes in adults who receive 1 mg/kg propofol followed by 0.5 mg/kg until sedated.5 Patients who receive propofol at those doses often demonstrate a response to noxious stimuli during the procedure (such a response is the defining characteristic of deep sedation). Propofol and remifentanil have been shown to have synergistic effects in terms of controlling this response to noxious stimuli, better than either alone.6 Previous work, however, has demonstrated that administering propofol concurrently with opioids may increase the likelihood of respiratory depression.7-10 Alfentanil, an opioid analgesic, is a derivative of fentanyl and has an analgesic potency and duration of action 25% to 33% that of fentanyl.11, 12 The duration of pain relief from a single bolus of 10 μg/kg alfentanil is 7 to 9 minutes, close to the typical duration of PS with propofol in the ED. It is capable of producing sedation, but, like fentanyl, lacks intrinsic amnestic properties.13 Adverse effects of alfentanil include respiratory depression, nausea and vomiting, and skeletal muscle rigidity, which are related to the dose administered.14 Propofol and alfentanil have been studied for PS in multiple settings.15-26 The goal of this study was to compare stress biomarkers between patients undergoing PS with propofol with and without supplemental alfentanil. The primary outcome of this study was the change in serum catecholamines between baseline and immediately after the procedure. Catecholamines are markers of physiologic stress that have been associated with pain, psychosocial stress, and physical exertion.8, 27-31 Secondary outcome measures included the level of sedation achieved, the rate of subclinical respiratory depression, the rate of clinical signs of respiratory depression, the time required for patients to return to baseline mental status after the procedure, the success of the procedure, and the patient-derived outcome factors of perceived pain, recall of the procedure, and satisfaction with the care they received. This was a prospective, randomized, nonblinded clinical trial of propofol alone versus propofol with alfentanil for ED PS of patients undergoing painful orthopedic procedures between September 1, 2010, and January 26, 2011. The study was registered with Clinicaltrials.gov (NCT00997113). The institutional review board of Hennepin County Medical Center approved the study. Patients provided prospective informed consent prior to enrollment. This study was performed at an urban, county medical center with approximately 99,000 ED patient visits per year. In our ED, deep PS with propofol is performed at the discretion of the treating emergency physician. All adult (age ≥ 18 years) ED patients who were to receive deep PS for fracture or dislocation reduction using propofol were eligible for study enrollment. Patients were excluded if they were unable to give consent, had an American Society of Anesthesiologists Physical Assessment Score > 2,32 had a known hypersensitivity to either study medication, were pregnant, or had clinical evidence of intoxication prior to the start of the procedure. Patients with pain prior to PS were treated with intravenous (IV) morphine (0.1 mg/kg IV followed by 0.05 mg/kg IV every 10 minutes as needed and tolerated for pain relief) as soon as possible in their treatment and at least 20 minutes prior to their sedation procedure. Patients were placed on cardiac, blood pressure, pulse oximeter, and nasal sample end-tidal CO2 (ETCO2) monitors, as per standard guidelines for PS in our ED. The ETCO2 monitor (Capnostream 20, Oridion Capnography Inc., Bedford, MA) displays a continuous numerical ETCO2 value and waveform. Additionally, patients were also placed on a bispectral electroencephalogram (EEG) monitor in order to monitor their level of awareness.33, 34 Patients were given supplemental oxygen by face mask prior to the start of the procedure. Baseline values were recorded. One minute prior to receiving medications for PS, patients had blood drawn in order to obtain preprocedure catecholamine levels.28, 29 Patients were then randomized to receive either propofol only as a 1 mg/kg bolus followed by 0.5 mg/kg every 3 minutes as needed for sedation or 10 μg/kg alfentanil IV followed by 1 mg/kg propofol bolus followed by 0.5 mg/kg every 3 minutes as need for sedation. Randomization was achieved by selecting a sequentially numbered sealed envelope containing the group assignment, which had been determined using a computer-generated list of random numbers. Neither patients nor physicians were blinded to the agent being administered. Patients did not receive pain medications other than the study drugs within 20 minutes of the start of the procedure. One minute prior to the administration of the randomized sedation medication, blood was drawn from the patient's IV for catecholamine levels. This was repeated 1 minute after the completion of the procedure for which the patient was sedated. Blood was measured for total catecholamines, epinephrine, norepinephrine, and dopamine. Subclinical respiratory depression was defined as a change from baseline ETCO2 of > 10 mm Hg, an oxygen saturation of < 92% at any time during the procedure, or airway obstruction with cessation of gas exchange at any time (noted by an absent ETCO2 waveform).2, 4, 33, 35, 36 These are criteria we have used to detect subclinical respiratory depression in previous studies of PS. In addition to these objective measures, clinical signs of respiratory depression were detected by specific queries to the physician performing the procedure after its completion, including any addition of or increase in the flow rate of supplemental oxygen, the use of a bag/valve/mask apparatus to increase ventilation, repositioning of the patient's airway to improve ventilation, or stimulation of the patient to induce breathing.37 After the procedure, the physician was asked to note any adverse events experienced by the patient, including but not limited to vomiting or aspiration, intubation, transfer to a higher level of care after the procedure, hypotension (defined as a systolic blood pressure < 100 mmHg), or arrhythmia. The depth of sedation was measured in two ways. A subjective scale, the modified observer's assessment of alertness score (OAAS),38 was used to measure the level of sedation. This is a five-point scale describing the patient's clinical appearance of sedation. The bispectral index monitor was also used in order to add an objective measure. It is an analog EEG that provides a score of 1 to 100, describing the patient's level of alertness.5, 17, 33, 35 Patients with bispectral index scores less than 90 have been found to be amnestic,5 and those with scores less than 70 have been shown to have an increased incidence of respiratory depression.33 After the patients returned to their baseline mental status, they were asked if they felt any pain during the procedure or were able to recall any of the procedure (yes/no).39 They were also asked if they were satisfied with the treatment they received during the procedure. We have previously used visual analog scales to measure these outcome parameters and have obtained scores that did not distribute in a way that allowed comparison, other than as a dichotomous variable. We therefore decided to collect this data in the format in which it would be analyzed.2, 4, 35, 40 During the procedure, pulse oximetry, heart rate, blood pressure, respiratory rate, ETCO2, and bispectral index scores were monitored continuously. The lowest value of each during every 1-minute period was manually recorded by trained research assistants. The OAAS was also recorded every minute. Any loss of ETCO2 waveform or use of airway adjuncts, such as bag–valve–mask-assisted respirations or oral airway placement, was noted. Any clinical signs of respiratory depression were recorded as well. Data were collected by designated research assistants during the procedures and then entered into an Excel (Microsoft Corp., Redmond, WA) database for further analysis. Data were analyzed using STATA 10.0 (StataCorp, College Station, TX). The baseline and postprocedure catecholamine values were compared using Wilcoxon rank sum tests. The changes in catecholamine values were compared using Wilcoxon signed rank tests. The proportions of patients with subclinical respiratory depression, pain, recall, and clinical signs of respiratory depression were compared using 95% confidence intervals (CIs). The time to return of baseline mental status, the bispectral index nadir, and the OAASs were described using medians and interquartile ranges (IQRs). Power analysis was performed using StudySize 2.0 (Crestat HB, Frolunda, Sweden) assuming the use of Wilcoxon rank sum tests. To detect a median total catecholamine value in one group greater than the other two groups 70% of the time, with an alpha of 0.05 and a beta of 0.2 (80% power), power analysis indicated that 10 patients per group were required. This difference was based on our previous work measuring catecholamine levels from acute pain and stress29, 40; we could not find previous work in sedation models using these markers. Thirty-four eligible patients presented during the study period, but 14 underwent sedation before they could be approached for enrollment in the study. Twenty patients were enrolled in the study. Ten patients received propofol and 10 received propofol, with alfentanil. The characteristics of the study subjects are presented in Table 1. The main results for the sedation procedures are described in Table 2. There were no differences in the sedation procedures between the groups except for a higher reported rate of recall among patients in the propofol/alfentanil group (0% vs. 50%, difference = −50%, 95% CI = −81% to −19%). The lowest systolic pressure recorded in the study was 64 mm Hg (median = 100.5 mm Hg, range = 64 to 137 mm Hg) and was not different between the groups. No cardiac rhythm abnormalities, episodes of vomiting or aspiration, intubation, transfers to a higher level of care after the procedure, or arrhythmias were noted during any of the procedures. No patients received naloxone during the procedure. There was no difference in the rate of subclinical respiratory depression between the two groups. There was no difference between the two groups in the number of patients with a change from baseline ETCO2 of > 10 mm Hg or an oxygen saturation of < 92%. There was no difference between the groups in the occurrence of clinical signs of respiratory depression. There was no difference in the maximum recorded heart rate during the procedure between the two groups (Table 2). There was no difference in the baseline catecholamines between the two groups (Table 3), the postprocedure catecholamines (Table 4), or the change in the catecholamines (Table 5). When the changes in catecholamines are compared based on the occurrence of respiratory depression, differences were found for the change in dopamine and the change in norepinephrine (Table 6). Compared to propofol alone, propofol with alfentanil for ED PS did not result in a difference in serum catecholamines that we could detect in this pilot study, indicating that there was not a large difference in physiologic stress between the groups. There were no differences in the depth of sedation, detected respiratory depression, or other complications noted during the procedures, but the study was too small to be able to detect such differences. The lack of supplemental opioid in the propofol-only group, however, did not appear to result in an increase in physiologic signs of stress, in terms of either changes in vital signs or changes in serum catecholamine levels. An increase in dopamine and norepinephrine levels was present among patients who were noted to have respiratory depression, suggesting that the occurrence of respiratory depression may cause physiologic stress. This represents an important area for future investigation. Our study was too small to detect differences in these sedation protocols and was designed to detect large differences in serum catecholamines that would be associated with untreated perceived pain.28, 29 The long-term negative effects of surgical pain and stress, such as increased postprocedure pain and vegetative symptoms, are well described.6, 8, 31, 41, 42 However, this information is based on studies of surgical stress of longer duration and with much more nociceptive stimulus that those typical of procedures for which ED PS and analgesia (PSA) are used. Attempts have been made to extrapolate what is known about the surgical stress response and preemptive analgesia to ED PSA, but very little specific information regarding the risks and benefits of ED PSA is available. Our study attempts to address this issue by determining if a large difference in stress biomarkers could be detected between patients sedated with and without a supplemental opioid. Previous work has shown the need for additional consideration of the increased respiratory depression and procedural time when supplemental opioids are given.9, 43 To justify the use of supplemental opioids for the relief of pain that a patient does not perceive, the benefit must be more than theoretical and at least be comparable to the risk of adding the opioid to the PS protocol. We were unable to detect signs of stress in patients who were not given supplemental opioid for PS that would indicate a benefit of supplemental opioids sufficient to justify the additional risk of respiratory depression associated with their use. All patients who complained of pain prior to the procedure received pain medications, and there were no differences in the amount of presedation pain medications given to patients in either of the two study groups. It is possible that this pain treatment was sufficient to blunt any subsequent stress responses from the procedures. Pain is generally measured by patient report, which reflects a patient's perception of pain rather than a direct measure of nociceptive stimulation. Unperceived painful stimulation also is likely to occur when a patient is sedated, such as when a patient responds to pain but cannot later recall the event.5 Even though the patients may have been in a great deal of pain during the procedure, any differences in the amount of pain a patient experienced and reported while in the study were likely due to pain experienced before and after the procedure in terms of the total amount of pain, determined by the pain's duration and intensity. With the backdrop of the total pain a patient experiences in the ED when he or she has an injury that requires treatment with PS, the brief unperceived pain of the procedure does not appear to be large enough to induce a detectable change in stress biomarkers. This may indicate that the pre- and postprocedural management of pain is a better place to focus efforts at improved patient management and decreases in stress due to pain than in the intraprocedural period. Our study suggests that supplemental opioids during PS with propofol do not appear beneficial in terms of markers of physiologic stress that would have occurred had there been unperceived pain contributing to a surgical stress response. In addition, differences in stress hormones were seen in patients who experienced respiratory depression, indicating that respiratory depression may contribute more to a patient's stress response than procedural pain. This was not a primary focus of this study but will be an important area of for further investigation. While it is possible that patients in the propofol-only group experienced more pain despite not having recall of the pain, this effect is likely to be much smaller than painful procedures typically associated with the surgical stress response and postprocedure hyperalgesia and too small to be reflected in a patients catecholamine levels in our small pilot study.31 We did not find evidence in our study that the addition of opioids to ED PS is necessary to relieve measurable physiologic stress from pain. There are three principal limitations to our trial. We did not blind patients, physicians, or data collectors to the agents used. All of the physicians who enrolled patients in this study are familiar with both propofol and alfentanil and likely had preconceived notions about the two agents’ effects. It is, therefore, very likely that the addition of alfentanil affected the dosing of propofol. We felt that since knowledge of the agents is an important clinical factor in decisions about clinical interventions and sedative dosing, this preconception was an important factor in comparing these clinical protocols. Similarly, patients have preconceived notions of the effect of receiving a dose of pain medication or not, and most studies of pain medication see pain-relieving effects in their placebo arms. Patients in this study were informed whether or not they would receive a supplemental dose of alfentanil. Had patients received blinded doses of placebo in the propofol-only group, the “analgesic effects” of this knowledge itself would have been extended to the propofol-only group, resulting in a less externally valid comparison of these sedation protocols. The second principal limitation is in the outcome measures. In the relative absence of significant adverse outcomes in PS studies of this size, it is unclear what the optimal measures of respiratory depression, safety, and procedural stress are. A wide range of outcome measures have been suggested for sedation research, and all have significant limitations. In the case of subclinical respiratory depression, our criteria have been used in several studies from our institution, and we chose to measure them in this study to maintain internal validity among our studies. In the case of catecholamines for stress, our previous work has shown changes in these levels from stress and pain that varied with the intensity of the stimulus, and we therefore assume that they would detect pain and stress differences in this sedation model.28, 29 The third and principle limitation of our study is its size. There is very little previous work on stress biomarkers in relation to pain. We chose a difference of 70% probability as a significant difference in stress based on the differences we found in previous work on the effects of pain on catecholamine levels.28, 29, 40 This represents a very large difference, however, and the number of patients in our study was not sufficient to detect larger differences. Future work using a large sample may be able to detect smaller differences between changes in catecholamines among the groups. The use of supplemental alfentanil with propofol for procedural sedation did not result in a difference in serum catecholamines associated with pain and stress detectable by this pilot study. There was an increase in dopamine and norepinephrine after the procedure in patients who experienced respiratory depression that warrants further investigation. The addition of supplemental opioid to procedural sedation with propofol does not appear to reduce physiologic stress from unperceived pain during procedural sedation at a level sufficient to detect in this pilot study, suggesting that the addition of supplemental opioids may not induce a large decrease in physiologic stress." @default.
• W2000924331 created "2016-06-24" @default.
• W2000924331 creator A5021307379 @default.
• W2000924331 creator A5022767181 @default.
• W2000924331 creator A5043016347 @default.
• W2000924331 creator A5060919122 @default.
• W2000924331 creator A5075900301 @default.
• W2000924331 creator A5077563307 @default.
• W2000924331 date "2013-04-01" @default.
• W2000924331 modified "2023-09-23" @default.
• W2000924331 title "Randomized Clinical Trial of the Effect of Supplemental Opioids in Procedural Sedation with Propofol on Serum Catecholamines" @default.
• W2000924331 cites W1498333557 @default.
• W2000924331 cites W190441754 @default.
• W2000924331 cites W1968664528 @default.
• W2000924331 cites W1970961086 @default.
• W2000924331 cites W1978883461 @default.
• W2000924331 cites W1982550671 @default.
• W2000924331 cites W2007426911 @default.
• W2000924331 cites W2016117206 @default.
• W2000924331 cites W2034769938 @default.
• W2000924331 cites W2038833653 @default.
• W2000924331 cites W2040057402 @default.
• W2000924331 cites W2042749683 @default.
• W2000924331 cites W2045995579 @default.
• W2000924331 cites W2049289092 @default.
• W2000924331 cites W2053253235 @default.
• W2000924331 cites W2060046000 @default.
• W2000924331 cites W2074396726 @default.
• W2000924331 cites W2079924177 @default.
• W2000924331 cites W2081883495 @default.
• W2000924331 cites W2082921602 @default.
• W2000924331 cites W2086514406 @default.
• W2000924331 cites W2100966332 @default.
• W2000924331 cites W2119200745 @default.
• W2000924331 cites W2123296629 @default.
• W2000924331 cites W2128643063 @default.
• W2000924331 cites W2138487631 @default.
• W2000924331 cites W2139580351 @default.
• W2000924331 cites W2145996826 @default.
• W2000924331 cites W2148853922 @default.
• W2000924331 cites W2409581964 @default.
• W2000924331 cites W39606323 @default.
• W2000924331 cites W4233837547 @default.
• W2000924331 cites W4240297882 @default.
• W2000924331 cites W4240880277 @default.
• W2000924331 cites W4241528477 @default.
• W2000924331 cites W4242282702 @default.
• W2000924331 cites W4245670591 @default.
• W2000924331 cites W4247487567 @default.
• W2000924331 cites W4256676791 @default.
• W2000924331 doi "https://doi.org/10.1111/acem.12110" @default.
• W2000924331 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23701339" @default.
• W2000924331 hasPublicationYear "2013" @default.
• W2000924331 type Work @default.
• W2000924331 sameAs 2000924331 @default.
• W2000924331 citedByCount "16" @default.
• W2000924331 countsByYear W20009243312014 @default.
• W2000924331 countsByYear W20009243312015 @default.
• W2000924331 countsByYear W20009243312016 @default.
• W2000924331 countsByYear W20009243312017 @default.
• W2000924331 countsByYear W20009243312018 @default.
• W2000924331 countsByYear W20009243312019 @default.
• W2000924331 countsByYear W20009243312020 @default.
• W2000924331 countsByYear W20009243312021 @default.
• W2000924331 crossrefType "journal-article" @default.
• W2000924331 hasAuthorship W2000924331A5021307379 @default.
• W2000924331 hasAuthorship W2000924331A5022767181 @default.
• W2000924331 hasAuthorship W2000924331A5043016347 @default.
• W2000924331 hasAuthorship W2000924331A5060919122 @default.
• W2000924331 hasAuthorship W2000924331A5075900301 @default.
• W2000924331 hasAuthorship W2000924331A5077563307 @default.
• W2000924331 hasBestOaLocation W20009243311 @default.
• W2000924331 hasConcept C126322002 @default.
• W2000924331 hasConcept C168563851 @default.
• W2000924331 hasConcept C2776277131 @default.
• W2000924331 hasConcept C2776814716 @default.
• W2000924331 hasConcept C42219234 @default.
• W2000924331 hasConcept C71924100 @default.
• W2000924331 hasConceptScore W2000924331C126322002 @default.
• W2000924331 hasConceptScore W2000924331C168563851 @default.
• W2000924331 hasConceptScore W2000924331C2776277131 @default.
• W2000924331 hasConceptScore W2000924331C2776814716 @default.
• W2000924331 hasConceptScore W2000924331C42219234 @default.
• W2000924331 hasConceptScore W2000924331C71924100 @default.
• W2000924331 hasIssue "4" @default.
• W2000924331 hasLocation W20009243311 @default.
• W2000924331 hasLocation W20009243312 @default.
• W2000924331 hasOpenAccess W2000924331 @default.
• W2000924331 hasPrimaryLocation W20009243311 @default.
• W2000924331 hasRelatedWork W163357817 @default.
• W2000924331 hasRelatedWork W1985198936 @default.
• W2000924331 hasRelatedWork W2001683931 @default.
• W2000924331 hasRelatedWork W20440739 @default.
• W2000924331 hasRelatedWork W2046685379 @default.
• W2000924331 hasRelatedWork W2361468386 @default.
• W2000924331 hasRelatedWork W2373888550 @default.
• W2000924331 hasRelatedWork W2377505480 @default.
• W2000924331 hasRelatedWork W67055460 @default.

• next