A randomized controlled clinical trial to investigate the efficacy and safety of dexmedetomidine in treating postoperative acute pain.

The uterus is a crucial female reproductive organ, primarily responsible for menstruation and fetal development. It is also a vulnerable area prone to various diseases, with benign conditions being more common, such as uterine leiomyomas, endometrial hyperplasia, and endometriosis. These conditions significantly impact the quality of life and health of patients. Therefore, for patients once diagnosed with a benign uterine disease, medical treatment is essential using scientifically effective methods.[ 1 ] In the treatment of benign uterine tumors, surgical intervention is commonly employed. Myomectomy is the preferred surgical treatment, which removes the tumor to prevent ongoing negative effects. However, for patients with severe conditions, menstrual disturbances, severe anemia, or without fertility requirements, a hysterectomy is recommended.[ 2 3 ] Although this procedure generally yields satisfactory results, it involves trauma for the patient, with high blood loss, prolonged exposure of the abdominal cavity, and a higher risk of postoperative uterine scarring. These complications can greatly affect the postoperative appearance of patients, often leading to dissatisfaction.[ 4 ] In recent years, with the advancement and application of laparoscopic techniques, laparoscopic-assisted surgery has gained popularity for the treatment of benign uterine diseases. Compared to abdominal hysterectomy, laparoscopic surgery offers minimally invasive procedures, providing clear and extensive visual access. The laparoscope’s magnification and exploration capabilities allow for precise identification of pelvic organ abnormalities, prompt diagnosis, and targeted removal of the lesion. Additionally, it avoids exposing the abdominal cavity, minimizing damage to the surrounding tissues and blood vessels, and facilitates more thorough hemostasis, promoting faster postoperative recovery.[ 5 ] This approach is highly versatile, effectively addressing issues such as pelvic adhesions and endometriosis by resolving them without the high trauma of open surgery or the challenges of vaginal procedures. For obese patients, the small incisions of laparoscopic surgery reduce the risk of poor wound healing.[ 6 7 ] However, there are some debates regarding the effectiveness and safety of this procedure.[ 8 ] Our clinical experience reveals that patients often experience acute postoperative pain, which is typically caused by surgical incisions, irritation from damaged internal organs, and discomfort from drainage. This significantly affects the physical well-being of patients. Additionally, surgical trauma and anesthetic drugs can induce a stress response in patients, negatively impacting their prognosis.[ 9 ] Postoperative pain is also a hindrance to healthcare providers in achieving high patient treatment satisfaction. Consequently, effective postoperative pain management is a crucial aspect of surgery, as it helps regulate the neuroendocrine stress responses of patients, reduces the risk of adverse events, and significantly contributes to alleviating postoperative pain and enhancing overall patient medical satisfaction.[ 10 11 ] Therefore, promptly treating postoperative acute pain and selecting anesthesia drugs with proven efficacy and high safety are essential for the postoperative outcomes of patients. The Enhanced Recovery After Surgery (ERAS) protocol not only emphasizes reducing surgical stress and minimizing interference with physiological functions to minimize postoperative complications, promote early patient activity and feeding, and shorten hospital stays but also underscores the significance of postoperative pain management.[ 12 ] Opioids are the primary drugs for treating acute postoperative pain. Multimodal pain management strategies, which employ pain medications or techniques with different mechanisms, such as opioids (e.g., morphine, oxycodone), nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, ketamine, antiepileptic drugs, epidural anesthesia, and transversus abdominis plane (TAP) block, not only enhance pain relief but also reduce the risk of adverse drug reactions, making them the standard approach.[ 12 ] However, opioid-based pain treatment often poses safety concerns, including inadequate postoperative pain control, and side effects such as nausea, vomiting, respiratory depression, bowel obstruction, hyperalgesia, and delirium, which can negatively impact both short-term and long-term recovery.[ 12 ] In recent years, the use of dexmedetomidine in postoperative acute pain management has been gaining attention; however, its efficacy and safety remain controversial, warranting further research.[ 13 ] Dexmedetomidine, a highly selective ɑ2-adrenergic receptor agonist, acts on both the central and peripheral nervous systems, providing sedation, anxiolysis, analgesia, and sympatholytic effects.[ 14 ] Its unique advantages include a lack of respiratory depression within the therapeutic dose range, providing a comfortable and easily reversible sedation. In 1999, the US Foods and Drug Administration (FDA) first approved its use for short-term sedation in mechanically ventilated patients with severe intubation.[ 15 ] The indications expanded in 2008 to include pre-and intraoperative sedation and anesthesia support.[ 16 ] The use of dexmedetomidine during surgery helps maintain perioperative hemodynamics, reduces the need for anesthetic and analgesic drugs, enhances postoperative pain relief, and decreases opioid-related side effects such as nausea and hyperalgesia, ultimately improving patient satisfaction.[ 17 18 ] Although the use of dexmedetomidine is increasingly prevalent, research is scarce on its efficacy and safety for postoperative acute pain, and its findings uniformly need to be supported by more practical studies. Consequently, this study primarily employed a randomized controlled trial to analyze the impact of dexmedetomidine on the stability of vital signs, pain degree, sedation degree, safety, and comprehensive satisfaction for patients with postoperative acute pain. The aim was to provide a reference for selecting pain management strategies for such patients.

This study selected 165 patients who underwent general anesthesia surgeries at our hospital from October 2022 to May 2023 as the research subjects. In this two-parallel RCT study, 150 patients were enrolled based on the inclusion and exclusion criteria. Patients were randomly assigned into two groups using a computer-generated randomization sequence with a 1:1 allocation ratio, generated by a random number table. Each group consisted of 75 patients. Inclusion criteria were patients undergoing general anesthesia laparoscopic total abdominal hysterectomy; patients aged 30 to 50 years; patients with a body mass index (BMI) 18 to 25 kg/m 2 ; patients who met surgical indications for total hysterectomy had benign uterine conditions such as uterine leiomyoma, endometriosis, adenomyosis[ 19 ]; patients with no reproductive need; patients with marked menstrual irregularities; patients with severe anemia; no previous history of relevant surgical treatment. Exclusion criteria: patients with dexmedetomidine allergy or other hypersensitivities; patients with consciousness, coma, mental disorders, and extreme language communication difficulties before or after surgery; patients with a history of substance abuse; patients who refused to follow up; patients with visual and hearing impairment or who still required tube respiratory support at follow-up after surgery; patients who were accepted local anesthesia and patients discharged or transferred before the first day of postoperative follow-up; patients who were unable to understand and complete the VAS scale; patients who were younger than 18 years old; patients who have been taking pain medications for a long time; patients with abnormal electrocardiogram (sinus bradycardia or heart block); patients who were pregnant or breastfeeding; patients with malignant lesions of endometrium, cervix, or other sites. During the study, there were 0 and 1 cases in the experimental and control groups, respectively, where participants dropped out for unknown reasons and did not proceed with follow-up. There was one case in each group where the intervention was voluntarily discontinued. The dropout rate for participants was 2.00% (3 out of 150), resulting in 147 participants who completed the study, with 74 in the experimental group and 73 in the control group. See Figure 1 . Flow chart of management The study protocol was approved by our hospital’s ethics committee (code: 2021[019]). All participants or their relatives signed the written informed consent before recruitment. Patients needed to fast for more than 8 h before surgery. All patients were given 10 mg of diazepam tablets orally the night before surgery to reduce anxiety and fear and ensure good sleep. An intravenous channel was opened in the operating room, and the balanced solution (10 mL/(kg·h) sodium lactate Ringer’s solution) plus hydroxyethyl starch 40 sodium chloride injection (5 mL/(kg·h)) was injected. Blood pressure, electrocardiogram, pulse oxygen saturation, and partial pressure of end-moisture carbon dioxide were routinely monitored. (1) Induction of anesthesia: midazolam 0.03 mg/kg, sufentanil 0.4–0.6 μg/kg, propofol 1.0–1.5 mg/kg, rocuronium 0.8 mg/kg were administered in sequence, and mechanical ventilation was performed after completion. The parameters were set as follows: tidal volume 8–10 mL/kg, suction/breathing ratio 1:2, The ventilation frequency was 12 times/min, and the partial pressure of carbon dioxide at the end of moisture was maintained at 30–40 mmHg (1 mmHg = 0.133 kPa). Experimental group: 1 μg/kg of dexmedetomidine hydrochloride was injected intravenously 15 min after tracheal intubation and then maintained at 0.2–0.6 mg/kg·h until 30 min before the end of surgery. Control group: no special treatment. (2) Anesthesia maintenance: continuous intravenous infusion of propofol 3–6 mg/kg·h, sufentanil 0.15–0.25 μg/(kg·h), cisatracurium 0.1–0.45 mg/kg·h, 1%–2% sevoflurane to maintain the depth of anesthesia. Sevoflurane and sufentanil were stopped 30 min before the end of the operation, propofol was stopped after the operation, and dexmedetomidine 0.02 mg/kg and atropine 0.01 mg/kg were injected intravenously after the recovery of spontaneous breathing. The tracheal intubation was pulled out after the patient was awake and had indications for extubation. All surgical and anesthetic procedures were performed by the same medical team. This study recorded and compared the general clinical data, including preoperative age, BMI, education degree, ASA classification, operation time, disease type, intraoperative bleeding loss, smoking history, and drinking history of the two groups. After surgery, we collected and recorded the patient’s visual analog scale (VAS) score at six specific time points: before surgery (T0), 1 h postoperatively (T1), 6 h postoperatively (T2), 12 h postoperatively (T3), 24 h postoperatively (T4), and 48 h postoperatively (T5). The VAS scale was graded as follows: 0 indicates no pain, a score below 3 denotes mild pain that the patient can tolerate, 4 to 6 signifies moderate pain that affects sleep but is still bearable, and 7 to 10 represents intense pain, unbearable, impacting both appetite and sleep.[ 20 ] After the surgery, we recorded the Ramsay sedation score at six specific time points: before surgery (T0), 1 h postoperatively (T1), 6 h postoperatively (T2), 12 h postoperatively (T3), 24 h postoperatively (T4), and 48 h postoperatively (T5). The Ramsay Scale was rated as follows: 1-agitated, 2-alert and cooperative, calm (adequate sedation), 3-drowsy, responsive to commands (adequate sedation), 4-light sleep, easily awakened (adequate sedation), 5-somnolent, slow to respond to stimuli (over-sedation), and 6-unresponsive, deep sleep (over-sedation).[ 21 ] We employed a monitor to continuously track patient’s vital signs, recording systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and blood oxygen saturation (SpO 2 ) at six specific time points: before surgery (T0), 1 h postoperatively (T1), 6 h postoperatively (T2), 12 h postoperatively (T3), 24 h postoperatively (T4), and 48 h postoperatively (T5). The main adverse reactions included nausea, vomiting, pruritus, low blood pressure, high blood pressure, lower limb paralysis, and their respective grading: Nausea: “No” indicated the absence of nausea or discomfort, whereas “Yes” indicated a feeling of nausea without actual vomiting of stomach contents. Vomiting: “No” indicated the absence of vomiting discomfort; “Yes” indicated the presence of vomiting with gastric contents expelled. level 1: 1–2 episodes of vomiting within 24 h (with a minimum 5-min interval), rated as “mild;” level 2: 3–5 episodes within 24 h (with a minimum 5-min interval), rated as “moderate;” level 3: 6 or more episodes within 24 h (with a minimum 5-min interval, involving nasogastric feeding, intravenous nutrition, or hospitalization), rated as “severe;” level 4: life-threatening and requiring immediate attention, rated as “extremely severe.”[ 22 ] Pruritus: Skin itching was rated on a 0–5 linear scale, where higher numbers indicated increasing severity. 0: no itching, 1–3: mild itching, 4–6: moderate itching, 7–10: severe itching.[ 23 ] Low blood pressure: Hypotension occurred if the drop in BP was more than 25% from the baseline or if SBP was less than 90 mm Hg. High blood pressure: Hypertension was diagnosed if blood pressure exceeded the patient’s pre-anesthesia baseline by 20% or if it rose to 160/95 mm Hg or above. Respiratory depression: Respiratory depression was assessed using arterial blood gas analysis for partial pressure of carbon dioxide (PaCO 2 ) or pulse oximetry (SpO 2 ). A PaCO 2 > 7 kPa, SpO 2 ≤ 90%, or respiratory rate < 10 breaths per minute indicates respiratory depression.[ 24 ] Lower limb paralysis: Lower limb paralysis was evaluated using the modified Bromage scale to assess motor block. A patient with a Bromage score of 1–2 was considered to have lower limb motor impairment, characterized by limb paralysis and movement restrictions. Modified Bromage scale: 0–no motor block, able to lift the thigh, 1–unable to lift the thigh, 2–unable to bend the knee, 3–unable to bend the ankle. The patients self-assessed their pain management, treatment measures, and sleep quality on a scale of satisfaction (satisfied, generally satisfied, unsatisfied), and the reasons for dissatisfaction were recorded. After the follow-up survey was completed by the investigators, the forms were collected and stored centrally. The hospital collected the forms every 2 days, with a trained third-party staff member responsible for double-checking and entering the data into a single-digit Excel spreadsheet, which was then unified and used to establish a database. Statistical analysis was performed using IBM Statistics Version 27.0.1 (SPSS Inc, Beijing, IL, China). Categorical variables should present as n (%) and if data met the criteria of theoretical frequencies greater than 5 and a sample size of at least 40, and comparisons between groups were performed using Pearson’s Chi-square test. First, we performed normality tests for continuous data (histograms and one-sample Shapiro–Wilk test). In the study, continuous variables following a normal distribution are represented as (± s). If data met the assumption of homogeneity of variance, inter-group comparisons were conducted using two independent sample t -tests. If the assumption was not met, Welch’s “ t ” test was employed for group comparison. Quantitative data with a skewed distribution are represented by the median (interquartile range), and the comparison between two groups was conducted using the Mann–Whitney U test for independent samples. For repeated-measures evaluation indicators, if these met the spherical assumption when comparing within or between groups, a two-factor repeated-measures analysis of variance (ANOVA) was employed. If not, the Greenhouse–Geisser and Huynh–Feldt methods were used to perform ε (epsilon) correction. Analysis of the interaction term between groups and time points was conducted to investigate whether there were differences in the change patterns within groups and between groups. If P < 0.05, it suggested a difference in trends over time, indicating that the factors of the two study objects, group and time point, can be tested for separate effects. Pairwise comparisons were then performed for different time points. If P > 0.05, this implied no interaction between the two study objects, and a main effect analysis was conducted, followed by pairwise comparisons. Post-hoc pairwise comparisons were employed in this situation. Differences were considered when P < 0.05 in the comparison.

There were no differences in preoperative age, BMI, education degree, ASA classification, operation time, disease type, intraoperative bleeding loss, smoking history, and drinking history between the two groups ( P > 0.05) [ Table 1 ]. Comparison of general clinical data between the two groups of patients Results expressed as means±SD, or the number of patients and percentage (%); BMI: body mass index; ASA: American Society of Anesthesiologists grading standards The VAS scores of patients in the experimental group were lower compared to those in the control group ( P < 0.05). There was a difference in the VAS score between the two groups at each time point of comparison (Fgroup × time = 6.480, P < 0.001) [ Table 2 ]. Comparison of pain degree between the two groups of patients Results expressed as means±SD; T0: before surgery, T1: 1 h postoperatively, T2: 6 h postoperatively, T3: 12 h postoperatively, T4: 24 h postoperatively; T5: 48 h postoperatively The Ramsay scores of patients in the experimental group were lower than those in the control group ( P < 0.05). There was a difference in the Ramsay score between the two groups at each time point of comparison (Fgroup × time = 11.754, P < 0.001) [ Table 3 ]. Comparison of sedative degree between the two groups of patients Results expressed as means±SD; T0: before surgery, T1: 1 h postoperatively, T2: 6 h postoperatively, T3: 12 h postoperatively, T4: 24 h postoperatively; T5: 48 h postoperatively Compared to the control group, the MAP, SBP, HR, and DBP were lower in the experimental group ( P 0.05). There was a difference in MAP between the two groups at each time point of comparison (Fgroup × time = 1.422, P = 0.230). There was no difference between the six time points for MAP (Ftime = 0.347, P = 0.846). There was a difference between the two groups for MAP (Fgroup = 515.448, P < 0.001). There was a difference in SBP (Fgroup × time = 14.440, P < 0.001). There was a difference in DBP (Fgroup × time = 3.624, P = 0.008). There was no interaction between the two groups and the six time points for HR (Fgroup × time = 0.871, P = 0.483). There was no difference between the six time points for HR (Ftime = 1.170, P = 0.327). There was a difference between the two groups for HR (Fgroup = 528.979, P < 0.001). There was no difference in SpO 2 between the two groups at each time point of comparison (Fgroup × time = 0.338, P = 0.852). There was no difference between the six time points for SpO 2 (Ftime = 0.513, P = 0.726). There was no difference between the two groups for SpO 2 (Fgroup = 0.009, P = 0.926) [ Table 4 ]. Comparison of vital signs between the two groups of patients Results expressed as means±SD; T0: before surgery, T1: 1 h postoperatively, T2: 6 h postoperatively, T3: 12 h postoperatively, T4: 24 h postoperatively; T5: 48 h postoperatively There was no difference in the incidence of adverse reactions between the experimental and control groups ( P = 0.398) [ Table 5 ]. Comparison of incidence of adverse reactions between the two groups of patients Results expressed as the number of patients and percentage (%) 3.6 Comparison of comprehensive satisfaction degree between the two groups of patients. The comprehensive satisfaction degree of patients in the experimental group was higher compared to the control group ( P = 0.015) [ Table 6 ]. Comparison of comprehensive satisfaction degree between the two groups of patients Results are expressed as the number of patients and percentage (%)

In summary, compared to conventional treatment, dexmedetomidine administration for patients with postoperative acute pain effectively regulated vital signs, enhanced treatment efficacy, alleviated pain, improved sedation, ensured safety, facilitated recovery, boosted overall patient satisfaction and reduced the burden on healthcare resources and society. It exhibited clinical value in the prevention and management of postoperative acute pain. Therefore, we recommend its further widespread application in the treatment of patients with postoperative acute pain. Yahui Liu: conceptualization, data curation, funding acquisition, investigation, methodology, writing–original draft; Qingxun Zhang: data curation, writing–original draft; Yang Li: formal analysis, software, writing–original draft; Pu Li: formal analysis, software, writing–original draft; Sha Li: writing–review and editing; Xiao Ma: writing–review and editing; Fupeng Xu: writing–review and editing; Jie Du: supervision, writing–review and editing. All authors have reviewed and approved the final version of the manuscript. This study complies with the Declaration of Helsinki and was approved by the Ethics Committee of Xingtai People’s Hospital (approval number: 2021[019]). Patients provided written informed consent. Data Sharing Statement: The data presented in this study are available on request from the corresponding author. There are no conflicts of interest.

The study findings revealed that the VAS score and Ramsay score of patients in the experimental group were both lower compared to those in the control group. The reason might be that the pain inhibitory system in the human body is located in the spinal cord. Dexmedetomidine, as an α2 receptor agonist, primarily targeted the central nervous system. It is selectively bound to adrenergic receptors, particularly α2 receptors, causing membrane hyperpolarization in the neurons. This led to the activation of α2 receptors on the presynaptic membrane of the spinal dorsal horn, suppressing the release of norepinephrine and thereby reducing the excitability of the central nervous system. It also inhibited the release of excitatory neurotransmitters such as substance P and glutamate, preventing the ascending transmission of noxious stimuli to the brain and even terminating pain signals, thus alleviating postoperative pain. The analgesic effect of dexmedetomidine was reportedly more than eight times that of morphine, enhancing pain relief.[ 25 ] Dexmedetomidine could act on α2 receptors in the locus coeruleus of the brainstem, promoting and maintaining non-rapid eye movement (NREM) sleep, resulting in a tranquil and near-natural state. Unlike benzodiazepines, which primarily targeted GABA receptors for sedation, dexmedetomidine exhibited minimal respiratory depression within therapeutic doses, with only a slight increase in arterial carbon dioxide levels (PaCO 2 ) and a slight decrease in the ventilation rate.[ 13 ] Furthermore, dexmedetomidine was a derivative of the imidazole class, and upon entering the patient’s body, it directly interacted with the central nervous system, demonstrating good selectivity. It is used as an adjunct to general anesthesia in surgical patients enhancing the anesthetic effect.[ 26 27 ] The sedative effect of dexmedetomidine could improve sleep quality, allowing patients to get adequate rest, which in turn alleviated pain at the surgical site exacerbated by sleep disturbances.[ 28 ] Studies have shown that post-anesthesia administration of intravenous dexmedetomidine could alleviate pain at 2 h, 4 h, 6 h, 12 h, and 48 h post-surgery, which was in line with the findings of this study.[ 29 ] This suggested that dexmedetomidine could effectively alleviate pain and enhance the sedation of patients with postoperative acute pain. After general anesthesia, patients often experience fluctuations in hemodynamic stability, which can result in respiratory and circulatory suppression during surgery. In severe cases, this may negatively impact cognitive function, leading to severe postoperative cognitive dysfunction that impedes recovery.[ 30 ] If the anesthesia technique used during treatment inadequately suppresses vital functions such as respiratory and circulatory functions, it can lead to more critical outcomes for the patient. Consequently, it is imperative to employ safer and more reliable anesthesia methods during surgery to ensure patient safety.[ 31 ] The study findings revealed that compared to the control group, the MAP, SBP, HR, and DBP were significantly lower in the experimental group, whereas SpO 2 showed no change. This suggested that dexmedetomidine could effectively manage the vital signs of patients with postoperative acute pain. The reason might be that dexmedetomidine acted on the α2A receptors in the medullary vasomotor center, stimulating parasympathetic neurons in the nucleus ambiguus, resulting in vasodilation, hypotension, and bradycardia. It also interacted with α2B receptors in peripheral blood vessel smooth muscles, causing vasoconstriction.[ 32 ] Simultaneously, dexmedetomidine acted on α2 receptors in the brainstem’s locus coeruleus, contributing to its sedative effect. With a relatively short half-life, it helped maintain hemodynamic stability, playing a crucial role in postoperative recovery.[ 33 ] The study findings revealed that there was no difference in the occurrence of adverse reactions between the experimental and control groups, and the comprehensive satisfaction degree of patients in the experimental group was higher compared to that in the control group. These suggested that dexmedetomidine could effectively ensure safety and enhance the comprehensive satisfaction of patients with postoperative acute pain. The reason might be that dexmedetomidine had a short half-life and did not cause respiratory depression. It worked by suppressing sympathetic nerve function, reducing surgical stress response, and exerting a stabilizing effect on blood pressure and heart rate. It also helped to alleviate anxiety in patients, enhancing their comfort levels during the perioperative period.[ 34 35 ] Previous research has suggested that the use of dexmedetomidine for anesthesia induction can significantly improve postoperative recovery, pain, and sedation in patients undergoing mastectomy.[ 36 ] Another study found that administering dexmedetomidine was beneficial for postoperative cognitive function in elderly patients with hip fractures and can ameliorate oxidative stress and inflammation.[ 37 ] Furthermore, several studies have shown that combining low-dose dexmedetomidine with postoperative intravenous analgesia could reduce the incidence of adverse effects, such as severe hypotension, excessive sedation, respiratory depression, and oxygen desaturation.[ 38 39 40 ] These previous findings were in line with the results of the current study. Consequently, dexmedetomidine could effectively improve cognitive functions in postoperative patients with acute pain, ensuring their safety, mitigating oxidative stress and inflammation, and enhancing overall patient satisfaction. This research primarily highlighted that postoperative acute pain patients treated with dexmedetomidine demonstrated improvements in treatment outcomes, pain relief, sedation, and a more stable vital sign, ensuring safety and enhancing overall satisfaction. It also improved the quality of life of patients, reduced the utilization of healthcare resources, and alleviated societal burdens. It held implications for clinical prevention and management of postoperative acute pain. Due to its single-center design, small sample size, short follow-up, and potential confounders, the study findings might be somewhat susceptible to bias. It was important to note that the incidence of adverse effects such as excessive sedation, severe bradycardia, and hypotension with dexmedetomidine was dose-dependent; hence, it was not advisable to rely on initial doses for pain management. For patients with pre-existing severe hypertension, sinus bradycardia, atrioventricular block, or those taking beta-blockers, these side effects should be monitored carefully.[ 13 ] However, this study has not yet investigated the efficacy and safety of different doses of dexmedetomidine for patients with postoperative acute pain. Additionally, there was a lack of clinical research on the use of dexmedetomidine in specific populations such as the elderly, children, and those with liver or kidney dysfunction, which could be further explored in future studies. These limitations might introduce bias in our findings, necessitating further multi-center, large-sample, prospective, and long-term follow-up studies to confirm the results.