http://informahealthcare.com/ptp ISSN: 0959-3985 (print), 1532-5040 (electronic) Physiother Theory Pract, 2015; 31(3): 166–172 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/09593985.2014.991465
RESEARCH REPORT
A randomized clinical trial comparing pulsed ultrasound and erythromycin phonophoresis in the treatment of patients with chronic rhinosinusitis Noureddin Nakhostin Ansari, PhD, PT1, Soofia Naghdi, PhD, PT1, Mojtaba Fathali, MD1, Jim Bartley, FRACS2, and Mohammad Saeed Rastak, MSc, PT1 1
Department of Physiotherapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran and 2Department of Surgery, University of Auckland, Auckland, New Zealand Abstract
Keywords
Therapeutic ultrasound, an important physiotherapy modality, has been used successfully in the treatment of patients with chronic rhinosinusitis (CRS). No study has compared pulsed ultrasound (PUS) with erythromycin phonophoresis (EP). The aim of this randomized, doubleblind, parallel group study with concealed allocation was to compare PUS with EP. Sixty CRS patients were randomly allocated into two groups. Group 1 had PUS and Group 2 had EP. Patients were treated 3 days a week for 10 sessions over 4 weeks. The severity of nine CRS symptoms was self-rated by patients on an ordinal scale of 0–3 (absent, mild, moderate or severe) at baseline and after the 10th treatment session. Individual symptom scores were summed to obtain a ‘‘Total Symptom Score’’ (TSS). The outcome measure included percentage improvement in the TSS. A statistically significant improvement in TSS occurred with both PUS and EP therapy groups (p50.05). The percentage improvement in the EP group was statistically greater than in the PUS group (67.2 versus 49.3%) (p ¼ 0.03). The effect sizes in both therapy groups were large; PUS: d ¼ 1.36 and EP: d ¼ 2.15. EP was found to be superior over PUS therapy.
Physiotherapy, rhinosinusitis, therapeutic ultrasound
Introduction Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the nose and paranasal sinuses affecting approximately one in seven adults in USA (Pleis, Lucas, and Ward, 2009) that is responsible for billions of dollars per year in healthcare expenditures (Benninger et al, 2003; Rosenfeld et al, 2007). One American study analyzing a multiemployer database ranked rhinosinusitis in the top 10 most costly physical health conditions (Goetzel, Hawkins, Ozminkowski, and Wang, 2003). The Rhinosinusitis Task Force has developed a list of major and minor diagnostic criteria (signs and symptoms) that a patient must have experienced for 412 weeks in order to be categorized as suffering from CRS. Major CRS symptoms include facial pain/pressure, nasal obstruction, anterior/posterior nasal drainage and hyposmia. Headache, fatigue and cough are among the minor CRS symptoms. Patients must have two major or one major and two minor symptoms, lasting for 412 weeks, and physical evidence of sinonasal inflammation confirmed by either endoscopic signs or CT scan changes for a diagnosis of CRS (Benninger et al, 2003).
Address correspondence to Dr Noureddin Nakhostin Ansari, PhD, PT, Department of Physiotherapy, School of Rehabilitation, Tehran Unversity of Medical Sciences, Enghelab Ave., Pitch-e-shemiran, Tehran 11489, Iran. E-mail: [email protected]
History Received 23 April 2014 Revised 25 September 2014 Accepted 25 September 2014 Published online 11 December 2014
CRS is considered a multifactorial disease, which can result from anatomic abnormalities, bacterial infection, allergy, air pollution, humoral or immune deficiencies, and genetic factors (Hamilos, 2011). Bacterial biofilms have been implicated in the pathogenesis of CRS, as they are frequently identified on the sinus mucosa (Foreman, Boase, Psaltis, and Wormald, 2012). Ostiomeatal complex (OMC) obstruction secondary to persistent mucosal thickening, which is common in CRS (Dykewicz and Hamilos, 2010) may trigger a vicious cycle of events consisting of mucostasis, mucociliary dysfunction and failure to remove bacteria from the sinuses, that in turn leads to increased inflammation and infection (Ah-See, MacKenzie, and Ah-See, 2012; Kennedy, 2004; Potter and Pawankar, 2012). A treatment goal for CRS patients is to facilitate natural sinus drainage. Typically, medical or surgical interventions are utilized. Currently, medical treatment comprises of a combination of systemic antibiotics and steroids, topical decongestants and nasal saline irrigations (Ah-See, MacKenzie, and Ah-See, 2012; Dykewicz and Hamilos, 2010; Fokkens et al, 2012; Rosenfeld et al, 2007). However, systemic drugs often have unwanted side effects and may be ineffective in many CRS cases (Bartley and Young, 2009; Ponikau, Sherris, Hirohito, and Kern, 2002; Vaughan and Carvalho, 2002). When CRS persists despite repeated drug therapy, surgery may be indicated. The surgical outcome is not always successful (Fokkens et al, 2012). These issues have led investigators to explore alternative strategies for CRS treatment
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(Albu, 2012; Ansari et al, 2013; Bartley and Young, 2009; Naghdi et al, 2013; Nakhostin Ansari, Naghdi, and Farhadi, 2004). Therapeutic ultrasound (US) has been shown to be an effective treatment for both acute rhinosinusitis and CRS (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari, Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi, and Jalaie, 2007; Ansari et al, 2012; Bartley, Ansari, and Naghdi, 2014; Høsøien, Lund, and Vasseljen, 2010; Naghdi, Ansari, and Farhadi, 2008; Rocha et al, 2011; Young, Morton, and Bartley, 2010). Recently, Ansari et al (2013) reported the successful treatment of a woman with CRS using the novel treatment of erythromycin phonophoresis (EP). Theoretically, EP facilitates antibiotic delivery through the skin-enhancing drug delivery to the paranasal sinuses. The purpose of this study was to compare the effect of EP with pulsed ultrasound (PUS) in CRS patients. We hypothesized that the group receiving EP would demonstrate significantly better outcomes.
A trial comparing PUS and EP in patients with CRS
167
Enrollment, n = 80
Pre-treatment examination for eligibility
• Excluded 8 • Did not meet study inclusion criteria, n = 6 • Declined to participate, n=2 Baseline examination/ randomized allocation, n = 72
Methods Study design This trial was a randomized, double-blind, parallel group study with concealed allocation. Approval for this study was obtained from the research deputy and the Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran. The Trial registration number was (www.irct.ir) ID No. IRCT201203273259N2. The methods used have been described previously (Ansari et al, 2012).
PUS group (n=36)
Lost to posttreatment examination (n = 6)
Lost to posttreatment examination (n = 6)
Reasons: 1 Journey 2 Lack of time 1 Catch cold 2 Busy work schedule
Reasons: 1 Journey 1 Lack of time 1 Daily treatment 1 Catch cold 2 Busy work schedule
Participants The study sample included adult patients 18 years of age with the clinical diagnostic criteria (more than or equal to two major symptoms or one major symptom and two minor symptoms) and CT scan findings of CRS, who had failed medical treatment or surgery, and who agreed to participate in the study. Patients with head and neck malignancy or who had a current medical disease for which US was contraindicated were excluded. All participants were recruited and referred by a single Ear, Nose, and Throat (ENT) surgeon. The study was conducted from 22 May 2011 to 11 March 2013 during which patients with CRS were referred to the Physiotherapy Clinic, School of Rehabilitation for US therapy. All patients were informed about the aims of the study, the study procedure and signed an informed consent form.
EP group (n=36)
Outcome analyzed n = 30
Outcome analyzed n = 30
Figure 1. CONSORT flowchart of patients.
for US in patients with CRS (Ansari et al, 2012). Assuming a large effect size (Cohen’s d) of 0.8, for comparison between groups, with two tails, an alpha error probability 0.05, and power 80%, a sample size of 26 patients in each treatment group would give a power of slightly over 80% to obtain statistical significance.
Study sample and demographics From a total of 80 patients screened, 72 satisfied the study inclusion criteria and underwent randomized allocation. Thirtysix patients were enrolled in each of the groups. Six patients dropped out from each group. The drop outs were not due to dissatisfaction with the treatment. Reasons for dropping out were very similar between the two groups. Two patients completed the treatment in the EP group, but did not complete the post-treatment examination because of the journey or lack of time. Figure 1 depicts the CONSORT study flowchart of patients. Sixty patients (43 males, 17 females) with a mean age of 40.5 ± 12.4 years and a mean disease duration of 98.9 ± 86.9 months completed the 4-week study protocol (Table 1). There were no statistically significant differences between the two groups in demographic data (p40.05).
Randomization Following a baseline examination by the ENT surgeon, patients were referred for treatment to the physiotherapy clinic. Patients were randomly assigned to one of two groups, PUS or EP, based on a system of opaque-sealed envelopes, which were mixed and drawn from envelopes in a bowl by the secretary who was not involved in the study. The envelopes contained a letter for the physiotherapist (PT) about patient group allocation. Both the ENT surgeon and the patients were blinded to the type of treatment. The PT who delivered the US was blinded to the results of the examinations. However, the PT was not blinded to the treatment. The erythromycin ointment and the regular US gel had similar tubes. Interventions
Sample size estimation The GPower 3.1.3 software package (Kiel, Germany) was used for performing sample size calculations. Sample size estimation calculations were based on a previously reported large effect size
The US device used for this study was model US-750 (ITO Co., Ltd, Tokyo, Japan). A 1 cm2 US head with an effective radiating area (ERA) of 0.9 cm2 was used. The beam non-uniformity ratio (BNR ¼ spatial peak/spatial average) of 3.6 was very low.
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Table 1. Baseline demographic for patients in the PUS and EP groups. Variables Age (years), mean (SD) Gender, male/female Disease duration to treatment (months), mean (SD) Comorbidities Septum deviation Polyp Asthma Smoker Cyst Previous sinus surgery Combination of two or more comorbidities
PUS group (n ¼ 30)
EP group (n ¼ 30)
39.7 (14.9) 21/9 100.3 (99.4) 18/12 5 3 0 2 1 1 6
41.23 (9.58) 22/8 97.5 (74.2) 22/8 4 2 1 1 4 2 8
p Value 0.64 0.77 0.9 0.27
(t) ( 2) (t) ( 2)
SD, standard deviation; t, independent sample t-test.
The lower BNR indicates that the beam intensity across the ERA is more uniform. PUS (20% duty cycle) at 1 MHz, spatial average/ temporal peak intensity, ISATP of 1.0 or 0.5 W/cm2 for maxillary or frontal sinuses, respectively, was applied coupled with US transmission gel (Sonogel, Bad Camberg, Germany). Each maxillary and frontal sinus was treated for 5 and 4 min, respectively. The US head was applied using small circular movements. The cheek and forehead were treated for maxillary and frontal sinusitis, respectively. The US machine was checked weekly for calibration throughout the study. For the EP, US was administered with erythromycin ointment 5% with a thickness 1–2 mm (prepared by a licensed pharmacist) applied to the treatment area using the same US machine and treatment settings (Ansari et al, 2013). Erythromycin was used because it has been documented to be effective in CRS treatment (Ragab, Lund, and Scadding, 2004; Wallwork et al, 2006). Erythromycin is an antibiotic macrolide which has anti-inflammatory and antimicrobial effects, and can inhibit biofilm formation (Cervin and Wallwork, 2007; Giamarellos-Bourboulis, 2008). All treatments (PUS and EP) were administered by the same PT, three times a week, every other day for 10 treatment sessions. Patients were prescribed no other treatments, and were instructed to refrain from other treatments during the trial. Assessment Eligible patients who agreed to participate in the study were asked to score the severity of their symptoms [facial pain/pressure, headache, nasal obstruction, nasal discharge, post-nasal drip (PND), smell disturbance, fatigue, cough and overall discomfort] on an ordinal scale of 0–3 (absent, mild, moderate or severe) at baseline, and after the 10th treatment session. The scores of the individual symptoms were then summed to obtain the ‘‘Total Symptom Score’’ (TSS) from 0 (no symptoms) to 27 (maximal symptoms). The ENT surgeon also rated CRS severity for each patient using the same scoring of 0–3 based on physical examination and CT scan changes. The ENT surgeon graded the pre-treatment CT scan on each side separately for the maxillary, anterior and posterior ethmoid, sphenoid and frontal sinuses based on a 0–3 system: 0 ¼ clear; 1 ¼ mild or moderate mucosal thickening; 2 ¼ severe mucosal thickening and 3 ¼ total opacification. The OMC was scored as 0 or 3 (not occluded or occluded). The individual sinus scores were added to obtain the total CT score for each side (0 ¼ clear to 18 ¼ total opacification) (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari et al, 2012; Ansari et al, 2013). The total CT score for each patient was obtained by adding the right and left CT scores ranging from 0 ¼ clear to 36 ¼ total opacification.
Outcome measures The main outcome measure was ‘‘percent improvement’’ of the TSS [(pre-treatment total score – post-treatment total score/pretreatment total score) 100] classified as follows: No change (0): 0–15%; Poor (1): 16–35%; Fair (2): 36–60%; Good (3): 61–85% and Excellent (4): 86–100% (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari, Naghdi, and Farhadi, 2007; Ansari et al, 2012; Ansari et al, 2013; Naghdi, Ansari, and Farhadi, 2008; Naghdi et al, 2013). The data were analyzed using SPSS statistical software for Windows 18.0 (SPSS Inc., Chicago, IL). Prior to all analyses, the Kolmogorov–Smirnov test was used to assess the normality of the data. Demographic characteristics of patients were analyzed with the independent t-test (parametric data), or 2 test (nominal data). Descriptive statistics for quantitative variables were calculated as means and standard deviations (SD), and for ordinal variables, median [interquartile range (IQR)] were determined. Between groups comparisons were made using independent t-test and nonparametric statistics of Mann–Whitney U-test where appropriate. The analyses of pre and post within group changes were carried out using paired t-test (quantitative variables), and Wilcoxon signed-rank test (ordinal variables). To measure the magnitude of the treatment effect for total score of symptoms, the Cohen’s d effect sizes were calculated for each group. A p value of 0.05 was accepted as significant.
Results At baseline, CRS severity for the 60 patients was rated by the ENT surgeon as: severe (n ¼ 18); moderate (n ¼ 28) or mild (n ¼ 14) (median ¼ 2, IQR ¼ 2–3) based on the physical findings and the CT scan. The median scores of CRS severity rated by the ENT surgeon for the PUS and EP groups were moderate. The baseline severity of the CRS symptoms was not different between the two groups (Mann–Whitney test, p ¼ 0.76). All patients had pre-treatment CT scans to confirm the diagnosis of CRS. The pre-treatment CT scans (n ¼ 60) revealed that the maxillary and frontal sinuses were affected in 59 and 37 patients, respectively. The OMCs were occluded in 50 patients (Table 2). The pre-treatment median scores of the affected maxillary sinuses and the OMCs on the CT scans were 2 and 3 (occluded), respectively (Table 2). The pre-treatment median scores of the affected right and left frontal sinuses were 1 and 0, respectively. The pre-treatment total mean CT scan scores were not statistically different between the PUS group (17.5 ± 9.7 range 2–35) and the EP group (15.9 ± 9.5 range 2–36) (p ¼ 0.51). The most common pre-treatment symptoms of the final study group (n ¼ 60) were nasal obstruction (90%), post-nasal drip
A trial comparing PUS and EP in patients with CRS
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(90%), nasal discharge (76.7%), fatigue (66.7%), facial pain (63.3%), headache (61.7%), hyposmia (51.7%) and cough (45%). All patients (100%) complained of overall discomfort. Rhinosinusitis Symptom Score Between groups, the mean pre-treatment TSSs were not statistically different between the two groups. However, the mean posttreatment TSS for the EP group was statistically better [mean group difference ¼ 2.50 (95% CI ¼ 0.03–5.03)] than that of the PUS group (t ¼ 1.98, df ¼ 58, p ¼ 0.05). The TSSs for the two groups are given in Table 3. Within groups, the TSSs improved significantly in both the PUS group (t ¼ 7.62, df ¼ 29, p50.001) and in the EP group (t ¼ 11.88, df ¼ 29, p50.001). The effect sizes for both treatment methods were large; PUS: d ¼ 1.36 and EP: d ¼ 2.15. Percent improvement of the TSS The percent improvement of the TSS in the EP group (67.2 ± 23.7) was statistically greater {mean group difference ¼ 17.9 [95% CI of the difference ¼ 34.0–(1.8)]} than in the PUS group (49.3 ± 37.2) (t ¼ 2.22, df ¼ 58, p ¼ 0.03) (Table 3). Symptom improvement classification The frequency of symptom improvement classification (SIC) in both groups is demonstrated in Table 4. The medians (IQR) of SIC for the PUS and EP groups were 2 (1–3) and 3 (2–4), respectively. The frequency of good and excellent improvements in the group treated with the EP was twice than that of the group treated with the PUS (20 versus 10). The severity of symptoms worsened in one patient in the PUS group. There was a statistically significant difference for SIC between the two intervention methods (Mann–Whitney U-test, p ¼ 0.01).
Table 2. Pre-treatment frequency of affected sinuses on the CT scan and median (IQR) scores of sinuses (n ¼ 60). Sinus
Right
Maxillary Frontal Anterior ethmoid Posterior ethmoid Sphenoid OMC
7 2 8 1 5 2 6 1 6 0 7 3
(1–3) (0–2) (1–2) (0–2) (0–1) (0–3)
Left 9 2 (1–2) 5 0 (0–1) 2 1.5 (0–2) 2 1 (0–2) 5 0 (0–1.75) 6 3 (0–3)
Both
Total
43
59
24
37
41
48
34
42
23
34
37
50
Symptoms Before treatment, there were no differences between the two groups in the severity of individual symptoms with the exception of nasal obstruction (Mann–Whitney U-test, p ¼ 0.01). After treatment, headache (p ¼ 0.003), nasal obstruction (p ¼ 0.02) and PND symptoms (p ¼ 0.01) were statistically different between the two groups in favor of the EP group. After treatment, the severity of symptoms was significantly improved in both groups (p50.05) (Table 5). Computed Tomography scan score After treatment, 31 patients voluntarily had sinus CT scans (14 from the PUS group and 17 from the EP group). The posttreatment mean total CT scan scores were not statistically different between the PUS group (12.8 ± 9.7 range 0–34) and the EP group (9.9 ± 8.4 range 0–26) (p ¼ 0.39). The mean percent improvement of CT scan scores in the PUS group and the EP group were not statistically different (30.3 ± 36.0 versus 33.2 ± 55.7) (p ¼ 0.87). Within groups, the total CT scores were significantly improved in both the PUS group (t ¼ 2.65, df ¼ 13, p ¼ 0.02) and the EP group (t ¼ 3.06, df ¼ 16, p ¼ 0.007). Statistical analysis showed no significant differences between the OMC scores pre- and post-treatment between the two groups (p40.05). The change in right OMC score was statistically better in the EP group than in the PUS group (Mann–Whitney U-test, p ¼ 0.046).
Discussion The primary aim of this study was to determine after 10 treatment sessions over 4 weeks whether EP would be more effective than PUS in improving symptoms in CRS patients. The percent improvement in the group receiving EP was significantly higher than the PUS group. Interestingly, the effect sizes in both groups were large, and the effect size in the group receiving EP was larger than that in the PUS group at post-test. To the authors’ knowledge, this is the first study to compare the efficacy of PUS and EP to treat symptoms in CRS patients. It has previously been reported that therapeutic US in either continuous or pulsed mode is effective in treating symptoms of patients with acute rhinosinusitis (Høsøien, Lund, and Vasseljen, 2010) or CRS (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari, Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi, and Jalaie, 2007; Ansari et al, 2012; Ansari et al, 2013; Naghdi, Ansari, and Farhadi, 2008; Nakhostin Ansari, Naghdi, and Farhadi, 2004; Rocha et al, 2011; Young, Morton, and Bartley, 2010). Overall, the results found in this study agree with prior reports. These findings are clinically important because they provide evidence that patients with CRS unresponsive to medical treatments may benefit from US therapy. The TSS improved using both PUS and EP methods of treatment; again the effect was significantly larger in the EP group at the end of 4 weeks treatment. In this study, the treatment groups
Table 3. Sinusitis Symptom Score and percent improvement for the PUS group and EP group. PUS
EP
Symptoms
Mean (SD)
Range
Mean (SD)
Range
p Value
Pre-treatment total score Post-treatment total score Percent improvement
14.9 (5.3) 7.3 (5.7) 49.3 (37.2)
7–27 0–27 85.7–100
14.2 (4.8) 4.8 (3.9) 67.2 (23.7)
3–21 0–16 12.5–100
0.59 0.05 (t)a 0.03 (t)a
a
169
Statistically significant between the two groups. t, independent sample t-test.
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were comparable in the demographic and pre-test clinical characteristics. The significant better post-test TSS and percent improvement in the EP group compared with the PUS group suggests that EP offers benefits over the PUS method in the treatment of CRS patients. We used the TSS because the SNOT-20 score had not been validated in Persian when this study was designed. The SNOT-20 has been recently translated and validated in the Persian language (Naghdi, Anjei, Ansari, and Fathali, 2013). The SNOT20 is a valid disease-specific, health-related quality-of-life questionnaire consisting of 20 nose, sinus and general items to assess problems associated with rhinosinusitis (Piccirillo, Merritt, and Richards, 2002). In this study, the application of PUS alone or EP led to the significant individual improvement of symptoms and better posttreatment TSS in this sample of patients with CRS. Inflammation and biofilm infection have been implicated in the pathophysiology of CRS (Fokkens et al, 2012; Madeo and Frieri, 2013). Bacterial biofilms are a complex community of bacteria that form on both biotic and abiotic surfaces contained in a hydrated polymeric matrix (Costerton, Stewart, and Greenberg, 1999; Smith, Buchinsky, and Post, 2011). A recent review has reported that 11 studies have detected bacterial biofilms in sinus mucosa samples obtained in CRS patients, providing evidence that the microbial biofilms may be an important factor in CRS pathogenesis (Foreman, Boase, Psaltis, and Wormald, 2012). Bacterial biofilms are highly recalcitrant to conventional antibiotics, and even surgery. Given that therapeutic US has been demonstrated to have antiinflammatory effects (Chung et al, 2012; Karosi, Sziklai, and Csomor, 2013); analgesic effects (Baker, Robertson, and Duck, 2001) and can destroy bacteria biofilms (Bartley and Young, 2009; Høsøien, Lund, and Vasseljen, 2010), it can be hypothesized that the therapeutic US used in the current study is in agreement with previously published investigations suggesting reduced inflammation and disrupted bacterial biofilms resulted in an improvement in CRS symptoms (Ansari, Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi, and Jalaie, 2007; Ansari et al,
2012; Naghdi, Ansari, and Farhadi, 2008; Young, Morton, and Bartley, 2010). US’s mechanical vibratory effects may restore cell membrane permeability and thus enhance the natural resolution of the innate anti-inflammatory tissue reactions. Low-intensity US has been recently shown to have an anti-inflammatory effect in an animal model reducing inflammatory markers in the synovium via a reduction in inflammatory cell infiltrate (Chung et al, 2012). In surgically removed nasal polyps, low-frequency US treatment decreased the number of inflammatory cells in the sub-epithelial and stromal layers (Karosi, Sziklai, and Csomor, 2013). Given the vital role the OMC plays in clearing mucosa of the sinuses, it is possible that the US by reduction of inflammation (Bartley, Ansari, and Naghdi, 2014) could facilitate sinus drainage and promote sinus healing and bacterial removal. There is no standard treatment for CRS (Cain and Lal, 2013). ENT physicians commonly prescribe prolonged courses of oral antibiotics as a significant component of the medical treatment of patients with CRS (Bhattacharyya, 2003; Fokkens et al, 2012; Kaszuba and Stewart, 2006). However, the efficacy of antibiotics is not strongly supported by high-level studies (Cain and Lal, 2013; Fokkens et al, 2012; Mandal, Patel, and Ferguson, 2012). Furthermore, prolonged antibiotic administration may cause systemic side effects some of which include bacterial resistance, allergic reactions and gastrointestinal disturbances (Albu, 2012). Phonophoresis is a non-invasive method used in physiotherapy to deliver drugs locally to treat various diseases. In this technique, US can be used as a physical enhancer for transdermal drug delivery to enhance drug distribution to the paranasal sinuses (Ansari et al, 2013). The advantage of local drug delivery to the paranasal sinuses using phonophoresis is that the rate and concentration of drug transport to the target site can be increased and subsequently drug effectiveness can be enhanced. US, by its mechanical action, could disrupt biofilms enough to enhance the antibacterial actions of both extrinsic (drug) and intrinsic (body) mechanisms (Bartley, Ansari, and Naghdi, 2014). The difference between the two groups on the percent improvement of TSS indicated that the EP is more effective in improving CRS symptoms than PUS alone. The statistically
Table 4. Frequency of symptoms improvement classification in both the PUS group and EP group. Improvement classification Groups PUS EP
Worse
No change (0–15%)
Poor (16–35%)
Fair (36–60%)
Good (61–85%)
Excellent (86–100%)
1 0
1 1
8 1
10 8
5 12
5 8
p Value 0.01 (M)a
a
Statistically significant between the two groups. M, Mann–Whitney test. Table 5. Median (IQR) scores for symptoms pre- and post-treatment in both the PUS group and EP group. PUSa Symptom Facial pain Headache Nasal obstruction Nasal discharge Post nasal drip Smell disturbance Fatigue Cough Overall discomfort a
EPa
Pre 1 1.5 2.5 2 2 0.5 2 0 2.5
(0–2.25) (0–3) (2–3)c (1–3) (2–3) (0–2.25) (0–3) (0–1) (2–3)
Post 0 0 1 0.5 1 0 0 0 1
(0–1) (0–1) (0–2) (0–1) (0.75–2) (0–1) (0–2) (0–0) (1–2)
Pre 1 1 2 1 2 1 2 0 3
(0–3) (0–3) (1–3)c (0–3) (1–3) (0–3) (0–3) (0–1.25) (2–3)
Post 0 0 0 0 0 0 0 0 1
(0–0) (0–0)b (0–1)b (0–1) (0–1)b (0–1.25) (0–1) (0–0.25) (0–2)
Within group significant improvement in severity of all symptoms after treatment with both methods (Wilcoxon signed-rank test, p50.05). bSignificant between the two groups after treatment (Mann–Whitney U-test, p50.05). cSignificant between the two groups at baseline (Mann–Whitney U-test, p ¼ 0.01).
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significant differences between two groups may be due to the high concentration of erythromycin delivered through phonophoresis through a synergistic action with 1 MHz US (Mitragotri, Edwards, Blankschtein, and Langer, 1995; Qian, Sagers, and Pitt, 1999). The enhanced erythromycin delivery to the sinuses may be explained by the fact that 5% erythromycin ointment has similar acoustic impedance with the skin, which minimized the US reflection and facilitated the drug delivery (Polat, Hart, Langer, and Blankschtein, 2011). The enhanced erythromycin delivery to the sinuses may also be explained by the likelihood of increased antibiotic concentrations in the superficial facial tissues that result from phonophoresis. The posterior superior alveolar and infraorbital arteries supply both the maxillary sinus and overlying soft tissue (Rosano, Taschieri, Gaudy, and Del Fabbro, 2009; Traxler et al, 1999). The supraorbital and supratrochlear arteries supply the forehead region and the frontal sinuses (Mafee, Valvassori, and Becker, 2005). The phonophoresis may increase blood flow, and the arterial blood vessels may be the most direct route by which antibiotic in cells and fluid compartments of the superficial facial tissues could arrive in the mucosa lining the interior of the maxillary and frontal sinuses (Ansari et al, 2013). The sinuses are continuous with the nasal passages. EP or PUS applied for either maxillary or frontal sinuses could improve the state of the OMC contributing to an overall improvement. The enhanced effects of EP compared with the PUS could also be due to the antibacterial as well as anti-inflammatory effects of both erythromycin and PUS. Study limitations Limitations of the study are acknowledged. The comparison of two treatments without a third control group does not allow for the calculation of relative effect sizes. We also acknowledge that erythromycin may not be the most appropriate antibiotic for every patient with CRS, and that alternative preparations may not be suitable for topical application via EP. The effective concentrations of the antibiotic were not measured. Another limitation is that the patients were not subcategorized to CRS with and without nasal polyp. The follow-up period was insufficient.
Conclusions EP, compared to the PUS, illustrated significantly higher percent improvement and larger effect size after 10 treatment sessions over 4 weeks. Large effect sizes for both treatment methods provide further evidence that therapeutic US may be specifically used to treat symptoms in patients with CRS.
Acknowledgments The authors thank the patients for their participation in this study.
Declaration of interest The authors report no conflicts of interest. This study was supported by Research Deputy, Tehran University of Medical Sciences (Grant No. 10200).
References Ah-See KL, MacKenzie J, Ah-See KW 2012 Management of chronic rhinosinusitis. BMJ 345: e7054. Albu S 2012 Novel drug-delivery systems for patients with chronic rhinosinusitis. Drug Design, Development and Therapy 6: 125–132. Ansari NN, Fathali M, Naghdi S, Bartley J, Rastak MS 2013 Treatment of chronic rhinosinusitis using erythromycin phonophoresis. Physiotherapy Theory and Practice 29: 159–165.
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RESEARCH REPORT
A randomized clinical trial comparing pulsed ultrasound and erythromycin phonophoresis in the treatment of patients with chronic rhinosinusitis Noureddin Nakhostin Ansari, PhD, PT1, Soofia Naghdi, PhD, PT1, Mojtaba Fathali, MD1, Jim Bartley, FRACS2, and Mohammad Saeed Rastak, MSc, PT1 1
Department of Physiotherapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran and 2Department of Surgery, University of Auckland, Auckland, New Zealand Abstract
Keywords
Therapeutic ultrasound, an important physiotherapy modality, has been used successfully in the treatment of patients with chronic rhinosinusitis (CRS). No study has compared pulsed ultrasound (PUS) with erythromycin phonophoresis (EP). The aim of this randomized, doubleblind, parallel group study with concealed allocation was to compare PUS with EP. Sixty CRS patients were randomly allocated into two groups. Group 1 had PUS and Group 2 had EP. Patients were treated 3 days a week for 10 sessions over 4 weeks. The severity of nine CRS symptoms was self-rated by patients on an ordinal scale of 0–3 (absent, mild, moderate or severe) at baseline and after the 10th treatment session. Individual symptom scores were summed to obtain a ‘‘Total Symptom Score’’ (TSS). The outcome measure included percentage improvement in the TSS. A statistically significant improvement in TSS occurred with both PUS and EP therapy groups (p50.05). The percentage improvement in the EP group was statistically greater than in the PUS group (67.2 versus 49.3%) (p ¼ 0.03). The effect sizes in both therapy groups were large; PUS: d ¼ 1.36 and EP: d ¼ 2.15. EP was found to be superior over PUS therapy.
Physiotherapy, rhinosinusitis, therapeutic ultrasound
Introduction Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the nose and paranasal sinuses affecting approximately one in seven adults in USA (Pleis, Lucas, and Ward, 2009) that is responsible for billions of dollars per year in healthcare expenditures (Benninger et al, 2003; Rosenfeld et al, 2007). One American study analyzing a multiemployer database ranked rhinosinusitis in the top 10 most costly physical health conditions (Goetzel, Hawkins, Ozminkowski, and Wang, 2003). The Rhinosinusitis Task Force has developed a list of major and minor diagnostic criteria (signs and symptoms) that a patient must have experienced for 412 weeks in order to be categorized as suffering from CRS. Major CRS symptoms include facial pain/pressure, nasal obstruction, anterior/posterior nasal drainage and hyposmia. Headache, fatigue and cough are among the minor CRS symptoms. Patients must have two major or one major and two minor symptoms, lasting for 412 weeks, and physical evidence of sinonasal inflammation confirmed by either endoscopic signs or CT scan changes for a diagnosis of CRS (Benninger et al, 2003).
Address correspondence to Dr Noureddin Nakhostin Ansari, PhD, PT, Department of Physiotherapy, School of Rehabilitation, Tehran Unversity of Medical Sciences, Enghelab Ave., Pitch-e-shemiran, Tehran 11489, Iran. E-mail: [email protected]
History Received 23 April 2014 Revised 25 September 2014 Accepted 25 September 2014 Published online 11 December 2014
CRS is considered a multifactorial disease, which can result from anatomic abnormalities, bacterial infection, allergy, air pollution, humoral or immune deficiencies, and genetic factors (Hamilos, 2011). Bacterial biofilms have been implicated in the pathogenesis of CRS, as they are frequently identified on the sinus mucosa (Foreman, Boase, Psaltis, and Wormald, 2012). Ostiomeatal complex (OMC) obstruction secondary to persistent mucosal thickening, which is common in CRS (Dykewicz and Hamilos, 2010) may trigger a vicious cycle of events consisting of mucostasis, mucociliary dysfunction and failure to remove bacteria from the sinuses, that in turn leads to increased inflammation and infection (Ah-See, MacKenzie, and Ah-See, 2012; Kennedy, 2004; Potter and Pawankar, 2012). A treatment goal for CRS patients is to facilitate natural sinus drainage. Typically, medical or surgical interventions are utilized. Currently, medical treatment comprises of a combination of systemic antibiotics and steroids, topical decongestants and nasal saline irrigations (Ah-See, MacKenzie, and Ah-See, 2012; Dykewicz and Hamilos, 2010; Fokkens et al, 2012; Rosenfeld et al, 2007). However, systemic drugs often have unwanted side effects and may be ineffective in many CRS cases (Bartley and Young, 2009; Ponikau, Sherris, Hirohito, and Kern, 2002; Vaughan and Carvalho, 2002). When CRS persists despite repeated drug therapy, surgery may be indicated. The surgical outcome is not always successful (Fokkens et al, 2012). These issues have led investigators to explore alternative strategies for CRS treatment
DOI: 10.3109/09593985.2014.991465
(Albu, 2012; Ansari et al, 2013; Bartley and Young, 2009; Naghdi et al, 2013; Nakhostin Ansari, Naghdi, and Farhadi, 2004). Therapeutic ultrasound (US) has been shown to be an effective treatment for both acute rhinosinusitis and CRS (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari, Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi, and Jalaie, 2007; Ansari et al, 2012; Bartley, Ansari, and Naghdi, 2014; Høsøien, Lund, and Vasseljen, 2010; Naghdi, Ansari, and Farhadi, 2008; Rocha et al, 2011; Young, Morton, and Bartley, 2010). Recently, Ansari et al (2013) reported the successful treatment of a woman with CRS using the novel treatment of erythromycin phonophoresis (EP). Theoretically, EP facilitates antibiotic delivery through the skin-enhancing drug delivery to the paranasal sinuses. The purpose of this study was to compare the effect of EP with pulsed ultrasound (PUS) in CRS patients. We hypothesized that the group receiving EP would demonstrate significantly better outcomes.
A trial comparing PUS and EP in patients with CRS
167
Enrollment, n = 80
Pre-treatment examination for eligibility
• Excluded 8 • Did not meet study inclusion criteria, n = 6 • Declined to participate, n=2 Baseline examination/ randomized allocation, n = 72
Methods Study design This trial was a randomized, double-blind, parallel group study with concealed allocation. Approval for this study was obtained from the research deputy and the Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran. The Trial registration number was (www.irct.ir) ID No. IRCT201203273259N2. The methods used have been described previously (Ansari et al, 2012).
PUS group (n=36)
Lost to posttreatment examination (n = 6)
Lost to posttreatment examination (n = 6)
Reasons: 1 Journey 2 Lack of time 1 Catch cold 2 Busy work schedule
Reasons: 1 Journey 1 Lack of time 1 Daily treatment 1 Catch cold 2 Busy work schedule
Participants The study sample included adult patients 18 years of age with the clinical diagnostic criteria (more than or equal to two major symptoms or one major symptom and two minor symptoms) and CT scan findings of CRS, who had failed medical treatment or surgery, and who agreed to participate in the study. Patients with head and neck malignancy or who had a current medical disease for which US was contraindicated were excluded. All participants were recruited and referred by a single Ear, Nose, and Throat (ENT) surgeon. The study was conducted from 22 May 2011 to 11 March 2013 during which patients with CRS were referred to the Physiotherapy Clinic, School of Rehabilitation for US therapy. All patients were informed about the aims of the study, the study procedure and signed an informed consent form.
EP group (n=36)
Outcome analyzed n = 30
Outcome analyzed n = 30
Figure 1. CONSORT flowchart of patients.
for US in patients with CRS (Ansari et al, 2012). Assuming a large effect size (Cohen’s d) of 0.8, for comparison between groups, with two tails, an alpha error probability 0.05, and power 80%, a sample size of 26 patients in each treatment group would give a power of slightly over 80% to obtain statistical significance.
Study sample and demographics From a total of 80 patients screened, 72 satisfied the study inclusion criteria and underwent randomized allocation. Thirtysix patients were enrolled in each of the groups. Six patients dropped out from each group. The drop outs were not due to dissatisfaction with the treatment. Reasons for dropping out were very similar between the two groups. Two patients completed the treatment in the EP group, but did not complete the post-treatment examination because of the journey or lack of time. Figure 1 depicts the CONSORT study flowchart of patients. Sixty patients (43 males, 17 females) with a mean age of 40.5 ± 12.4 years and a mean disease duration of 98.9 ± 86.9 months completed the 4-week study protocol (Table 1). There were no statistically significant differences between the two groups in demographic data (p40.05).
Randomization Following a baseline examination by the ENT surgeon, patients were referred for treatment to the physiotherapy clinic. Patients were randomly assigned to one of two groups, PUS or EP, based on a system of opaque-sealed envelopes, which were mixed and drawn from envelopes in a bowl by the secretary who was not involved in the study. The envelopes contained a letter for the physiotherapist (PT) about patient group allocation. Both the ENT surgeon and the patients were blinded to the type of treatment. The PT who delivered the US was blinded to the results of the examinations. However, the PT was not blinded to the treatment. The erythromycin ointment and the regular US gel had similar tubes. Interventions
Sample size estimation The GPower 3.1.3 software package (Kiel, Germany) was used for performing sample size calculations. Sample size estimation calculations were based on a previously reported large effect size
The US device used for this study was model US-750 (ITO Co., Ltd, Tokyo, Japan). A 1 cm2 US head with an effective radiating area (ERA) of 0.9 cm2 was used. The beam non-uniformity ratio (BNR ¼ spatial peak/spatial average) of 3.6 was very low.
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Table 1. Baseline demographic for patients in the PUS and EP groups. Variables Age (years), mean (SD) Gender, male/female Disease duration to treatment (months), mean (SD) Comorbidities Septum deviation Polyp Asthma Smoker Cyst Previous sinus surgery Combination of two or more comorbidities
PUS group (n ¼ 30)
EP group (n ¼ 30)
39.7 (14.9) 21/9 100.3 (99.4) 18/12 5 3 0 2 1 1 6
41.23 (9.58) 22/8 97.5 (74.2) 22/8 4 2 1 1 4 2 8
p Value 0.64 0.77 0.9 0.27
(t) ( 2) (t) ( 2)
SD, standard deviation; t, independent sample t-test.
The lower BNR indicates that the beam intensity across the ERA is more uniform. PUS (20% duty cycle) at 1 MHz, spatial average/ temporal peak intensity, ISATP of 1.0 or 0.5 W/cm2 for maxillary or frontal sinuses, respectively, was applied coupled with US transmission gel (Sonogel, Bad Camberg, Germany). Each maxillary and frontal sinus was treated for 5 and 4 min, respectively. The US head was applied using small circular movements. The cheek and forehead were treated for maxillary and frontal sinusitis, respectively. The US machine was checked weekly for calibration throughout the study. For the EP, US was administered with erythromycin ointment 5% with a thickness 1–2 mm (prepared by a licensed pharmacist) applied to the treatment area using the same US machine and treatment settings (Ansari et al, 2013). Erythromycin was used because it has been documented to be effective in CRS treatment (Ragab, Lund, and Scadding, 2004; Wallwork et al, 2006). Erythromycin is an antibiotic macrolide which has anti-inflammatory and antimicrobial effects, and can inhibit biofilm formation (Cervin and Wallwork, 2007; Giamarellos-Bourboulis, 2008). All treatments (PUS and EP) were administered by the same PT, three times a week, every other day for 10 treatment sessions. Patients were prescribed no other treatments, and were instructed to refrain from other treatments during the trial. Assessment Eligible patients who agreed to participate in the study were asked to score the severity of their symptoms [facial pain/pressure, headache, nasal obstruction, nasal discharge, post-nasal drip (PND), smell disturbance, fatigue, cough and overall discomfort] on an ordinal scale of 0–3 (absent, mild, moderate or severe) at baseline, and after the 10th treatment session. The scores of the individual symptoms were then summed to obtain the ‘‘Total Symptom Score’’ (TSS) from 0 (no symptoms) to 27 (maximal symptoms). The ENT surgeon also rated CRS severity for each patient using the same scoring of 0–3 based on physical examination and CT scan changes. The ENT surgeon graded the pre-treatment CT scan on each side separately for the maxillary, anterior and posterior ethmoid, sphenoid and frontal sinuses based on a 0–3 system: 0 ¼ clear; 1 ¼ mild or moderate mucosal thickening; 2 ¼ severe mucosal thickening and 3 ¼ total opacification. The OMC was scored as 0 or 3 (not occluded or occluded). The individual sinus scores were added to obtain the total CT score for each side (0 ¼ clear to 18 ¼ total opacification) (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari et al, 2012; Ansari et al, 2013). The total CT score for each patient was obtained by adding the right and left CT scores ranging from 0 ¼ clear to 36 ¼ total opacification.
Outcome measures The main outcome measure was ‘‘percent improvement’’ of the TSS [(pre-treatment total score – post-treatment total score/pretreatment total score) 100] classified as follows: No change (0): 0–15%; Poor (1): 16–35%; Fair (2): 36–60%; Good (3): 61–85% and Excellent (4): 86–100% (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari, Naghdi, and Farhadi, 2007; Ansari et al, 2012; Ansari et al, 2013; Naghdi, Ansari, and Farhadi, 2008; Naghdi et al, 2013). The data were analyzed using SPSS statistical software for Windows 18.0 (SPSS Inc., Chicago, IL). Prior to all analyses, the Kolmogorov–Smirnov test was used to assess the normality of the data. Demographic characteristics of patients were analyzed with the independent t-test (parametric data), or 2 test (nominal data). Descriptive statistics for quantitative variables were calculated as means and standard deviations (SD), and for ordinal variables, median [interquartile range (IQR)] were determined. Between groups comparisons were made using independent t-test and nonparametric statistics of Mann–Whitney U-test where appropriate. The analyses of pre and post within group changes were carried out using paired t-test (quantitative variables), and Wilcoxon signed-rank test (ordinal variables). To measure the magnitude of the treatment effect for total score of symptoms, the Cohen’s d effect sizes were calculated for each group. A p value of 0.05 was accepted as significant.
Results At baseline, CRS severity for the 60 patients was rated by the ENT surgeon as: severe (n ¼ 18); moderate (n ¼ 28) or mild (n ¼ 14) (median ¼ 2, IQR ¼ 2–3) based on the physical findings and the CT scan. The median scores of CRS severity rated by the ENT surgeon for the PUS and EP groups were moderate. The baseline severity of the CRS symptoms was not different between the two groups (Mann–Whitney test, p ¼ 0.76). All patients had pre-treatment CT scans to confirm the diagnosis of CRS. The pre-treatment CT scans (n ¼ 60) revealed that the maxillary and frontal sinuses were affected in 59 and 37 patients, respectively. The OMCs were occluded in 50 patients (Table 2). The pre-treatment median scores of the affected maxillary sinuses and the OMCs on the CT scans were 2 and 3 (occluded), respectively (Table 2). The pre-treatment median scores of the affected right and left frontal sinuses were 1 and 0, respectively. The pre-treatment total mean CT scan scores were not statistically different between the PUS group (17.5 ± 9.7 range 2–35) and the EP group (15.9 ± 9.5 range 2–36) (p ¼ 0.51). The most common pre-treatment symptoms of the final study group (n ¼ 60) were nasal obstruction (90%), post-nasal drip
A trial comparing PUS and EP in patients with CRS
DOI: 10.3109/09593985.2014.991465
(90%), nasal discharge (76.7%), fatigue (66.7%), facial pain (63.3%), headache (61.7%), hyposmia (51.7%) and cough (45%). All patients (100%) complained of overall discomfort. Rhinosinusitis Symptom Score Between groups, the mean pre-treatment TSSs were not statistically different between the two groups. However, the mean posttreatment TSS for the EP group was statistically better [mean group difference ¼ 2.50 (95% CI ¼ 0.03–5.03)] than that of the PUS group (t ¼ 1.98, df ¼ 58, p ¼ 0.05). The TSSs for the two groups are given in Table 3. Within groups, the TSSs improved significantly in both the PUS group (t ¼ 7.62, df ¼ 29, p50.001) and in the EP group (t ¼ 11.88, df ¼ 29, p50.001). The effect sizes for both treatment methods were large; PUS: d ¼ 1.36 and EP: d ¼ 2.15. Percent improvement of the TSS The percent improvement of the TSS in the EP group (67.2 ± 23.7) was statistically greater {mean group difference ¼ 17.9 [95% CI of the difference ¼ 34.0–(1.8)]} than in the PUS group (49.3 ± 37.2) (t ¼ 2.22, df ¼ 58, p ¼ 0.03) (Table 3). Symptom improvement classification The frequency of symptom improvement classification (SIC) in both groups is demonstrated in Table 4. The medians (IQR) of SIC for the PUS and EP groups were 2 (1–3) and 3 (2–4), respectively. The frequency of good and excellent improvements in the group treated with the EP was twice than that of the group treated with the PUS (20 versus 10). The severity of symptoms worsened in one patient in the PUS group. There was a statistically significant difference for SIC between the two intervention methods (Mann–Whitney U-test, p ¼ 0.01).
Table 2. Pre-treatment frequency of affected sinuses on the CT scan and median (IQR) scores of sinuses (n ¼ 60). Sinus
Right
Maxillary Frontal Anterior ethmoid Posterior ethmoid Sphenoid OMC
7 2 8 1 5 2 6 1 6 0 7 3
(1–3) (0–2) (1–2) (0–2) (0–1) (0–3)
Left 9 2 (1–2) 5 0 (0–1) 2 1.5 (0–2) 2 1 (0–2) 5 0 (0–1.75) 6 3 (0–3)
Both
Total
43
59
24
37
41
48
34
42
23
34
37
50
Symptoms Before treatment, there were no differences between the two groups in the severity of individual symptoms with the exception of nasal obstruction (Mann–Whitney U-test, p ¼ 0.01). After treatment, headache (p ¼ 0.003), nasal obstruction (p ¼ 0.02) and PND symptoms (p ¼ 0.01) were statistically different between the two groups in favor of the EP group. After treatment, the severity of symptoms was significantly improved in both groups (p50.05) (Table 5). Computed Tomography scan score After treatment, 31 patients voluntarily had sinus CT scans (14 from the PUS group and 17 from the EP group). The posttreatment mean total CT scan scores were not statistically different between the PUS group (12.8 ± 9.7 range 0–34) and the EP group (9.9 ± 8.4 range 0–26) (p ¼ 0.39). The mean percent improvement of CT scan scores in the PUS group and the EP group were not statistically different (30.3 ± 36.0 versus 33.2 ± 55.7) (p ¼ 0.87). Within groups, the total CT scores were significantly improved in both the PUS group (t ¼ 2.65, df ¼ 13, p ¼ 0.02) and the EP group (t ¼ 3.06, df ¼ 16, p ¼ 0.007). Statistical analysis showed no significant differences between the OMC scores pre- and post-treatment between the two groups (p40.05). The change in right OMC score was statistically better in the EP group than in the PUS group (Mann–Whitney U-test, p ¼ 0.046).
Discussion The primary aim of this study was to determine after 10 treatment sessions over 4 weeks whether EP would be more effective than PUS in improving symptoms in CRS patients. The percent improvement in the group receiving EP was significantly higher than the PUS group. Interestingly, the effect sizes in both groups were large, and the effect size in the group receiving EP was larger than that in the PUS group at post-test. To the authors’ knowledge, this is the first study to compare the efficacy of PUS and EP to treat symptoms in CRS patients. It has previously been reported that therapeutic US in either continuous or pulsed mode is effective in treating symptoms of patients with acute rhinosinusitis (Høsøien, Lund, and Vasseljen, 2010) or CRS (Ansari, Fathali, Naghdi, and Hasson, 2010; Ansari, Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi, and Jalaie, 2007; Ansari et al, 2012; Ansari et al, 2013; Naghdi, Ansari, and Farhadi, 2008; Nakhostin Ansari, Naghdi, and Farhadi, 2004; Rocha et al, 2011; Young, Morton, and Bartley, 2010). Overall, the results found in this study agree with prior reports. These findings are clinically important because they provide evidence that patients with CRS unresponsive to medical treatments may benefit from US therapy. The TSS improved using both PUS and EP methods of treatment; again the effect was significantly larger in the EP group at the end of 4 weeks treatment. In this study, the treatment groups
Table 3. Sinusitis Symptom Score and percent improvement for the PUS group and EP group. PUS
EP
Symptoms
Mean (SD)
Range
Mean (SD)
Range
p Value
Pre-treatment total score Post-treatment total score Percent improvement
14.9 (5.3) 7.3 (5.7) 49.3 (37.2)
7–27 0–27 85.7–100
14.2 (4.8) 4.8 (3.9) 67.2 (23.7)
3–21 0–16 12.5–100
0.59 0.05 (t)a 0.03 (t)a
a
169
Statistically significant between the two groups. t, independent sample t-test.
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were comparable in the demographic and pre-test clinical characteristics. The significant better post-test TSS and percent improvement in the EP group compared with the PUS group suggests that EP offers benefits over the PUS method in the treatment of CRS patients. We used the TSS because the SNOT-20 score had not been validated in Persian when this study was designed. The SNOT-20 has been recently translated and validated in the Persian language (Naghdi, Anjei, Ansari, and Fathali, 2013). The SNOT20 is a valid disease-specific, health-related quality-of-life questionnaire consisting of 20 nose, sinus and general items to assess problems associated with rhinosinusitis (Piccirillo, Merritt, and Richards, 2002). In this study, the application of PUS alone or EP led to the significant individual improvement of symptoms and better posttreatment TSS in this sample of patients with CRS. Inflammation and biofilm infection have been implicated in the pathophysiology of CRS (Fokkens et al, 2012; Madeo and Frieri, 2013). Bacterial biofilms are a complex community of bacteria that form on both biotic and abiotic surfaces contained in a hydrated polymeric matrix (Costerton, Stewart, and Greenberg, 1999; Smith, Buchinsky, and Post, 2011). A recent review has reported that 11 studies have detected bacterial biofilms in sinus mucosa samples obtained in CRS patients, providing evidence that the microbial biofilms may be an important factor in CRS pathogenesis (Foreman, Boase, Psaltis, and Wormald, 2012). Bacterial biofilms are highly recalcitrant to conventional antibiotics, and even surgery. Given that therapeutic US has been demonstrated to have antiinflammatory effects (Chung et al, 2012; Karosi, Sziklai, and Csomor, 2013); analgesic effects (Baker, Robertson, and Duck, 2001) and can destroy bacteria biofilms (Bartley and Young, 2009; Høsøien, Lund, and Vasseljen, 2010), it can be hypothesized that the therapeutic US used in the current study is in agreement with previously published investigations suggesting reduced inflammation and disrupted bacterial biofilms resulted in an improvement in CRS symptoms (Ansari, Naghdi, and Farhadi, 2007; Ansari, Naghdi, Farhadi, and Jalaie, 2007; Ansari et al,
2012; Naghdi, Ansari, and Farhadi, 2008; Young, Morton, and Bartley, 2010). US’s mechanical vibratory effects may restore cell membrane permeability and thus enhance the natural resolution of the innate anti-inflammatory tissue reactions. Low-intensity US has been recently shown to have an anti-inflammatory effect in an animal model reducing inflammatory markers in the synovium via a reduction in inflammatory cell infiltrate (Chung et al, 2012). In surgically removed nasal polyps, low-frequency US treatment decreased the number of inflammatory cells in the sub-epithelial and stromal layers (Karosi, Sziklai, and Csomor, 2013). Given the vital role the OMC plays in clearing mucosa of the sinuses, it is possible that the US by reduction of inflammation (Bartley, Ansari, and Naghdi, 2014) could facilitate sinus drainage and promote sinus healing and bacterial removal. There is no standard treatment for CRS (Cain and Lal, 2013). ENT physicians commonly prescribe prolonged courses of oral antibiotics as a significant component of the medical treatment of patients with CRS (Bhattacharyya, 2003; Fokkens et al, 2012; Kaszuba and Stewart, 2006). However, the efficacy of antibiotics is not strongly supported by high-level studies (Cain and Lal, 2013; Fokkens et al, 2012; Mandal, Patel, and Ferguson, 2012). Furthermore, prolonged antibiotic administration may cause systemic side effects some of which include bacterial resistance, allergic reactions and gastrointestinal disturbances (Albu, 2012). Phonophoresis is a non-invasive method used in physiotherapy to deliver drugs locally to treat various diseases. In this technique, US can be used as a physical enhancer for transdermal drug delivery to enhance drug distribution to the paranasal sinuses (Ansari et al, 2013). The advantage of local drug delivery to the paranasal sinuses using phonophoresis is that the rate and concentration of drug transport to the target site can be increased and subsequently drug effectiveness can be enhanced. US, by its mechanical action, could disrupt biofilms enough to enhance the antibacterial actions of both extrinsic (drug) and intrinsic (body) mechanisms (Bartley, Ansari, and Naghdi, 2014). The difference between the two groups on the percent improvement of TSS indicated that the EP is more effective in improving CRS symptoms than PUS alone. The statistically
Table 4. Frequency of symptoms improvement classification in both the PUS group and EP group. Improvement classification Groups PUS EP
Worse
No change (0–15%)
Poor (16–35%)
Fair (36–60%)
Good (61–85%)
Excellent (86–100%)
1 0
1 1
8 1
10 8
5 12
5 8
p Value 0.01 (M)a
a
Statistically significant between the two groups. M, Mann–Whitney test. Table 5. Median (IQR) scores for symptoms pre- and post-treatment in both the PUS group and EP group. PUSa Symptom Facial pain Headache Nasal obstruction Nasal discharge Post nasal drip Smell disturbance Fatigue Cough Overall discomfort a
EPa
Pre 1 1.5 2.5 2 2 0.5 2 0 2.5
(0–2.25) (0–3) (2–3)c (1–3) (2–3) (0–2.25) (0–3) (0–1) (2–3)
Post 0 0 1 0.5 1 0 0 0 1
(0–1) (0–1) (0–2) (0–1) (0.75–2) (0–1) (0–2) (0–0) (1–2)
Pre 1 1 2 1 2 1 2 0 3
(0–3) (0–3) (1–3)c (0–3) (1–3) (0–3) (0–3) (0–1.25) (2–3)
Post 0 0 0 0 0 0 0 0 1
(0–0) (0–0)b (0–1)b (0–1) (0–1)b (0–1.25) (0–1) (0–0.25) (0–2)
Within group significant improvement in severity of all symptoms after treatment with both methods (Wilcoxon signed-rank test, p50.05). bSignificant between the two groups after treatment (Mann–Whitney U-test, p50.05). cSignificant between the two groups at baseline (Mann–Whitney U-test, p ¼ 0.01).
DOI: 10.3109/09593985.2014.991465
significant differences between two groups may be due to the high concentration of erythromycin delivered through phonophoresis through a synergistic action with 1 MHz US (Mitragotri, Edwards, Blankschtein, and Langer, 1995; Qian, Sagers, and Pitt, 1999). The enhanced erythromycin delivery to the sinuses may be explained by the fact that 5% erythromycin ointment has similar acoustic impedance with the skin, which minimized the US reflection and facilitated the drug delivery (Polat, Hart, Langer, and Blankschtein, 2011). The enhanced erythromycin delivery to the sinuses may also be explained by the likelihood of increased antibiotic concentrations in the superficial facial tissues that result from phonophoresis. The posterior superior alveolar and infraorbital arteries supply both the maxillary sinus and overlying soft tissue (Rosano, Taschieri, Gaudy, and Del Fabbro, 2009; Traxler et al, 1999). The supraorbital and supratrochlear arteries supply the forehead region and the frontal sinuses (Mafee, Valvassori, and Becker, 2005). The phonophoresis may increase blood flow, and the arterial blood vessels may be the most direct route by which antibiotic in cells and fluid compartments of the superficial facial tissues could arrive in the mucosa lining the interior of the maxillary and frontal sinuses (Ansari et al, 2013). The sinuses are continuous with the nasal passages. EP or PUS applied for either maxillary or frontal sinuses could improve the state of the OMC contributing to an overall improvement. The enhanced effects of EP compared with the PUS could also be due to the antibacterial as well as anti-inflammatory effects of both erythromycin and PUS. Study limitations Limitations of the study are acknowledged. The comparison of two treatments without a third control group does not allow for the calculation of relative effect sizes. We also acknowledge that erythromycin may not be the most appropriate antibiotic for every patient with CRS, and that alternative preparations may not be suitable for topical application via EP. The effective concentrations of the antibiotic were not measured. Another limitation is that the patients were not subcategorized to CRS with and without nasal polyp. The follow-up period was insufficient.
Conclusions EP, compared to the PUS, illustrated significantly higher percent improvement and larger effect size after 10 treatment sessions over 4 weeks. Large effect sizes for both treatment methods provide further evidence that therapeutic US may be specifically used to treat symptoms in patients with CRS.
Acknowledgments The authors thank the patients for their participation in this study.
Declaration of interest The authors report no conflicts of interest. This study was supported by Research Deputy, Tehran University of Medical Sciences (Grant No. 10200).
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