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1 Braz J Otorhinolaryngol. 2020;xxx(xx):xxx---xxx
2

3 Brazilian Journal of

OTORHINOLARYNGOLOGY
www.bjorl.org

REVIEW ARTICLE

4 Efficacy of nasal irrigation with hypertonic saline on

5 chronic rhinosinusitis: systematic review and
6 meta-analysis夽,夽夽
∗
7 Lei Liu , Min Pan, Yimin Li, Guojing Tan, Yucheng Yang

8 Chongqing Medical University, The First Affiliated Hospital, Department of Otorhinolaryngology, Chongqing, China

9 Received 28 November 2019; accepted 28 March 2020

10 KEYWORDS Abstract
11 Chronic rhinosinusitis; Introduction: Currently, several different concentrations of saline are recommended for use
12 Nasal irrigation; in nasal irrigation. Increasing studies show that nasal irrigation with hypertonic saline is more
13 Hypertonic saline; effective than traditional saline in the treatment of rhinosinusitis, but there have been few
14 Treatment; systematic analyses of the effect of nasal irrigation with hypertonic saline on chronic rhinosi-
15 Meta-analysis nusitis.
16 Objective: We sought to compare the effects of hypertonic saline and isotonic saline in the
17 treatment of rhinosinusitis in order to provide a reference for clinical nasal irrigation for chronic
18 rhinosinusitis treatment.
19 Methods: Medline, Cochrane library, EMBASE, PubMed, Chinese biomedical journal database,
20 China national knowledge infrastructure, Wanfang database, and other databases were
21 searched, and the searching was supplemented by manual searches for relevant references
22 to treatment of rhinosinusitis by saline nasal irrigation. The last retrieval date was March 2018.
23 The included studies were evaluated for quality, and data were extracted for meta-analysis
24 using RevMan 5.3.
25 Results: Seven studies were included. Effects favoring hypertonic saline on nasal symptoms
26 were greater in 4 subgroups. These were (1) Patients with nasal secretion (SMD = 1.52; 95% CI:
27 1.04, 2.00; p < 0.01), (2) Patients with congestion (SMD = 1.52; 95% CI: 1.04, 2.00; p < 0.01),
28 (3) Patients with headache (SMD = 0.82; 95% CI: 0.38, 1.26; p < 0.01), (4) Patients with overall
29 symptomatic relief (SMD = 1.63; 95% CI: 0.83, 2.44; p < 0.01). However, no difference was shown
30 in smell improvement (SMD = 0.47; 95% CI: −0.65, 1.59; p = 0.41) and radiologic scores improve-
31 ment (SMD = 2.44; 95% CI: −3.14, 8.02; p < 0.01). Besides, hypertonic saline showed greater
32 improvement in mucociliary clearance time scores than did the isotonic saline group (SMD = 1.19;
33 95% CI: 0.78, 1.60; p < 0.01). Hypertonic saline brought greater minor adverse effects.

34 夽 Please cite this article as: Liu L., Pan M., Li Y., Tan G., Yang Y. Efficacy of nasal irrigation with hypertonic saline on chronic rhinosinusitis:

systematic review and meta-analysis. Braz J Otorhinolaryngol. 2020. https://doi.org/10.1016/j.bjorl.2020.03.008

夽夽 Peer Review under the responsibility of Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial.
∗ Corresponding author.

E-mail: yychxh@163.com (Y. Yang).

https://doi.org/10.1016/j.bjorl.2020.03.008
1808-8694/© 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. This is an open
access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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35 Conclusion: Compared with isotonic saline, hypertonic saline nasal irrigation for the treatment
36 of chronic rhinosinusitis is significantly more effective and has mild side effects in improving
37 nasal symptoms and ciliary movement, but there is no significant difference in imaging findings
38 and smell improvement. Although hypertonic saline is worthy of widespread use in clinical
39 practice, it is still necessary to further study the exact manner and concentration of nasal
40 irrigation.
41 © 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published
42 by Elsevier Editora Ltda. This is an open access article under the CC BY license (http://
43 creativecommons.org/licenses/by/4.0/).

44
PALAVRAS-CHAVE Eficácia da irrigação nasal com solução salina hipertônica na rinossinusite crônica:
45
Rinossinusite crônica; revisão sistemática e meta-análise
Irrigação nasal;
46 Resumo
Solução salina
47 Introdução: Atualmente, a utilização de várias concentrações diferentes de solução salina são
hipertônica;
48 recomendadasna irrigação nasal. Um número crescente de estudos mostram que a irrigação
Tratamento;
49 nasal com solução salina hipertônica é mais eficaz que a solução salina tradicional no tratamento
Meta-análise
50 de rinossinusite, mas existem poucas análises sistemáticas do efeito da irrigação nasal com
51 solução salina hipertônica em rinossinusite crônica.
52 Objetivo: Comparar os efeitos da solução salina hipertônica com a solução salina isotônica
53 no tratamento da rinossinusite, para fornecer uma referência clínica de irrigação nasal no
54 tratamento da rinossinusite crônica.
55 Método: Foram pesquisados os bancos de dados medline, cochrane library, EMBASE, PubMed,
56 Chinese biomedical journal database, China national knowledge infrastructure, Wanfang
57 database e outros, e a pesquisa foi complementada por pesquisas manuais de referências
58 relevantes ao tratamento da rinossinusite por irrigação nasal com solução salina. A data da
59 última recuperação de dados foi março de 2018. Os estudos incluídos foram avaliados quanto à
60 qualidade e os dados foram extraídos para a meta-análise utilizando o software RevMan 5.3.
61 Resultados: Sete estudos foram incluídos. Os efeitos favoráveis à solução salina hipertônica nos
62 sintomas nasais foram maiores em 4 subgrupos. Estes foram (1) pacientes com secreção nasal
63 (DMP = 1,52; IC95%: 1,04, 2,00; p < 0,01); (2) pacientes com congestão (DMP = 1,52; IC95%: 1,04,
64 2,00; p < 0,01); (3) Pacientes com dor de cabeça (DMP = 0,82; IC95%: 0,38, 1,26; p < 0,01); (4)
65 Pacientes com alívio sintomático geral (DMP = 1,63; IC95%: 0,83, 2,44; p < 0,01). Entretanto, não
66 houve diferença na melhora do olfato (DMP = 0,47; IC95%: -0,65, 1,59; p = 0,41) e na melhora
67 dos escores radiológicos (DMP = 2,44; IC95%: -3,14, 8,02; p < 0,01). Além disso, o grupo solução
68 salina hipertônica mostrou maior melhora nos escores do tempo de clearence muco-ciliar do
69 que o grupo solução salina isotônica (DMP = 1,19; IC95%: 0,78, 1,60; p < 0,01). A solução salina
70 hipertônica causou efeitos adversos menores.
71 Conclusão: Em comparação com a solução salina isotônica, a irrigação nasal com solução salina
72 hipertônica para o tratamento da rinossinusite crônica é significantemente mais eficaz e apre-
73 senta efeitos colaterais mais leves, melhora mais acentuada dos sintomas nasais e no movimento
74 ciliar, mas não há diferença significante nos achados de imagem e na melhora do olfato. Emb-
75 ora a solução salina hipertônica seja digna de uso generalizado na prática clínica, ainda são
76 necessários mais estudos sobre a forma de utilização e a concentração ideal da solução nasal.
77 © 2020 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Publicado
78 por Elsevier Editora Ltda. Este é um artigo Open Access sob uma licença CC BY (http://
79 creativecommons.org/licenses/by/4.0/).

80 Introduction popularization of a simple and effective therapeutic regi- 87

men are in great demand. 88

81 Chronic rhinosinusitis (CRS), defined as a condition of inflam- Nasal irrigation is a common auxiliary treatment method, 89

82 mation in the paranasal sinus mucosa persisting for more regarded as a simple and effective adjunct in the treatment 90

83 than 12 weeks, is a common disease worldwide, with a of a variety of sinonasal disease, which is recommended 91

84 prevalence between 6% and 27.1%.1---5 CRS is associated with by the UCSD (University of California, San Diego) nasal 92

85 a significantly impaired quality of life6 and accounts for sub- dysfunction clinic and otorhinolaryngologists worldwide.8---11 93

86 stantial health burdens.5---7 Therefore, the application and When saline nasal irrigation washes out secretions and 94

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95 antigens, it physiologically propels a superficial gel layer, Information sources and search strategy 147

96 increases hydration in the sol layer, and enhances mucocil-

97 iary function. In addition, saline nasal irrigation removes Electronic searches were conducted in Medline, Cochrane 148
98 inflammatory mediators, thus resulting in better control of Library, EMBASE, PubMed, Chinese Biomedical Journal 149
99 adverse nasal symptoms.12 Consequently, nasal irrigation Database, China National Knowledge Infrastructure, Wan- 150
100 exerts its effect not only in the relief of nasal symptoms fang Database and other databases, and were supplemented 151
101 but also in restrains inflammation and accordingly has been by manual searches. The date of the searches was March 152
102 recommended as an adjunctive treatment for rhinosinusitis, 2018. A combination of MESH terms and keywords was used 153
103 allergic rhinitis and other sinonasal diseases.13 as follows: ‘‘hypertonic solution’’, ‘‘isotonic solutions’’, 154
104 Recently, more otolaryngologists noticed that hypertonic ‘‘saline solutions’’, ‘‘sodium chloride’’, ‘‘nose disease’’, 155
105 saline was more effective than isotonic saline in nasal ‘‘chronic disease’’, ‘‘paranasal disease’’, ‘‘chronic rhini- 156
106 irrigation. Hypertonic solution, with higher osmotic pres- tis’’, ‘‘chronic sinusitis’’, ‘‘chronic rhinosinusitis’’, ‘‘nasal 157
107 sure, allows for higher efficacy in reducing mucosal edema. irrigation’’, ‘‘nasal spray’’ and ‘‘treatment’’. 158
108 Although there have been some prospective studies on the
109 efficacy of different saline concentrations in the treatment
110 of CRS, the clinical effectiveness of nasal irrigation with Study records: data management, selection 159

111 hypertonic saline remains unclear, and reasonable clinical process and data collection process 160

112 recommendations cannot be made because of the lack of a

113 systematic evaluation of its effectiveness. In order to inves- First, the appraisers read the title of the article, and then 161

114 tigate the evidence for efficacy and safety of hypertonic read the relevant literature abstracts and selected docu- 162

115 saline in the clinical management of CRS, we performed this ments that initially met the inclusion criteria; they then read 163

116 systematic review and meta-analysis, including randomized the full text. The two appraisers independently applied the 164

117 controlled trials where patients suffer from CRS and were exclusion criteria for document screening and classified the 165

118 treated with hypertonic saline nasal irrigation to provide documents that met the inclusion criteria. The appraisers 166

119 more reliable clinical evidence. used Kappa values to calculate the consistency of the assess- 167

ment, and if there was a disagreement, it was ultimately 168

resolved by discussion. 169

120 Methods
Risk of bias in individual studies 170
121 Eligibility criteria
The quality of included studies was assessed by evaluat- 171
122 Type of study
ing the risk of bias according to the Cochrane Handbook 172
123 Published randomized controlled trials or quasi-randomized
for Systematic Reviews of Interventions. Six domains were 173
124 controlled trials of CRS treated with hypertonic saline were
assessed: random sequence generation, allocation con- 174
125 included.
cealment, blinding of participants, blinding of outcome 175

assessment, incomplete outcome data and selective report- 176

126 Participants ing. The included studies had a low risk of bias when the 177

127 The participants included adults who were clinically diag- methods used for each domain were clearly described. They 178

128 nosed with CRS. The following patients were excluded: had a high risk of bias when high risk was shown under the 179

129 (1) Patients with functional nasal surgery, (2) patients description. Unclear risk of bias was determined when there 180

130 with acute upper respiratory tract infections, (3) patients was insufficient information to judge. 181

131 with acute rhinosinusitis, (4) patients with clinically

132 severe metabolic, cardiovascular, immune, neurological, Data synthesis 182
133 hematological, gastrointestinal, cerebrovascular, respira-
134 tory diseases or anything that the clinicians considered
Data were pooled for meta-analysis. Treatment effects of all 183
135 might interfere with the assessment of the results of the
continuous outcomes were presented as standardized mean 184
136 study or affect the safety of the subject.
difference (SMD) with standard deviation (SD) and 95% confi- 185

dence interval (CI). When total symptom score improvement 186

137 Intervention was missing, the sum of individual score improvement was 187

138 Studies assessing the effects of hypertonic saline compared used for analysis. When the data included in each study 188

139 with isotonic saline were included. Any delivery method, were sufficiently similar (p ≥ 0.10, I2 ≤ 50%), a fixed effect 189

140 saline concentration, frequency, and duration of saline model was used for the combined analysis; if the studies had 190

141 treatment were included. clinical homogeneity with significant heterogeneity, then a 191

random effect model was used for the combined analysis. 192

Statistical assessments were performed using Review Man- 193

142 Outcomes ager (RevMan) version 5.3 (The Nordic Cochrane Centre, 194

The Cochrane Collaboration, Copenhagen, Denmark), and 195

143 Studies were included when they assessed the following the significance of discrepancies in estimates of treatment 196
144 outcomes: nose symptom score (visual analog pain scale), effects from different trials was assessed by Cochran’s Q 197
145 mucociliary clearance time (saccharin clearing time) and test for heterogeneity and by measurement of the I2 statis- 198
146 imaging scores. tic. An I2 of less than 40%, 40%---60% and greater than 60% 199

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Figure 1 Flow chart of study retrieval and selection.

200 represented low, moderate and substantial heterogeneity,

201 respectively. Otherwise sensitivity analysis was performed
202 to test whether the effects were still significant. To incor-
203 porate crossover trials in a meta-analysis, all measurements
204 from both hypertonic and isotonic periods were analyzed as
205 if the trials were performed in parallel.

206 Results

207 Study selection

208 A total of seven randomized controlled trials meet our

209 inclusion criteria.14---20 Information on the included research
210 methods, objects, interventions and outcomes are shown
211 in the following description of the included literature fea-
212 tures (Table 1). The method of administration of hypertonic
213 saline, the specific formulation of the solution, the treat-
214 ment time and the outcome measures used in each study Figure 2 Quality of the included studies, assessed by risk of
215 varied. A flowchart of study retrieval and selection is pre- bias.
216 sented in Fig. 1.

p < 0.01). There was no heterogeneity among studies 232

217 Participants
(I2 = 0%). 233

2. Nasal congestion: The HSNI group showed greater 234

218 A total of 454 participants were recruited. Characteristics of
improvements in the reduction of nasal congestion than 235
219 the included studies are shown in Table 1. The quality of the
the ISNI group (SMD = 1.36; 95% CI: 0.03, 2.42; p = 0.01). 236
220 included studies assessed according to risk of bias is shown
There was heterogeneity among studies (I2 = 80%), which 237
221 in Fig. 2.
may be due to the difference base between the two trails 238

in the cardinality. 239

222 Effects of interventions 3. Headache: The HSNI group showed greater improvements 240

in headache reduction than the ISNI group (SMD = 0.82; 241

223 Hypertonic saline vs. isotonic saline 95% CI: 0.38, 1.26; p < 0.01). There was no heterogeneity 242

224 Nasal symptom score. Two trials assessed improvement in among studies (I2 = 0%). 243

225 nasal symptom scores in patients with CRS (88 patients). 4. Smell: There was no difference in smell between the 244

226 When the data were pooled for meta-analysis (a forest plot HSNI and the ISNI group (SMD = 0.47; 95% CI: −0.65, 1.59; 245

227 is shown in Fig. 3): p = 0.41). The results show that it is not statistically sig- 246

nificant. 247

228 1. Nasal secretion: The Hypertonic Saline Nasal Irrigation 5. Overall symptomatic relief: The HSNI group showed 248

229 (HSNI) group showed greater improvements in the reduc- greater improvements in overall symptomatic relief than 249

230 tion of nasal secretion than the Isotonic Saline Nasal the ISNI group (SMD = 1.63; 95% CI: 0.83, 2.44; p < 0.01). 250

231 Irrigation (ISNI) group (SMD = 1.52; 95% CI: 1.04, 2.00; There was heterogeneity among studies (I2 = 62%). It may 251

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Table 1 Characteristics of the included studies.

Authors Year Number of Age (year) Tonicity of Duration Withdrawals Outcomes
patients HS (%)
Shoseyov 1998 34 3---16 3.5 4 weeks 4 (1)(4)
Bachmann 2000 40 28---56 1.1 1 weeks 1 (1)(2)(3)(4)(5)
Hauptman 2007 80 21---64 3.0 10 min 0 (1)(3)(6)
Kumar 2013 50 18---45 3.5 4 weeks 8 (1)(4)
Mohan 2016 50 20---45 3.0 4 weeks 0 (1)(4)
Cai 2016 124 12---63 2.3 3 months 0 (1)(3)
Rabago 2002 76 18---65 2.0 2 weeks 7 (2)
(1) Nasal symptom scores; (2) Quality of life scores; (3) Mucociliary clearance time; (4) Radiologic scores; (5) Endoscopy scores; (6) Nasal
reflex scores.

Figure 3 Meta-analysis of improvements in symptom scores when comparing HSNI and ISNI treatments.

252 be due to the difference base between the two trails in groups (SMD = 2.44; 95% CI: −3.14, 8.02; p < 0.01). There was 258

253 the cardinality. substantial heterogeneity (I2 = 98%). Heterogeneity may be 259

caused by different methods of measuring results. A forest 260

254 Radiological scores. There were two trials assessing plot is shown in Fig. 4. 261

255 improvement in radiological scores (70 patients). When Mucociliary clearance time. There were two trial assessing 262

256 data were pooled for meta-analysis, there was no dif- improvement in MCT scores (120 patients). When data were 263

257 ference in imaging score between the HSNI and the ISNI pooled for meta-analysis, the HSNI group showed greater 264

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Figure 4 Meta-analysis of improvements in radiologic scores when comparing HSNI and ISNI treatments.

Figure 5 Absolute improvement in MCT when comparing HSNI and ISNI treatments.

265 improvement in the MCT scores than did the ISNI group and edema. In addition, it is also necessary to slow adjust- 306

266 (SMD = 1.19; 95% CI: 0.78, 1.60; p < 0.01). There was substan- ments according to the comfort level of the patient about 307

267 tial heterogeneity (I2 = 95%). Heterogeneity may be caused pressure selection, from small to large. Different methods 308

268 by different methods of measuring results. A forest plot is and different flushing fluids produce different feelings for 309

269 shown in Fig. 5. different patients, so nasal irrigation will inevitably produce 310

270 Adverse events. As the forest plot is shown in Fig. 6, HS had different adverse reactions in some individuals with lower 311

271 higher risk (13.8%) over IS (4.1%; risk ratio 3.33; 95% CI 1.35, tolerance. 312

272 8.20). Most of adverse events were nasal irritation and burn- Keeri et al. have polled 134 patients with questionnaires. 313

273 ing sensation. Other events included tearing, nosebleeds, They report that 95% of patients thought that nasal irrigation 314

274 headache, or nasal drainage. was a simple and easy method of treatment, and 84.7% of 315

patients thought that this treatment was comfortable. Thus, 316

the authors assumed that nasal irrigation is a valid treatment 317

275 Discussion for patients.24 318

Some studies have examined treatment of sinus symp- 319

276 This study disclosed significantly improved effectiveness of toms with hypertonic saline, thus further demonstrating 320
277 hypertonic saline nasal irrigation in management of CRS the effectiveness of hypertonic saline in treating sinusitis. 321
278 patients’ nasal symptoms and MCT scores, as compared However, these studies examined not only chronic sinusitis 322
279 to isotonic saline. However, neither hypertonic saline nor but also acute sinusitis, allergic rhinitis and so forth. Our 323
280 isotonic saline causes any significant improvement when study involved only patients with chronic sinusitis before 324
281 evaluated by imaging. In various studies different concen- surgery and thus may be more valuable in guiding clini- 325
282 trations of hypertonic saline solutions have been used. cal treatment. The following limitations were identified in 326
283 Talbot21 detected the mucociliary clearance rate of normal the present study: (1) The loss of patients was not docu- 327
284 humans after nasal irrigation in buffered hypertonic saline mented in further detail, and the calculations were slightly 328
285 (2%, pH = 7.6) and buffered saline groups. He found that different. (2) Some studies did not use uniform result mea- 329
286 hypertonic saline nasal irrigation can significantly improve sures. (3) Each study involved only a small sample size. (4) 330
287 mucociliary clearance rate. He believes that buffering Various nasal irrigation methods were used. (5) The hetero- 331
288 hypertonic saline can increase the thickness of the mucus geneity may be increased by comparing children with adults 332
289 layer and reduce the viscosity of the mucus, which is more in evaluating CT scores. The concentrations of nasal irri- 333
290 conducive to improved movement of the cilia. Lansley22 gation fluid also differed. There were no strict differences 334
291 found that hypertonic saline can cause an increase in intra- between the various forms and the concentration of the 335
292 cellular Ca2+ release, while Ca2+ increases tile rate of ciliary rinsing solution. Future clinical randomized controlled stud- 336
293 oscillation. They also found that hypertonic saline nasal irri- ies should be designed to include a larger sample size. It 337
294 gation was more effective in improving symptoms and did needs to adopt more rigorous randomization methods, assign 338
295 not increase the incidence of side effects concealed and double-blinded study designs, formulate and 339
296 In terms of safety, the side effects of nasal irrigation were adopt uniform therapeutic efficacy criteria, and use uniform 340
297 minimal. No uniform standard for clinical nasal irrigation measurement units and uniform nasal irrigation methods and 341
298 exists and each person has different feelings on nasal irriga- rinse concentration. Also, negative results should be pub- 342
299 tion. It is difficult to avoid certain side effects. For example, lished. The limits above may increase the heterogeneity of 343
300 Liu23 has studied the effects of nasal irrigation fluid temper- the article, but it has fewer impacts on the main results of 344
301 ature on the healing time of nasal mucosa. He has found the study and has a greater impact on adverse effects. 345
302 that nasal irrigation fluid of 32 to 34 degree centigrade does For clinical applications, according to the results of our 346
303 not burn or stimulate the nasal mucosa. It can also promote systematic review of the information included in the liter- 347
304 mucosal blood flow in the operating chamber, improve local ature, it is not yet possible to recommend specific nasal 348
305 anti-inflammatory effects and remove mucosal inflammation

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Figure 6 Adverse events when comparing HSNI and ISNI treatments.

349 irrigation methods, devices, doses or frequency. Hypertonic 9. Wei CC, Adappa ND, Cohen NA. Use of topical nasal thera- 391

350 saline nasal irrigation produces better results than isotonic pies in the management of chronic rhinosinusitis. Laryngoscope. 392

351 saline, and there is more evidence that hypertonic saline 2013;123:2347---59. 393

352 can better improve mucociliary clearance in patients. Dif- 10. Achilles N, Mösges R. Nasal saline irrigations for the symptoms 394

ferent treatments should be tailored to individual patient of acute and chronic rhinosinusitis. Curr Allergy Asthma Rep. 395
353
2013;13:229---35. 396
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358 Conclusion 2018;32:269---79. 402

13. Tomooka LT, Murphy C, Davidson TM. Clinical study 403
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365 widespread use in clinical practice, but further study of the the nose with isotonic salt solution on adult patients with 411

366 methods and concentrations in nasal irrigation is necessary. chronic paranasal sinus disease. Eur Arch Otorhinolaryngol. 412
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