The effect of intra-nasal tetra sodium pyrophosphate on decreasing elevated nasal calcium and improving olfactory function post COVID-19: a randomized controlled trial

Study design

A prospective, randomized, blinded, double-controlled clinical trial was conducted from January 2021 to April 2021 in the Department of Otolaryngology, Damietta Faculty of Medicine, Al Azhar University, Egypt. The Ethics Committee of Damietta Faculty of Medicine approved this study (approval number: IRB 00012367-21-03-010). Prior to participation in the study, participants were informed by an assigned member of the study team about the aim of the study and the anticipated benefits and adverse effects. The participant signed informed consent statement form. After that, the patient received the blinded randomized proposed treatment. The flow chart of the proposed study is shown in Fig. 1.

Fig. 1figure 1

The flow chart of the described study

Sample size

In many reports, it was shown that 79.5% of patients recovered completely from the olfactory dysfunction through the first 2 months after COVID-19 infection [15]. Even considering the exclusion criteria, the sample rejection was up to 10%. A total of 400 patients were screened for eligibility. Thus, 64 patients were selected for the study and randomly allocated to 2 groups.

Inclusion criteria

To be enrolled in this study the patients had to meet the following inclusion criteria: adults with previous COVID-19 infection confirmed by reverse transcription polymerase chain reaction (RT-PCR) in nasopharyngeal swabs, recovery from infection confirmed by at least two negative nasopharyngeal swabs, clinically confirmed signs of olfactory dysfunction persisted more than 90 days after SARS-CoV-2 negative testing. Only patients with measured olfactory augmented Sniffin' Sticks TDI test scores (threshold, discrimination and identification) ≤ 13, which represented only anosmia manifestations, were included in the study.

Exclusion criteria

The exclusion criteria included: (1) patients with a history of previous olfactory dysfunction related to trauma or surgery; (2) patients with congenital olfactory loss and neurodegenerative diseases; (3) patients with psychiatric or neurological diseases; (4) patients who receive active medication for olfactory dysfunction; (5) patients with a history of adverse reactions to sodium salts; (6) pregnancy and (7) any patient with current participation in other COVID-19 trials.

Study regimen proceduresRandomization

Patients were randomly divided to sodium chloride and TSPP groups by unratified block randomization with a block size of four. Computer generated randomization plan was developed to provide block randomization. Groups allocation and organization were blinded for the physicians and the patients. The record book remained in the hands of certain tem member who did not communicate with the patients or the interviewer.

Medication preparation

The Department of Pharmaceutical Analytical Chemistry, Cairo Faculty of Pharmacy, Al-Azhar University, Egypt presented the standard procedures for preparing the medications under the study. The medications were prepared as follows: group A, 0.9% sodium chloride intranasal spray; and group B, 1% TSPP in borate buffer solution with a pH of 8. As FDA has determined that TSPP is generally recognized as safe chemical compound and the commonly used concentration of TSPP may be up to 10% [16], so 1% TSPP was appropriate and safe to be used as topical nasal solution. The formulations were provided in identical opaque nasal spray bottles which deliver a standardized volume of 0.1 mL There was a specific sealed code for the assigned bottles and was not available to the team members involved in the study. This remained sealed, unless there was a need to recognize the secrecy due to any adverse effects presented by any of the patients.

Treatment procedures

Patients were divided into 2 equal groups. The first group received intranasal spray 0.9% sodium chloride (group A). The second group received intranasal spray 1% TSPP in borate buffer solution with a pH of 8 (group B). Patients received their assigned bottle and were instructed to apply 2 sprays into each nostril three times daily for 1 month. An endoscopic examination of the olfactory cleft was performed. Improvement in olfactory function after intranasal treatment with sodium chloride and TSPP was clinically demonstrated. Patients were monitored for side effects throughout the study. Nasal secretions were also collected from all participants before treatment and one month later. Calcium concentration in nasal secretions was determined using a designed ion-selective electrode.

Olfactory function assessment

The ‘Sniffin’ Sticks’ test (Burghardt®, Wedel, Germany) is a clinical evaluation of the olfactory function based on pen-like odor dispensers. It includes 3 tests of olfactory function, odor threshold (T), odor discrimination (D), and odor identification (I) [17, 18]. By measuring these tests, the TDI value could be determined. It was done before treatment and 1 month later. The patient was asked to identify an odor from a set of 4 visual and written cues. A TDI score of 30.75 points or more represents normosmia, a score between 16.75 and 30.50 points represents hyposmia and a score less than 16.75 points represents anosmia [19, 20].

Determination of calcium in the nasal secretions

The nasal secretions were collected before treatment and 1 month later immediately after sneezing. The collection was done using a small stainless steel clamp (approximately 10 mm × 5 mm × 2 mm) on the septum between the nostrils to allow the secretions to drain into a special 1.5-mL tube [22]. The secretions were diluted by adding 2 mL borate buffer solution. The protein contents were denatured by adding 3 mL acetonitrile. Then, the solutions were evaporated to dryness and the residues were diluted with borate buffer solution in 10-mL volumetric flasks. Ion selective electrode using carbon paste [22, 23] was designed by the Department of Pharmaceutical Analytical Chemistry, Cairo Faculty of Pharmacy, Al-Azhar University. The designed electrode was used for the determination of the calcium concentration of the nasal secretions before treatment and 1 month later.

Statistical analysis

The statistical assessment was done using SPSS v23 statistical software (SPSS, Inc, Chicago, Illinois). The results obtained were checked for normality and parametric or nonparametric tests were used accordingly. In general, results were expressed as mean ± standard deviation, unless otherwise stated. Differences in frequencies of the sample populations were assessed using Fisher’s exact probability test. Unpaired t-test, was used to compare and test the significance of the results of the 2 groups. Statistical significance was assigned when p < 0.05.

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