Effects of Photobiomodulation Therapy Combined with Static Magnetic Field in Severe COVID-19 Patients Requiring Intubation: A Pragmatic Randomized Placebo-Controlled Trial

Figures & data

Figure 1 PBMT-sMF device. Figure 1 shows the device used to applied the PBMT-sMF and placebo. A cluster probe with 20 diodes containing 4 diodes of 905 nm, 8 diodes of 633 nm and 8 diodes of 850 nm was used: A - Red LEDs; B - Infrared LEDs; C - Super-pulsed laser; D - Magnetic field.

Figure 2 Irradiation of interventions. (A) shows the sites where PBMT-sMF and placebo were irradiated. The interventions were irradiated at six sites in the lower thorax/upper abdominal cavity and two sites in the neck area. (B) shows the full description of the parameters of PBMT-sMF applied in the treatment. This figure is owned by the authors.

Table 1 Demographic and Clinical Characteristics of the Patients at Baseline

	Placebo (n = 15)	PBMT-sMF (n = 15)	P value
Age (years)	67.93 (11.68)	64.2 (18.67)	0.51
Gender (%)
Female	8	6
Male	6	8
Body mass (Kg)	77.96 (18.49)	72.40 (16.94)	0.39
Height (cm)	165.06 (11.57)	168 (7.98)	0.42
SPAS 3	63.40 (13.43)	59.73 (13.24)	0.46
Comorbidities (%)
Hypertension	9 (60.0)	5 (33.3)
Diabetes	8 (53.3)	4 (26.7)
Obesity	4 (26.7)	3 (20.0)
Dementia	3 (20.0)	2 (13.3)
Depression	2 (13.3)	0 (0.00)

Notes: Categorical variables are expressed as number (%). Continuous variables are expressed as mean (SD).

Abbreviations: PBMT-sMF, photobiomodulation therapy combined with static magnetic field; SAPS 3, Simplified Acute Physiology Score 3.

Figure 3 CONSORT flow diagram of the study. Figure 3 shows the flow diagram of the study including enrollment, randomization, intervention allocation, follow-up and data analysis of the two groups.

Table 2 Hospitalization Outcomes

	Placebo	PBMT-sMF	Between Groups Comparisons	Mean Difference [95% CI]	Effect Size Cohen d
Length of stay in ICU (Days)	Total (n=15): 23.06 (± 20.37) Non-survivors (n=10): 20.4 (± 20.58) Survivors (n=5): 28.4 (± 21.12)	Total (n=15): 16.26 (± 9.61) Non-survivors (n=8): 18.65 (± 9.88) Survivors (n=7): 13.57 (± 9.25)	Total: p=0.25 Non-survivors: p=0.82 Survivors: p=0.12	Total: - 6.80 [−18.71 to 5.11] Non-survivors: −1.75 [−18.6 to 15.1] Survivors: −14.83 [−34.61 to 4.94]	Total: 0.4 (small) Non-survivors: 0.1 (small) Survivors: 0.9 (large)
Hospitalization length (Days)	Total (n=15): 24.33 (± 20.24) Non-survivors (n=10): 20.40 (± 20.58) Survivors (n=5): 32.20 (± 19.09)	Total (n=15): 18.33 (± 8.95) Non-survivors (n=8): 18.75 (± 10.08) Survivors (n=7): 17.85 (± 8.17)	Total: p=0.30 Non-survivors: p=0.83 Survivors: p=0.10	Total: −6.0 [−17.7 to 5.69] Non-survivors: −1.65 [−18.56 to 15.26] Survivors: −14.35 [−32.13 to 3.43]	Total: 0.4 (small) Non-survivors: 0.1 (small) Survivors: 0.9 (large)
Deaths/Discharges	10/5	8/ 7	p=0.46	——–	——–

Notes: Continuous variables are expressed as mean (standard deviation). Categorical variables are expressed as number.

Abbreviations: PBMT-sMF, photobiomodulation therapy combined with static magnetic field; ICU, intensive care unit; CI, confidence interval.

Table 3 Ventilatory Parameters

	Placebo (n = 15)			PBMT-sMF (n = 15)			Placebo vs PBMT-sMF
	Baseline	Day 10	Endpoint	Baseline	Day 10	Endpoint	Between Groups Comparisons	Mean Difference [95% CI]	Effect Size Cohen d
Thickness fraction diaphragm (%)	25.28 (± 12.85)	22.90 (± 7.58)	23.76 (± 13.15)	29.55 (± 13.56)	37.09 (± 17.02)	44.22 (± 12.59)**	Baseline: p=0.99 Day 10: p=0.0117 Endpoint: p=0.0001	Baseline: 4.27 [−7.41 to 15.95] Day 10: 14.19 [2.50 to 25.87] Endpoint: 20.46 [8.77 to 32.14]	Day 10: 1.1 (large) Endpoint: 1.6 (large)
PEEP (cmH2O)	9.13 (± 2.64)	8.93 (± 2.46)	8.20 (± 4.09)	9.00 (± 1.96)	7.53 (± 2.82)	6.60 (± 2.82)	Baseline: p=0.99 Day 10: p=0.5540 Endpoint: p=0.3931	Baseline: −0.13 [−2.69 to 2.43] Day 10: −1.40 [−3.96 to 1.16] Endpoint: −1.60 [- 4.16 to 0.96]	Day 10: 0.5 (moderate) Endpoint: 0.5 (moderate)
PO2 (mmHg)	91.46 (± 20.78)	99.74 (± 29.93)	92.74 (± 28.00)	108.22 (± 29.68)	106.46 (± 33.98)	109.29 (± 26.16)	Baseline: p=0.99 Day 10: p=0.99 Endpoint: p=0.34	Baseline: 16.76 [−8.64 to 42.16] Day 10: 6.72 [−18.68 to 32.12] Endpoint: 16.55 [−8.85 to 41.95]	Day 10: 0.2 (small) Endpoint: 0.6 (moderate)
FiO2 (%)	69.66 (± 21.91)	63.20 (± 26.72)	75.46 (± 31.59)	62.33 (± 21.03)	51.26 (± 26.07)	51.53 (± 29.68)	Baseline: p= 0.33 Day 10: p=0.6590 Endpoint: p=0.0456	Baseline: −7.33 [−30.92 to 16.26] Day 10: −11.94 [- 35.53 to 11.65] Endpoint:- 23.93 [−47.52 to −0.34]	Day 10: 0.5 (moderate) Endpoint: 0.8 (large)
PO2/FiO2 (mmHg)	146.71 (± 61.85)	183.32 (± 81.85)	158.26 (± 102.37)	199.65 (± 109.82)	261.28 (± 156.21)	276.15 (± 163.07)	Baseline: p=0.67 Day 10: p=0.2246 Endpoint: p=0.0233	Baseline: 52.94 [−53.63 to 158.50] Day 10: 77.95 [−27.63 to 183.50] Endpoint: 117.90 [12.31 to 223.50]	Day 10: 0.6 (moderate) Endpoint: 0.9 (large)

Notes: **Intragroup difference (PBMT-sMF) compared to the baseline (p<0.01). Continuous variables are expressed as mean (SD).

Abbreviations: PBMT-sMF, photobiomodulation therapy combined with static magnetic field; PEEP, positive end-expiratory pressure levels; PO₂, arterial partial pressure of oxygen; FiO₂, fraction of inspired oxygen; PO₂/FiO_2, ratio of arterial partial pressure of oxygen and fraction of inspired oxygen.

Table 4 Biochemical Markers and Hemogram Parameters

	Placebo (n = 15)			PBMT-sMF (n = 15)
	Baseline	Day 10	Endpoint	Baseline	Day 10	Endpoint	Between Groups Comparisons	Mean Difference [95% CI]	Effect Size Cohen d
CRP (mg/dL)	201.30 (± 65.39)	118.79 (± 71.00)	156.53 (± 124.49)	152.29 (± 108.88)	98.70 (± 95.24)	72.66 (± 75.40)	Baseline: p=0.41 Day 10: p=0.99 Endpoint: p=0.045	Baseline: - 49.01 [−131.60 to 33.58] Day 10: −20.09 [−102.70 to 62.50] Endpoint: −83.87 [−166.50 to −1.28]	Day 10: 0.2 (small) Endpoint: 0.8 (large)
TNF-alpha (pg/mL)	17.23 (± 13.46)	12.28 (± 5.42)	17.05 (± 7.54)	19.71 (± 17.51)	18.40 (± 13.43)	14.19 (± 5.44)	Baseline: p=0.99 Day 10: p=0.44 Endpoint: p=0.99	Baseline: 2.48 [−7.71 to 12.68] Day 10: 6.11 [−4.08 to 16.32] Endpoint: - 2.87 [−13.07 to 7.33]	Day 10: 0.5 (moderate) Endpoint:0.4 (small)
Vitamin D (ng/mL)	14.88 (± 5.13)	18.28 (± 9.95)	14.16 (± 4.80)	19.04 (± 10.83)	17.85 (± 6.67)	21.07 (± 7.07)	Baseline: p=0.43 Day 10: p=0.99 Endpoint: p=0.0502	Baseline: 4.15 [−2.75 to 11.07] Day 10: −0.42 [−7.34 to 6.48] Endpoint: 6.90 [−0.004 to 13.82]	Day 10: 0.1 (small) Endpoint:1.1 (large)
Erythrocytes (millions/mm^3)	4.20 (± 0.58)	3.73 (± 0.55)	3.40 (± 0.54)^##	3.75 (±0.64)	3.18 (± 0.59)	3.04 (± 0.90)**	Baseline: p=0.19 Day 10: p=0.065 Endpoint: p=0.389	Baseline: −0.45 [−1.02 to 0.13] Day 10: −0.55 [−1.13 to 0.02] Endpoint: −0.36 [−0.94 to 0.21]	Day 10: 0.9 (large) Endpoint: 0.5 (moderate)
Haemoglobin (g/dL)	12.57 (± 1.91)	11.47 (± 1.78)	9.97 (± 1.73)^##	11.34 (± 2.14)	9.50 (± 1.55)*	9.03 (± 2.75)**	Baseline: p=0.29 Day 10: p=0.026 Endpoint: p=0.6173	Baseline: −1.23 [−3.03 to 0.56] Day 10: −1.97 [−3.77 to −0.17] Endpoint: −0.94 [−2.74 to 0.86]	Day 10: 1.2 (large) Endpoint: 0.4 (small)
Hematocrit (%)	36.92 (± 4.94)	32.66 (± 5.46)	30.57 (± 4.58)^##	33.67 (± 5.04)	29.03 (± 4.04)	27.78 (± 7.20)**	Baseline: p=0.29 Day 10: p=0.194 Endpoint: p=0.459	Baseline: −3.25 [−7.98 to 1.48] Day 10: −3.62 [−8.36 to 1.10] Endpoint: −2.79 [−7.52 to 1.94]	Day 10: 0.8 (large) Endpoint: 0.5 (moderate)
Leukocytes (mm^3)	11,466.00 (± 6677.06)	14,221.92 (± 5231.44)	17,742.66 (± 11,630.20)	12,175.33 (± 9330.37)	23,449.13 (± 33,682.68)	23,186.66 (± 21,612.65)	Baseline: p=0.99 Day 10: p=0.476 Endpoint: p=0.99	Baseline: 709.30 [−15,147 to 16,566] Day 10: 9227 [−6629 to 25,083] Endpoint: 5444 [−10,412 to 21,300]	Day 10: 0.4 (small) Endpoint: 0.3 (small)
Segmented Neutrals (mm^3)	9890.16 (± 5904.32)	13,010.82 (± 3191.26)	13,655.49 (± 10,037.05)	9834.14 (± 7425.83)	10,154.81 (± 3450.12)	15,017.58 (± 11,566.73)	Baseline: p=0.99 Day 10: p=0.91 Endpoint: p=0.99	Baseline: −56.02 [−6836 to 6724] Day 10: −2856 [−9636 to 3924] Endpoint: 1362 [−5418 to 8142]	Day 10: 0.9 (large) Endpoint: 0.1 (small)
Eosinophiles (mm^3)	47.43 (± 90.35)	19.41 (± 29.58)	1070.21 (± 2825.97)^#	49.73 (± 108.99)	115.11 (± 114.62)	223.86 (± 229.56)	Baseline: p=0.99 Day 10: p=0.99 Endpoint: p=0.146	Baseline: 2.30 [−1032 to 1037] Day 10: 95.70 [−939 to 1130] Endpoint: - 846.40 [−1881 to 188.3]	Day 10: 1.1 (large) Endpoint: 0.4 (small)
Basophils (mm^3)	5.84 (± 6.07)	7.83 (± 11.16)	18.54 (± 27.53)	7.57 (± 11.23)	10.77 (± 18.75)	22.88 (± 30.30)	Baseline: p=0.99 Day 10: p=0.99 Endpoint: p=0.99	Baseline: 1.73 [−15.79 to 19.26] Day 10: 2.93 [−14.59 to 20.46] Endpoint: 4.33 [−13.19 to 21.86]	Day 10: 0.2 (small) Endpoint: 0.2 (small)
Lymphocyte (mm^3)	764.31 (± 415.39)	1138.70 (± 484.81)	1554.00 (± 1072.52)	1183.26 (±1224.40)	1309.53 (± 560.02)	2713.83 (± 1899.26)**, ^$*	Baseline: p=0.87 Day 10: p=0.99 Endpoint: p=0.0125	Baseline: 418.9 [−543 to 1381] Day 10: 170.8 [−791.1 to 1133] Endpoint: 1160.00 [197.90 to 2122.00]	Day 10: 0.3 (small) Endpoint: 0.8 (large)
Monocytes (mm^3)	557.06 (± 459.19)	936.71 (± 499.14)	1057.01 (± 646.43)	661.23 (± 542.04)	1224.89 (± 496.07)*	1346.20 (± 862.56)**	Baseline: p=0.99 Day 10: p=0.576 Endpoint: p=0.571	Baseline: 104.2 [−431.3 to 639.6] Day 10: 288.2 [−247.2 to 823.6] Endpoint: 289.2 [−246.2 to 824.6]	Day 10: 0.6 (moderate) Endpoint: 0.4 (small)
Platelets (mm^3)	189,800.00 (± 92,499.57)	237,890.86 (± 71,588.08)	231,266.66 (± 104,779.67)	210,028.26 (± 90,254.29)	261,858.03 (± 145,159.59)	288,800.00 (± 166,270.09)	Baseline: p=0.99 Day 10: p=0.99 Endpoint: p=0.54	Baseline: 20,228 [−83,748 to 124,204] Day 10: 23,967 [−80,009 to 127,943] Endpoint: 57,533 [−46,443 to 161,509]	Day 10: 0.2 (small) Endpoint: 0.4 (small)

Notes: *Intragroup difference (PBMT-sMF) compared to the baseline (p<0.05); ^$*Intragroup difference (PBMT-sMF) compared to the Day 10 (p<0.01); **Intragroup difference (PBMT-sMF) compared to the baseline (p<0.01); ^#Intragroup difference (Placebo) compared to the baseline (p<0.05; ^##Intragroup difference (Placebo) compared to baseline (p<0.01). Continuous variables are expressed as mean (standard deviation).

Abbreviations: PBMT-sMF, photobiomodulation therapy combined with static magnetic field; CI, confidence interval; CRP, C-reactive protein; TNF-alpha, tumor necrosis factor.