Albuterol as an adjuvant in acute anticholinesterase pesticide poisoning: a randomized, placebo-controlled clinical trial

Abstract

Acute anticholinesterase pesticide poisoning is a serious clinical problem, particularly in developing countries. Atropine is the most acceptable treatment for acute anticholinesterase poisoning. However, it only stops fluid production. Albuterol is a beta-2 receptor agonist that can increase fluid removal and speed the return of effective oxygen exchange. This study aims to evaluate the safety and efficacy of nebulized albuterol as an adjuvant therapy in patients with acute anticholinesterase poisoning. This stratified block randomized, single-blinded, placebo-controlled, parallel-group clinical trial was conducted between November 2020 and October 2021. It enrolled 80 patients with acute anticholinesterase pesticide poisoning who were admitted to Tanta University Poison Control Center. Patients were allocated into two groups (40 patients each). The strata were based on the severity of poisoning (moderate and severe). Patients in group I received 10 mg of nebulized albuterol. Group II received an equivalent volume of nebulized normal saline. Additionally, standard treatment was provided to both groups. Outcomes included oxygenation, mortality, need for endotracheal intubation and mechanical ventilation, hospital stay duration, time to atropinization, and total doses of atropine and oxime. We found insignificant differences in sociodemographics, exposure characteristics, clinical manifestations, or routine laboratory tests between the studied groups. The median values of oxygen saturation by pulse oximetry were 99% in the albuterol moderate toxicity group and 98% in the control moderate toxicity group. Albuterol significantly improved oxygen saturation in moderate intoxicated patients (P = 0.039). Therefore, nebulized albuterol is a safe drug. Moreover, it may improve oxygenation in acute anticholinesterase pesticide poisoning.

Introduction

Pesticides are substances that kill pestiferous organisms. These compounds are massively used in crop protection and insect pest control, which leads to an increased incidence of acute or chronic poisoning in humans.^1,2

Anticholinesterase pesticides, including organophosphates (OPs) and carbamates, are the most commonly used pesticides in Egypt and developing countries due to their effectiveness and availability.^3,4

Acute poisoning with anticholinesterase pesticides is a serious clinical problem in many countries around the world, the majority of which are caused by OPs ingestion.^5,6 Acute poisoning with anticholinesterase pesticides may occur from intentional, accidental, or occupational exposure.^7,8 Self-poisoning with OPs is the most important form of acute poisoning worldwide, affecting over one million people and killing approximately 100,000 each year.⁹ In Egypt, acute OP poisoning is a toxicological problem of substantial concern. El-Maddah¹⁰ found that organophosphorus pesticides are among the most common causes of acute poisoning in Egypt.

Anticholinesterase pesticides inhibit cholinesterase activity, resulting in the overstimulation of nicotinic and muscarinic acetylcholine receptors.¹¹ Most deaths from acute anticholinesterase poisoning are due to respiratory failure, which can result from excessive airway secretions, airway obstruction, central apnea, and muscle weakness.¹²

The clinical care of patients with acute organophosphorus poisoning has little improved over the last six decades.¹³ Despite the use of antidotes (atropine and oximes) and supportive care, the mortality rate associated with OP poisoning remains high. Therefore, the research continues to identify effective new treatments for acute anticholinesterase pesticide poisoning.¹⁴

Supplemental antidotes, such as, clonidine, magnesium, nicotinic receptor antagonists, beta-adrenergic agonists and lipid emulsions are being explored in large experimental models and in pilot clinical trials.¹³

Atropine is the most acceptable and widely used antidote for OP and carbamate poisoning. It inhibits secretions of the nose, mouth, pharynx, and bronchi and thus dries the mucous membranes of the respiratory tract, especially if secretions are excessive. However, atropine only reduces fluid production and does not eliminate the secretions that have already formed in the lungs.^15,16

Albuterol is a widely available, selective beta-2 receptor agonist with rapid onset and short duration of action.^13,17 It is administered either by inhalation or orally to relax airway smooth muscles and reverse bronchoconstriction.¹⁸ It can increase alveolar fluid clearance by enhancing salt and water transfer across the alveolar and distal airways. This accelerates the return of effective oxygen exchange and improves respiratory function.^13,19

Recent randomized, controlled clinical trials have investigated the beneficial effects of beta-2 receptor agonists during resuscitation of acute anticholinesterase pesticide poisoning to achieve two goals: bronchodilation and clearance of secretions. .^19–21

Chowdhury et al.²⁰ conducted a pilot study on 75 patients comparing the effects of two different doses of nebulized salbutamol (2.5 mg and 5 mg) versus saline placebo in addition to standard treatment in the treatment of acute OPs-poisoned patients. Another clinical trial was carried out by El-Mansy et al.²¹ on 60 patients with acute anticholinesterase poisoning who received single doses (either 2.5 mg or 5 mg) of aerosolized albuterol besides the standard treatment. Unfortunately, the use of aerosolized albuterol as an adjuvant treatment could not improve oxygenation. These studies have recommended that future clinical trials should evaluate the effects of higher doses of aerosolized albuterol as adjuvant therapy in acute anticholinesterase pesticide poisoning. Hence, the current study aimed to evaluate the safety and efficacy of nebulized 10 mg of albuterol as an adjuvant therapy in patients with acute anticholinesterase poisoning.

Methods

Ethical considerations

This study was approved by the Research Ethics Committee of the Faculty of Medicine, Tanta University, Egypt (Approval code: 34150/9/20). Informed written consent was obtained from each patient or his guardians (if incapable of participating in the consent process). Confidentiality of the patient’s data was assured. This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT20210331050797N1).

Study design, setting, and date

This was a stratified block, randomized, single-blinded, placebo-controlled, parallel-group clinical trial. The study enrolled patients with acute anticholinesterase pesticide poisoning who were admitted to Tanta University Poison Control Centre between 2020 November 1, and 2021 October 31.

Eligibility criteria

We included patients (male or female, aged 12 years or older) with moderate or severe acute anticholinesterase pesticide poisoning. The diagnosis was based on a history of exposure to OPs or carbamates (identification of the container or the trade name of the pesticide), characteristic clinical manifestations, amelioration of symptoms and signs after administration of atropine, and a low serum pseudocholinesterase level.²²

We excluded patients younger than 12 years, pregnant and lactating women, patients exposed to other substances in addition to the anticholinesterase agent, and asymptomatic or mildly poisoned patients. We also excluded patients with major medical conditions (e.g. respiratory or cardiovascular disease, renal or hepatic insufficiency), late presenters (12 h or more after exposure to the anticholinesterase agent), and those who received unreported treatment before admission to our center.

Sample size calculation

The sample size was calculated using the G^*power 3.1.9.2 software. The alpha error level was set at 0.05, and the power was set at 0.80. The effect size was calculated based on the difference between the mean oxygen saturation level in anticholinesterase-poisoned patients and the hypothesized mean that could be achieved with the use of albuterol. Grmec et al.²³ reported a mean of 88.9% in OP poisoned patients, and we hypothesized that albuterol treatment could increase the mean oxygen saturation level to 94%. The calculated sample size was 35 patients per group. An expected attrition rate of 15% was added to the sample size to account for loss to follow-up, resulting in a final sample size of 40 patients per group.

Randomization and allocation concealment

Eighty patients were enrolled and randomly allocated to receive either albuterol 10 mg (intervention group, n = 40) or saline (control group, n = 40) in addition to the conventional treatment. Patient allocation was concealed using the method of sequentially numbered, opaque, sealed envelopes.²⁴ Two plastic containers were then prepared and labeled: one for the moderate poisoning stratum “A” and the other for the severe poisoning stratum “B.” The investigators performed a block randomization scheme with variable block sizes of 4 and 6, with groups I and II equally distributed. Finally, there were 50 envelopes in the severe poisoning stratum and 70 envelopes in the moderate poisoning stratum.

Blinding

After a participant was enrolled in the study, the investigator selected the proper envelope based on the participant's stratum and number, opened the envelope, and determined the participant’s allocation to group I or group II. Participants were blinded to intervention allocation.

Intervention

Eighty patients were allocated into two groups in a 1:1 ratio (40 patients in each group). The strata were based on the severity of the poisoning according to Minton & Murray²⁵ and included only moderate and severe grades of poisoning.

All patients received the standard care in addition to albuterol (intervention) or saline (placebo) according to the allocation sequence in each stratum. Standard care included all or some of the following: resuscitation, decontamination, and antidote administration (atropine with or without obidoxime). Resuscitation was indicated in some patients, and it included airway suctioning, oropharyngeal airway device placement, endotracheal intubation, and oxygen administration.

Gastric lavage was performed, and a single dose (50 g) of activated charcoal was administered to individuals who presented within 2 h of ingestion of the anticholinesterase agent. Skin decontamination was performed with soap and water.

Atropine was administered intravenously (IV) in bolus doses of 1–3 mg. The dose was doubled every three to five minutes until dryness of bronchial secretions was achieved. Once the patient was stable, atropinization was maintained by IV infusion for 24 h, starting with 10%–20% of the total dose required to stabilize the patient. Obidoxime (Toxogonin®, produced by Merck, Darmstadt, Germany) was administered as a 250 mg IV bolus followed by 250 mg/8 h for 24 h until at least 12 h after atropine was no longer required.

Group I (albuterol group or intervention group) received albuterol (Farcolin respirator solution containing salbutamol sulphate 0.5%, PHARCO Pharmaceuticals, Alexandria, Egypt) twice via a face mask nebulizer after resuscitation of the patient. An initial dose of 5 mg diluted in 2 mL of normal saline was inhaled by a face mask nebulizer over 10 min, and then the same dose was repeated 20 min after the beginning of the first dose. Patients were monitored for adverse effects of the nebulized albuterol, such as tachycardia, arrhythmias, and hypokalemia. Any adverse effect due to albuterol therapy was documented. During the aerosolization, if the heart rate raised by more than 30 beats/min or if the patient developed atrial or ventricular arrhythmias, albuterol administration was discontinued.

Group II (the control group) received a placebo (an equivalent volume of normal saline) by nebulization.

Outcome

The primary outcome was the change in oxygen saturation from baseline, measured during the first 60 min of receiving treatment. Measurements of oxygen saturation were obtained by pulse oximetry and arterial blood gas (ABG) analysis before the intervention and one hour after the start of the intervention. Secondary outcomes included mortality, need for endotracheal intubation, need for mechanical ventilation and ICU admission, length of hospital stay, time required for atropinization, and total doses of atropine and obidoxime received.

Statistical analysis

The collected data were statistically analyzed using the SPSS software statistical computer package for Windows, version 25 (IBM Corp., Armonk, N.Y., USA). The Shapiro–Wilk test for normality was used to assess the distribution of numerical data. Non-parametric data were presented as range, median, and interquartile range, whereas parametric data were presented as mean, standard deviation (SD), and range. Qualitative data were presented as counts and percentages. Results were tabulated, grouped, and statistically analyzed using the following tests: Mann–Whitney U test (U) was used to compare two independent groups for nonparametric quantitative variables. Independent t-test (t) was used for comparison between two independent groups for parametric quantitative variables. Wilcoxon signed rank test (z) was used for comparison between 2 dependent groups (before and after intervention) regarding non-parametric quantitative variables. Pearson Chi-Square test (χ²) was used to determine whether there was a significant association between different categorical variables and when it was inappropriate, it was replaced by Fischer Exact or Monte Carlo Exact test. P values ˂ 0.05 were considered statistically significant.

Results

A total of 149 patients were assessed for eligibility. Sixty-seven patients were excluded (40 had mild toxicity, 24 were younger than 12 years, three were late presenters, and two had hypokalemia at presentation), and 80 patients were allocated into two groups (40 patients each) (Fig. 1).

Fig. 1.

CONSORT flow diagram.

The study groups were comparable concerning their sociodemographic data and exposure characteristics, with no significant differences between the two groups (all P values >0.05, Table 1).

Table 1.

Baseline characteristics (N = 80).

	Albuterol group (n = 40)	Control group (n = 40)	P-value
Gender, n (%)			0.501 χ2
Male	20 (50.0%)	17 (42.5%)
Female	20 (50.0%)	23 (57.5%)
Age groups, year, n (%)			0.631 χ2
12–20	16 (40.0%)	18 (45.0%)
>20–40	19 (47.5%)	15(37.5%)
>40	5 (12.5%)	7 (17.5%)
Residence, n (%)			0.592 χ2
Rural	30 (75.0%)	32 (80.0%)
Urban	10 (25.0%)	8 (20.0%)
Marital status, n (%)			0.823 χ2
Single	21(52.5%)	20 (50.0%)
Married	19 (47.5%)	20 (50.0%)
Education, n (%)			0.420 MC
Illiterate	2 (5.0%)	4 (10.0%)
Primary—preparatory	20 (50.0%)	23 (57.5%)
Secondary—university	18 (45.0%)	13 (32.5%)
Occupation, n (%)			0.792 χ2
Unemployed	14 (35.0%)	9 (22.5%)
Farmer	4 (10.0%)	6 (15.0%)
Housewife	9 (22.5%)	10 (25.0%)
Students	12 (30.0%)	14 (35.0%)
Employee	1 (2.5%)	1 (2.5%)
Mode of poisoning, n (%)			0.592 χ2
Accidental	8 (20.0%)	10 (25.0%)
Intentional	32 (80.0%)	30 (75.0%)
Medical treatment before arrival, n (%)			0.809 χ2
No	28 (70.0%)	27 (67.5%)
Yes	12 (30.0%)	13 (32.5%)
Route, n (%)			0.057 FE
Ingestion	39 (97.5%)	33 (82.5%)
Inhalation	1 (2.5%)	7 (17.5%)
Amount, n (%)			0.398 χ2
Small	14 (35.0%)	9 (22.5%)
Large	12 (30.0%)	12 (30.0%)
Unknown	14 (35.0%)	19 (47.5%)
Type of poison, n (%)			0.237 χ2
Carbamates	29 (72.5%)	24 (60.0%)
Organophosphates	11 (27.5%)	16 (40.0%)
Time interval from poisoning to admission, h			0.853 U
Min – Max	1.0–10.0	1.0–10.0
Median (IQR)	3.0 (1.5–4.0)	3.0 (1.6–4.0)
Mean rank	40.0	41.0

χ²: Chi-square test, MC: Monte Carlo Exact test, FE: Fischer Exact test, Min: minimum, Max: maximum, IQR: interquartile range, U: Mann–Whitney U test

At the time of presentation, non-significant differences were observed as regards the vital signs, arterial blood gas analysis (Table 2), clinical manifestations (muscarinic, nicotinic, and CNS), and pseudocholinesterase levels (Table 3) between both groups with moderate and severe toxicity (all P values >0.05).

Table 2.

Vital signs and arterial blood gas analysis at the time of admission (N = 80).

	Albuterol moderate toxicity group (n = 30)	Control moderate toxicity group (n = 31)	P value a	Albuterol severe toxicity group (n = 10)	Control severe toxicity group (n = 9)	P value b
SBP, mmHg			0.866 U			0.402 U
Min – Max	90.0–150.0	100.0–170.0		80.0–170.0	70.0–140.0
Median (IQR)	122.5 (117.5–130.0)	120.0 (110.0–140.0)		135.0 (107.5–142.5)	130.0 (120.0–135.0)
Mean rank	31.4	30.6		11.0	8.9
DBP, mmHg			0.853 U			0.585 U
Min – Max	60.0–110.0	50.0–100.0		50.0–100.0	40.0–100.0
Median (IQR)	75.0 (70.0–90.0)	80.0 (70.0–90.0)		85.0 (77.5–100.0)	80.0 (75.0–90.0)
Mean rank	30.6	31.4		10.7	9.3
MAP, mmHg			0.931 U			0.539 U
Min – Max	70.0–120.0	66.7–120.0		60.0–123.3	50.0–113.3
Median (IQR)	91.7 (85.8–100.8)	93.3 (83.3–103.3)		101.7 (85.8–114.2)	96.7 (91.7–105.0)
Mean rank	30.8	31.2		10.8	9.2
Pulse, beat/m			0.164 U			0.805 U
Min – Max	38.0–120.0	55.0–150.0		50.0–120.0	40.0–150.0
Median (IQR)	81.5 (73.5–93.3)	92.0 (73.0–121.0)		103.5 (73.5–120.0)	100.0 (36.5–116.5)
Mean rank	27.8	34.1		10.3	9.7
RR, cycle/m			0.245 U			0.837 U
Min – Max	12.0–36.0	18.0–36.0		16.0–60.0	18.0–40.0
Median (IQR)	20.0 (18.0–22.0)	21.0 (19.0–24.0)		28.0 (18.0–38.5)	30.0 (20.0–32.0)
Mean rank	28.4	33.6		10.3	9.7
Temperature, C ο			0.422 U			0.636 U
Min – Max	36.5–37.3	36.5–37.5		36.5–37.4	36.0–37.5
Median (IQR)	37.0 (36.8–37.0)	37.0 (37.0–37.0)		37.0 (37.0–37.0)	37.0 (36.5–37.2)
Mean rank	28.8	32.1		10.5	9.4
O 2 saturation, % by pulse oximetry			0.315 U			0.712 U
Min – Max	85.0–100.0	80.0–100.0		51.0–100.0	40.0–99.0
Median (IQR)	97.5 (95.8–99.0)	98.0 (97.0–99.0)		83.0 (58.8–91.3)	81.0 (65.0–88.5)
Mean rank	28.7	33.2		10.5	9.5
pH			0.617 t			0.461 U
Min - Max	7.30–7.55	7.34–7.58		7.26–7.42	7.26–7.51
Mean ± SD	7.44 ± 0.06	7.43 ± 0.06		7.34 (7.29–7.40)	7.36 (7.33–7.37)
PCO 2 , mmHg			0.395 U			0.142 U
Min – Max	23.5–55.3	24.1–47.5		28.7–68.9	19.9–46.2
Median (IQR)	34.3 (31.1–39.9)	32.5 (28.3–40.1)		44.8 (32.4–51.4)	42.3 (26.9–45.7)
Mean rank	33.0	29.1		11.80	8.0
HCO 3 , mmol/L			0.082 U			0.086 U
Min – Max	20.4–30.2	13.5–30.3		19.5–34.1	14.5–23.9
Median (IQR)	22.8 (21.7–25.0)	21.5 (19.7–25.2)		22.7 (19.3–24.4)	19.2 (15.7–23.6)
Mean rank	35.0	27.1		12.1	7.7
PO 2 , mmHg			0.942 U			0.661 U
Min – Max	33.5–279.0	48.6–294.0		62.8–174.0	64.3–241.0
Median (IQR)	78.1 (64.3–103.0)	75.4 (64.3–113.0)		89.9 (70.7–126.3)	98.8 (85.0–114.1)
Mean rank	31.2	30.8		9.4	10.7
SO 2 , % by ABG			0.329 U			0.356 U
Min – Max	83.9–99.8	64.6–99.9		92.2–99.9	89.9–99.8
Median (IQR)	94.3 (92.2–97.5)	96.2 (92.2–98.5)		98.9 (92.2–99.6)	95.6 (92.6–97.3)
Mean rank	28.8	33.2		11.2	8.7

a: P value from a test comparing albuterol and control group with moderate toxicity, b: P value from a test comparing albuterol and control group with severe toxicity, SBP: systolic blood pressure, Min: minimum, Max: maximum, IQR: interquartile range, U: Mann–Whitney U test, DBP: diastolic blood pressure, MAP: mean arterial pressure, RR: respiratory rate, SD: standard deviation, t: Student's t-test, PCO₂: partial pressure of carbon dioxide, HCO₃: bicarbonate, PO₂: partial pressure of oxygen, SO₂: oxygen saturation, ABG: arterial blood gas

Table 3.

Clinical data at the time of admission (N = 80).

Manifestations		Albuterol moderate toxicity group (n = 30)	Control moderate toxicity group (n = 31)	P value a	Albuterol severe toxicity group (n = 10)	Control severe toxicity group (n = 9)	P value b
Muscarinic	Miosis	24 (80.0%)	22 (71.0%)	0.541 MC	9 (90.0%)	9 (100.0%)	1.000 FE
	Crepitations, n (%)	6 (20.0%)	3 (9.7%)	0.301 FE	8 (80.0%)	9 (100.0%)	0.474 FE
	Wheeze, n (%)	1 (3.3%)	0 (0.0%)	0.492 FE	3 (30.0%)	2 (22.2%)	1.000 FE
	Vomiting, n (%)	30 (100.0%)	31 (100.0%)	NA	10 (100.0%)	9 (100.0%)	NA
	Diarrhea, n (%)	16 (53.3%)	14 (45.2%)	0.523ꭓ2	6 (60.0%)	6 (66.7%)	1.000 FE
	Colic, n (%)	29 (96.7%)	30 (96.8%)	1.000 FE	3 (30.0%)	5 (55.6%)	0.370 FE
	Salivation, n (%)	0 (0.0%)	1 (3.2%)	1.000 FE	3 (30.0%)	3 (33.3%)	1.000 FE
	Sweating, n (%)	6 (20.0%)	8 (25.8%)	0.590ꭓ2	5 (50.0%)	3 (33.3%)	0.650 FE
	Bradycardia, n (%)	4 (13.3%)	1 (3.2%)	0.079 MC	2 (20.0%)	2 (22.2%)	1.000 MC
	Hypotension, n (%)	0 (0.0%)	1 (3.2%)	0.663 MC	1 (10.0%)	1 (11.1%)	0.809 MC
Nicotinic	Fasciculation, n (%)	29 (96.7%)	26 (83.9%)	0.195 FE	8 (80.0%)	9 (100.0%)	0.474 FE
	Hypertension, n (%)	7 (23.3%)	9 (29.0%)	0.663 MC	5 (50.0%)	3 (33.3%)	0.809 MC
	Tachycardia, n (%)	6 (20.0%)	14 (45.2%)	0.079 MC	5 (50%)	5 (55.6%)	1.000 MC
	Hypotonia, n (%)	14 (46.7%)	15 (48.4%)	0.893 ꭓ2	10 (100.0%)	8 (100.0%)	NA
	Mydriasis, n (%)	0 (0.0%)	2 (6.5%)	0.541 MC	0 (0.0%)	0 (0.0%)	NA
CNS	DCL	1 (3.3%)	0 (0.0%)	0.492 FE	9 (90.0%)	8 (88.9%)	0.149 U
Pseudocholinesterase level, U/L	Min – Max	1256.0–5624.0	2257.0–6254.0	0.334 U	1254.0–4158.0	1454.0–5274.0	0.191 U
	Median (IQR)	3853.5 (2799.8–4357.3)	4124.0 (3395.0–4785.0)		2528.0 (1433.8–2723.8)	3,418 (2366.5–4375.5)
	Mean Rank	28.8	33.2		8.4	11.8

a: P value from a test comparing albuterol and control group with moderate toxicity, b: P value from a test comparing albuterol and control group with severe toxicity, MC: Monte Carlo Exact test, FE: Fischer Exact test, NA: non-applicable, ꭓ2: Chi-square test, CNS: central nervous system, DCL: disturbed consciousness level, U: Mann–Whitney U test, Min: minimum, Max: maximum, IQR: interquartile range

After the intervention, the respiratory rate in the albuterol group with moderate toxicity became significantly lower than that in the control group (mean ranks: 26.6 and 35.2, P = 0.045). The HCO₃ values in the control group with severe toxicity became significantly lower than those in the albuterol group (mean ranks: 5.6 and 14.0, P = 0.001, Table 4).

Table 4.

Vital signs and arterial blood gas analysis after intervention (N = 80).

	Albuterol moderate toxicity group (n = 30)	Control moderate toxicity group (n = 31)	P value a	Albuterol severe toxicity group (n = 10)	Control severe toxicity group (n = 9)	P value b
SBP, mmHg			0.436 U			0.370 U
Min – Max	90.0–130.0	100.0–160.0		100.0–140.0	90.0–140.0
Median (IQR)	110.0 (100.0–120.0)	120.0 (110.0–120.0)		120.0 (107.5–120.0)	120 (120.0–125.0)
Mean rank	29.3	32.7		9.1	11.1
DBP, mmHg			0.257 U			0.461 U
Min – Max	50.0–90.0	60.0–90.0		60.0–80.0	60.0–80.0
Median (IQR)	70.0 (60.0–80.0)	70.0 (70.0–80.0)		70.0 (67.5–72.5)	70.0 (70.0–80.0)
Mean rank	28.5	33.4		9.2	10.9
MAP, mmHg			0.292 U			0.352 U
Min – Max	70.0–103.3	73.3–113.3		73.3–93.3	70.0–100.0
Median (IQR)	85.0 (75.9–90.0)	86.7 (80.0–93.3)		86.7 (80.0–93.3)	86.7 (86.7–93.3)
Mean rank	28.6	33.3		8.9	11.2
Pulse, beat/m			0.149 U			0.838 U
Min – Max	66.0–120.0	55.0–138.0		60.0–125.0	87.0–139.0
Median (IQR)	85.5 (77.8–95.3)	77.0 (73.0–93.0)		106.5 (88.8–113.3)	107.0 (89.0–119.0)
Mean rank	34.3	27.8		9.8	10.3
RR, cycle/m			0.045* U			0.967 U
Min – Max	12.0–28.0	18.0–30.0		17.0–48.0	18.0–33.0
Median (IQR)	20.0 (18.0–20.0)	20.0 (20.0–21.0)		26.5 (18.0–32.3)	24.0 (20.5–31.0)
Mean rank	26.6	35.2		10.1	9.9
Temperature, C ο			0.608 U			0.352 U
Min – Max	37.0–38.0	37.0–38.0		37.0–38.0	37.0–38.0
Median (IQR)	37.0 (37.0–37.2)	37 (37–37.5)		37.0 (37.0–37.4)	37.2 (37.0–37.5)
Mean rank	29.9	32.1		8.9	11.2
pH			0.088 t			0.513 U
Min – Max	7.34–7.56	7.36–7.51		7.25–7.54	7.29–7.53
Mean ± SD	7.41 ± 0.05	7.40 ± 0.04		7.41 (7.31–7.47)	7.37 (7.31–7.45)
PCO2, mmHg			0.564 U			0.288 U
Min – Max	19.2–46.5	24.0–50.6		24.4–61.8	16.4–44.0
Median (IQR)	35.1 (31.9–37.4)	35.4 (32–38.8)		36.4 (30.3–49.6)	33 (27.05–36.6)
Mean rank	29.7	32.3		11.3	8.6
HCO 3 , mmol/L			0.116 U			0.001* U
Min – Max	16.0–27.7	18.9–30.7		19.8–32.0	13.9–23.7
Median (IQR)	21.8 (21.2–24.1)	23.0 (21.3–26.7)		22.9 (20.7–26.1)	18.3 (17.7–19.0)
Mean rank	27.4	34.5		14.0	5.6
PO 2 , mmHg			0.248 U			0.356 U
Min – Max	29.8–402.5	33.9–170.0		50.5–167.3	64.3–154.0
Median (IQR)	91.4 (65.6–122.5)	85.9 (64.3–104.0)		84.2 (77.7–107.1)	88.6 (86.3–133.2)
Mean rank	33.7	28.4		8.8	11.3

a: P value from a test comparing albuterol and control group with moderate toxicity, b: P value from a test comparing albuterol and control group with severe toxicity, SBP: systolic blood pressure, Min: minimum, Max: maximum, IQR: interquartile range, U: Mann–Whitney U test, DBP: diastolic blood pressure, MAP: mean arterial pressure, RR: respiratory rate, ^*significant at P ˂ 0.05, SD: standard deviation, t: Student's t-test, PCO₂: partial pressure of carbon dioxide, HCO₃: bicarbonate, mmol/L: millimole/liter, PO₂: partial pressure of oxygen.

After the intervention, the median values of oxygen saturation by pulse oximeter were 99% in the albuterol group and 98% in the control group with moderate toxicity. Meanwhile, the median values of oxygen saturation by ABG analysis were 96.8% in both groups. There was a significant difference in oxygen saturation measured by pulse oximeter between the two studied groups after the intervention (P = 0.039). In the severe poisoning groups, the median oxygen saturation values measured by either pulse oximetry or ABG analysis showed insignificant differences between the two groups (all P values >0.05, Table 5).

Table 5.

Primary and secondary outcomes (N = 80).

	Albuterol moderate toxicity group (n = 30)	Control moderate Toxicity group (n = 31)	P value a	Albuterol severe Toxicity group (n = 10)	Control severe toxicity group (n = 9)	P value b
O 2 saturation by pulse oximeter, %
Min – Max	96.0–100.0	95.0–100.0	0.039* U	92.0–100.0	88.0–100.0	0.367 U
Median (IQR)	99.0 (98.0–99.0)	98.0 (98.0–99.0)		96.0 (93.0–97.3)	98.0 (92.3–99.0)
Mean rank	35.5	26.7		8.9	11.2
O 2 saturation by ABG, %
Min – Max	65.3–100.0	56.9–99.9	0.471 U	89.7–98.8	88.6–99.6	0.968 U
Median (IQR)	96.8 (92.6–98.1)	96.8 (95.0–98.8)		98.1 (92.2–98.3)	95.3 (92.2–98.9)
Mean rank	29.3	32.6		10.0	10.1
Total atropine dose, mg			0.742 U			0.250 U
Min – Max	1.0–13.0	1.0–15.0		3.0–50.0	3.0–29.0
Median (IQR)	3.0 (2.0–6.0)	3.0 (2.0–6.0)		18.5 (10–28)	8.0 (3.0–20.5)
Mean rank	31.75	30.27		11.40	8.44
Time needed for full atropinization, h			0.983 U			0.712 U
Min – Max	1.0–12.0	1.0–24.0		1.0–48.0	1.0–13.0
Median (IQR)	3.0 (1.0–5.6)	2.0 (1.5–5.0)		4.75 (1.75–22.5)	8.0 (3.0–11.0)
Mean rank	30.95	31.05		9.55	10.50
Total number of obidoxime ampoules			0.891 U			0.207 U
Min – Max	0.0–5.0	0.0–5.0		4.0–17.0	4.0–10.0
Median (IQR)	4.0 (3.8–4.0)	4.0 (4.0–4.0)		7.0 (4.0–12.8)	5.0 (4.0–7.0)
Mean rank	30.75	31.24		11.50	8.33
LOS, h			0.509 U			0.437 U
Min – Max	6.0–72.0	9.0–72.0		20.0–624.0	20.0–1440.0
Median (IQR)	21.5 (18.8–24.0)	24.0 (19.0–27.0)		52.0 (41.5–240.0)	36.0 (23.0–168.0)
Mean rank	29.5	32.5		10.95	8.94
Need for intubation, n (%)	0 (0.0%)	0 (0.0%)	NA	4 (40.0%)	6 (66.7%)	0.245 FE
Need for ICU admission/MV, n (%)	0 (0.0%)	0 (0.0%)	NA	3 (30.0%)	3 (33.3%)	1.000 FE
Mortality, n (%)	0 (0.0%)	0 (0.0%)	NA	1 (10.0%)	2 (22.2%)	0.582 FE

a: P value from a test comparing albuterol and control group with moderate toxicity, b: P value from a test comparing albuterol and control group with severe toxicity, Min: minimum, Max: maximum, IQR: interquartile range, U: Mann–Whitney U test, ^*significant at P ˂ 0.05, ABG: arterial blood gas, LOS: length of hospital stay, ICU: intensive care unit, MV: mechanical ventilation, NA: non-applicable, FE: Fischer Exact test.

No significant differences were observed between the two groups with moderate and severe toxicity with respect to total atropine dose, the median time to full atropinization, the median number of Toxogonin® ampoules administered, and the length of hospital stay (all P values >0.05, Table 5).

Both groups with moderate and severe toxicity were comparable regarding intubation, need for ICU with mechanical ventilation, and mortality rate (all P values >0.05, Table 5).

Serum potassium level after intervention became significantly lower than serum potassium level before intervention in the albuterol moderate toxicity group (P = 0.007). Serum potassium levels significantly decreased after intervention in the albuterol severe toxicity group (P = 0.011, Fig. 2).

Fig. 2.

Serum potassium level (mmol/L) before and after intervention in the studied Albuterol group with moderate and severe toxicity (n = 40). ^*significant at P ˂ 0.05 (from related-samples Wilcoxon signed rank test).

Discussion

Anticholinesterase pesticides are the most widely used pesticides in Egypt and other developing countries due to their low cost and availability.^3,26 Organophosphorus compounds are a leading cause of self-poisoning and mortality, particularly in Southeast Asia, China, and Africa.²⁷

Despite the use of these antidotes and supportive care, the mortality rate associated with OP poisoning remains high. Thus, the search continues for new alternative treatments.¹⁴

The aim of the current study was to evaluate the safety and efficacy of nebulized albuterol at a dose of 10 mg as an adjuvant therapy in patients with acute anticholinesterase pesticide poisoning.

This study found insignificant differences between the studied groups concerning patients’ sociodemographics, exposure characteristics, vital signs, and clinical manifestations. This ensures effective randomization and reduces the potential for selection bias.²⁴

To evaluate the safety of albuterol, vital parameters (especially heart rate) were assessed after the intervention in patients with moderate and severe toxicity. None of the patients in this study had to discontinue aerosolization or seek cardiac consultation, as the median pulse rate after intervention in the albuterol group with moderate toxicity was 85.5 beats per minute. In comparison, the albuterol group with severe toxicity showed a slight increase in pulse rate of less than 10 beats per minute (106.5 beats per minute). These results are comparable to those of El-Mansy et al.,²¹ who reported that none of the patients needed to stop albuterol aerosolization or consultation of cardiology as a single dose of aerosolized albuterol was safe and showed no changes in heart rate. Similarly, Chowdhury et al.²⁰ recorded an initial increase in the mean heart rate across all groups, and the heart rates were higher in patients receiving salbutamol 5 mg than in those receiving salbutamol 2.5 mg but the increase in heart rates was never hazardous.

Serum potassium levels were estimated before and after albuterol aerosolization to assess the safety of albuterol. Despite the statistically significant decrease in potassium level after the intervention, there was no evidence of hypokalemia before and after albuterol administration in patients with moderate and severe toxicity. This finding agrees with Burggraaf et al.²⁸ and El-Mansy et al.²¹ who reported no hypokalemia with the salbutamol doses used in their studies.

Outcomes evaluated to assess the efficacy of albuterol included mean blood oxygen saturation, time to full atropinization, doses of atropine and oximes, need for mechanical ventilation, length of hospital stay, and mortality.

Oxygen saturation was measured by pulse oximetry and ABG analysis. After the intervention, no significant difference was found in oxygen saturation calculated by ABG analysis was found between the two groups with moderate toxicity. However, there was a significant increase in oxygen saturation measured by pulse oximetry in the albuterol moderate toxicity group (99%) compared with the control group (98%). This result coincides with Eddleston²⁹ and Herbert et al.,¹⁹ who suggested that salbutamol can improve oxygen exchange in acute OP poisoning by reversal of bronchoconstriction and clearance of secretions through accelerating the removal of alveolar fluid and improving the passage of salt and water through the alveolar and distal airways. These findings disagree with El-Mansy et al.²¹ and Chowdhury et al.,²⁰ who found no significant improvement in oxygen saturation by pulse oximetry between the studied groups. This discrepancy may be explained by the low dose of nebulized albuterol used in their studies, as they used two different doses (2.5 mg and 5 mg), while the present study used a higher dose of albuterol (10 mg).

After the intervention in severe toxicity, the median oxygen saturation by pulse oximetry and ABG analysis was within the normal range with no significant difference between albuterol and control groups with severe toxicity. This finding is consistent with Chowdhury et al.²⁰ and El-Mansy et al.,²¹who reported no significant differences between the studied groups regarding oxygen saturation measured by either pulse oximetry or ABG analysis after treatment with no apparent evidence that nebulized salbutamol therapy is beneficial. However, in earlier studies conducted on guinea pigs with parathion poisoning, Segura et al.³⁰ and Chávez et al.³¹ reported a transient improvement of respiratory function following intraperitoneal injection of salbutamol.. The interpretation of this result can be explained by the abundance of bronchial secretions in patients with severe toxicity. The pulmonary fluid could reduce the ability of salbutamol to penetrate the alveolar epithelium.¹³

In the present study, the two moderate toxicity groups had comparable total doses of atropine, with no significant difference. Meanwhile, the albuterol group with severe toxicity required higher doses of atropine than the control group with severe toxicity, as the median total dose was 18.5 mg compared to 8 mg; however, this difference didn’t reach statistical significance. These results are comparable to Chowdhury et al.²⁰ and Sagah & Elhawary,³² who reported that the atropine doses in their studies ranged from 5 mg to 13 mg. Chowdhury et al.²⁰ also reported that salbutamol was ineffective in reducing the dose of atropine required to resolve cholinergic crisis. Despite lower doses of atropine were needed by El-Mansy et al.²¹ for full atropinization, there was no significant difference among the studied groups regarding atropine doses. This variation in atropine dose might be attributed to the difference in severity of poisoning among cases in both studies.

The median time to full atropinization was longer in the albuterol group than in the control group with moderate toxicity (3 h and 2 h, respectively), but shorter in the albuterol group than in the control group with severe toxicity (4.75 h and 8 h, respectively). However, these differences didn’t reach statistical significance. These results are comparable with data gathered by Ishfaq et al.,³³ who reported that the minimum time needed for complete atropinazation was 1 hour whereas the maximum time was 49 h. This disagrees with Chowdhury et al.,²⁰ who found that the median time to full atropinization was 15 min in all groups. This variation could be due to the different endpoint for atropinization in both studies, and most patients included in their study were mildly intoxicated.

As regards the obidoxime dose, it was observed that the median obidoxime dose required was four ampoules in both groups with moderate toxicity, whereas the median obidoxime dose required was seven ampoules in the albuterol group and five ampoules in the control group with severe toxicity. There were no significant differences between the two studied groups in moderate and severe toxicity. Such a result was in accordance with the findings of Ghonem et al.³⁴ and Shama et al.,³⁵ who found that the total doses of obidoxime used ranged between 4 and 5 ampoules. Another study conducted by El-Gendy et al.³⁶ showed that the total doses of oximes were higher in the group with severe acute OP toxicity compared to the mild and moderate toxicity groups.

In this study, the median length of hospital stay was 21.5 h in the albuterol group and 24 h in the control group with moderate toxicity. However, it was longer in the severe toxicity groups (52 h in the albuterol group and 36 h in the control group). There were no significant differences between the two groups regarding hospital stays in moderate and severe toxicity. These findings agreed with those of El-Ebiary et al.,³⁷ El-Mansy et al.,²¹ Hodeib & Khalifa,³⁸ and Eltramss et al.,³⁹ in which the length of hospital stay ranged from 6 to 48 h. Similar observations were reported in other studies where the length of hospital stay was longer in severe cases requiring ICU admission and mechanical ventilation.⁴⁰ Many factors could lead to the prolongation of hospital stay, including aspiration pneumonia, respiratory failure, cardiovascular collapse, and septic shock.⁴¹

None of the patients with moderate toxicity in either group required intubation or mechanical ventilation. Among patients with severe toxicity, 4 patients in the albuterol group required intubation compared to 6 patients in the control group. Three patients in each group with severe toxicity required ICU admission with mechanical ventilation, with no significant difference. These results are comparable with El-Mansy et al.²¹ who reported that four patients were intubated in the control group, and two of them required mechanical ventilation. Three patients in the intervention group were intubated and two of them required mechanical ventilation and ICU admission with no significant differences being detected in the studied groups.

These rates of ICU admission in the current study are similar to those reported by Acikalin et al.⁴² and El Taftazany et al.,⁴³ which ranged from 27% to 35%. A much lower rate (14%) was reported by Shahin & Hafez.⁶ These variations in the need for mechanical ventilation may be due to differences in the severity of poisoning in the studied samples.⁴⁴ Many parameters are used to determine the need for mechanical ventilation in acute OP poisoning, including PO₂ < 60 mmHg, pH < 7.2, tachypnea, persistent cyanosis, and apnea.⁴⁵

The mortality rate of OP poisoning ranges from 10 to 40% according to data from Asia.^46,47 In the current study, no deaths were recorded in either group with moderate toxicity. The mortality rate with severe toxicity was non-significantly higher in the control group (22.2%) than in the albuterol group (10%). Chowdhury et al.²⁰ reported an overall mortality rate of approximately 10%. In addition, El-Mansy et al.²¹ showed mortality rates of 10% in the control group and the group receiving albuterol (5 mg). This result is comparable to another Indian study using lipid emulsion with acute OPs poisoning which stated that the fatality rate was 12.5% in the study group and 13.8% in the controls.⁴⁸ Moreover, Szponar⁴⁹ reported that almost half of the patients requiring mechanical ventilation died. The low mortality rate in the current study may be due to the short time between exposure and hospital admission, early identification of the patients at risk, and intervention with early intubation and mechanical ventilation, as well as intensive patient monitoring. Death in patients with acute anticholinesterase pesticide poisoning is usually attributed to respiratory failure as a result of respiratory center inhibition, bronchospasm, bronchorrhea, aspiration of gastric contents, and flaccid paralysis of the respiratory muscles.^41,50

Limitations

This clinical trial was conducted at a single center, so the generalizability of the results should be considered with caution. This may be due to the fact that the patients in this study were enrolled during the COVID-19 pandemic era. Potential challenges, such as travel bans, quarantines, and social isolation made it difficult to collaborate in multicenter studies. The study was not powered to detect potential differences in mortality rates between the two groups. Serial recordings of oxygen saturation for each patient were not performed due to the lack of facilities.

Conclusions and implications

In conclusion, albuterol can be used safely in acute anticholinesterase poisoning. Aerosolized albuterol has no apparent benefit for acute anticholinesterase poisoning, despite the improvement in oxygen saturation measured by pulse oximetry in the moderate toxicity group, but this improvement was statistically not clinical. Future multicenter randomized clinical trials are strongly recommended to evaluate the safety and efficacy of IV albuterol in acute anticholinesterase pesticide poisoning. Further serial recordings of oxygen saturation are needed to demonstrate any improvement in oxygenation.

Authors' contributions

All authors contributed to the study's conception and design. Dr Samar Mohammed Magdy Zein-Elabdeen performed material preparation and data collection. Data interpretation and analysis were performed by Dr Samar Mohammed Magdy Zein-ElAbdeen, Dr Amal Saeed Ahmed Fathy Hafez, and Dr Aliaa Abd Elhakam Hodeib. The first draft of the manuscript was written by Dr Samar Mohammed Magdy Zein-ElAbdeen, Dr Amal Saeed Ahmed Fathy Hafez, and Dr Aliaa Abd Elhakam Hodeib. All authors commented on the manuscript’s previous versions, read, and approved the final version.

Funding

The authors did not receive support from any organization for the submitted work.

Conflict of interest statement. The authors have no conflicts of interest to declare that are relevant to the content of this article.

Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Consent to participate

An informed written consent was obtained from either patients or the legal guardians (in case of incompetent patients).

Consent for publication

Not applicable.

Ethics approval

The study was carried out with the agreement of the Faculty of Medicine's Research Ethics Committee, Faculty of Medicine, Tanta University (Approval number: 34150/9/20) and according to the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT20210331050797N1).