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ORIGINAL ARTICLE
Year : 2021 | Volume
: 70
| Issue : 1 | Page : 60-70
Extra pulmonary boosting in chronic obstructive pulmonary disease: leverage of piracetam as an adjunctive therapy on respiratory and neuropsychiatric functions in patients with chronic obstructive pulmonary disease
Ahmed M Abumossalam1, Amr F Sheta2, Sahar E Ahmed3, Dalia A Elhalaby4, Amro A Moawad5
1 Department of Thoracic Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Neuropsychiatry, Dakhlia Psychiatric Hospital, Mansoura, Egypt
3 Psychiatry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
4 Department of Radiology, Mansoura International Hospital, Ministry of Health, Mansoura, Egypt
5 Department of Thoracic Medicine, Mansoura University, Mansoura, Egypt
Correspondence Address:
MD Ahmed M Abumossalam
Department of Thoracic Medicine, Faculty of Medicine, Mansoura University, 35611
Egypt
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ejcdt.ejcdt_112_20
Background Promotion of central control of respiration might contribute in minimization of chronic obstructive lung disease disability.
Objectives Our study was done to evaluate the effect of oral supplementation of piracetam tablets in low dose (400 mg twice daily) versus high dose (1200 mg twice daily) in patients with chronic obstructive pulmonary disease grade IV with type II respiratory failure, on respiratory parameters (spirometric, respiratory muscle strength, and diaphragmatic echographic measurements; velocity and excursion), in addition to neuropsychiatric parameters (cognitive functions and brain changes with MRI).
Patients and methods This randomized controlled study was conducted on 126 patients who were subjected to oral piracetam and classified into group A (42 patients received 800 mg daily for 3 months), group B (44 patients received 2400 mg daily for 3 months) for 3 months, and group C (40 patients) as a control group. Pulmonary evaluation, by spirometry and respiratory muscle study by Pimax, Pemax, Sniff test, and diaphragmatic echography, was conducted in addition to neuropsychiatric evaluation by Alzheimer disease 8 cognitive score assessment and brain MRI.
Results Total pulmonary fractional functional progress of piracetam was higher in group B (28.12%) than group A (23.27%) and the control group (5.68%). On the contrary, neuropsychiatric fractional functional progress was higher in group B (29.11%) than group A (15.7%), and lastly, the control group (<1%).
Conclusion Oral piracetam demonstrated enhanced spirometric parameters and improved cognition with low dose, but with high dose, it enhanced both spirometric and respiratory muscle strength and cognitive parameters with brain MRI and apparent diffusion coefficient changes.
Keywords: Alzheimer disease 8, chronic obstructive pulmonary disease, diaphragm echography, fractional progress, piracetam, spirometry
Chronic obstructive pulmonary disease (COPD) still presents a major disabling etiology of respiratory morbidity as well as mortality. It is not only limited to be of pulmonary consequences but also extends to other body systems [1]. By definition, COPD is a chronic inflammation complicated by airflow limitation that is not entirely reversible [2]. Acute COPD exacerbations frequently give rise to irreversible hypoxemia and hypercapnea with marked pulmonary dysfunction, frequent hospital admissions, may end with mechanical ventilation, and deterioration of patients’ quality of life [3],[4]. Ventilatory drive alterations originate from mixed neurogenic, psychogenic, and metabolic stimuli. In recent times, research on blood gases imbalance in animals and human studies on functional neuroimaging modalities revealed that chronic hypoxemia and hypercapnea in COPD may be accompanied by cerebral cortex functional derangement as well as cognitive decline and descending tracts affection [5],[6],[7]. Hence, vascular fortification may improve the quality of life and reduce morbidity and mortality among patients with COPD [8].
Cerebral damage in patients with COPD could be multifactorial, including hypoxemia and vascular derangement, supported by data from available imaging studies in heterogeneous populations [9],[10]. Pulmonary dysfunction has been linked to greater cerebral white matter lesions, irrespective of conventional vascular risk factors together with smoking [11],[12], and a significant correlation was ascertained by lung dysfunction, cerebral cortical atrophy, and white matter lesions in cases with ‘chronic respiratory disease’ [13]. This correlation, also, stated that there is a consistent link between smoking together with reduction in volume and hypodensity of frontal gray matter, and cerebral cortical atrophy on MRI [14].
Piracetam is considered as one of pyrrolidone family members of chemicals and first developed in France in the 1970s as an example of a nootropic agent to ‘enhance learning and memory.’ The importance of this group of medications relies on their use in mild cognitive impairment as well as epilepsy. The pyrrolidone family of chemical compounds is distinctive in that subtle modifications in their structure cause diverse effects on the central nervous system (CNS). The common mechanism of action of them is the potentiation of acetylcholine by either increasing its production or decreasing its breakdown. Furthermore, piracetam potentiates neuron function with supplementary neuroprotective functions as augmenting cellular metabolism and oxidative glycolysis, as well as improving cerebral blood flow and reducing the risk of thrombosis by optimizing erythrocyte function and decreasing platelet aggregation, accordingly enhancing cerebral perfusion and resultant improved pulmonary function and respiratory derive [15]. So, our aim was to evaluate the effect of oral supplementation of piracetam tablets in low dose (400 mg twice daily) versus high dose (1200 mg twice daily) in patients with COPD grade IV with type II respiratory failure, on respiratory parameters (spirometric, respiratory muscle strength, and diaphragmatic echographic measurements; velocity and excursion) in addition to neuropsychiatric parameters (cognitive functions and brain changes with MRI).
Patients and methodsStudy
Type of study: the study was a true experimental study (randomized controlled clinical study).Date of study: it was conducted from February 2019 till January 2020.Place of study: it was performed at Intermediate Care Unit in Chest and Neurology Departments Mansoura International Hospital, Dakhlia, Egypt.Ethical approval: departmental and institutional review board acceptance from Ministry of Health was obtained.All cases participating in our study were informed of the research and subjected to oral consent according to legal protocols.
Patients
This study was conducted on 126 cases of patients with COPD admitted in intermediate critical care unit, in Chest and Neurology Departments Mansoura International Hospital, Dakhlia, Egypt.
Inclusion criteria
Patients with COPD grade IV with type II respiratory failure [forced expiratory volume of the 1 s (FEV1)/forced vital capacity (FVC)<0.70, with postbronchodilator spirometryàFEV1<30% of normal or <50% of normal with chronic respiratory failure] according to grades of COPD severity using GOLD guidelines (2020) were included [2].
Exclusion criteria
The following were the exclusion criteria:
Mild and moderate COPD: type I respiratory failure.Organ failure (liver cell failure, renal failure, and left-sided heart failure).Neuromuscular diseases (myasthenia, myopathy, and neuropathy).Known cerebrovascular disorders.Autoimmune diseases.Musculoskeletal disorders.Patients’ allocation
Group A included 42 patients who were advised to receive oral piracetam tablet 400 mg twice daily for 3 months.Group B included 44 patients who were advised to receive oral piracetam tablets 1200 mg twice daily for 3 months.Group C: control group included 40 patients who did not receive piracetam drug.Patients were strictly observed by first-degree relative to ensure oral intake of the piracetam drug. All patients continued to take their COPD medications.
Regarding interventions, all patients in our work were subjected to the following:
Data collection: history taking (age, sex, disease duration, smoking duration, smoking index, duration of strict adherence to COPD therapy, and frequency of hospital admission in the last 5 years).Procedures:Pulmonary function tests:Spirometry was accomplished using Smart pulmonary function test Set (Medical Equipment Europe GmbH Company, Leibnizstrasse, Hoechberg, Germany, consistent with the standardized protocol. Patients were instructed to be operated in the sitting position with slight head elevation with wearing a nose clip using the tube mouthpiece [FEV1, FVC, FEV1/FVC ratio, and maximum voluntary ventilation-peak expiratory flow rate (MVV-PEFR)] before and after therapy for measuring fractional functional progress (FFP).Respiratory pressures measurement was performed using a handheld mouth pressure meter (Micro MPM; Micro Medical Company, United Kingdom), measuring maximal inspiratory pressure, Pimax-maximal expiratory pressure, and Pemax-Sniff nasal inspiratory pressure. Components of this device were a pressure transducer plus an electronic calculator. A small leak of ∼1–2-mm hole was permitted to avoid closure of glottis and decrease use of buccal muscles. It was performed starting from near RV and near TLC, respectively.Echography for diaphragmatic excursion and velocity: they were evaluated by both B and M mode ultrasound of the right posterior diaphragm during different voluntary breathing maneuvers using Mindray Dp 2200, 2018 machine with low frequency (2.5–5 MHz) convex probe. All patients underwent diaphragmatic measurement through three echographic views (anterior subcostal, lateral axillary, and posterior infra-scapular).The Alzheimer disease (AD8) Administration and Scoring Guidelines [16] (pre–post):A spontaneous self-correction was permitted for all answers without counting them as an error. The questions were applied on a clipboard to the respondent for self-demonstration or could be read loudly to the respondent either over the phone or in personal form.Framingham stroke risk profile: this score was used to anticipate the probability of cerebrovascular diseases and consisted of the following features: age, cigarette smoking status, history of cardiovascular disease, systolic blood pressure, diabetes, antihypertensive medication, atrial fibrillation, and left ventricular hypertrophy [17].MRI:Image acquisition:
Patients’ examinations were conducted on MRI scanner (1.5 T) Philips In genie (Philips Health Care, Heide, the Netherland). MRI protocol of the brain included the following: sagittal spin-echo T1-weighted images/axial T2-weighted/axial fluid-attenuated inversion recovery sequence and coronal images. Diffusion-weighted spin-echo single-shot echo planar pulse sequence was performed to generate apparent diffusion coefficient (ADC) values. It was obtained by setting repetition time 4600 ms-echo time/110 ms-FOV 212 mm-matrix 212×212-NEX 3. Images were achieved with values of b 0, 500, and 1000 mm2/s.
ADC is a measure of the magnitude of water molecule diffusion within tissue and is routinely clinically measured using MRI with diffusion-weighted imaging. ADC maps of the images were automatically created, and the ADC values were estimated on this map for all studied cases.
Image analysis:
Conventional MRI analysis was done to assess vascular white matter hyperintensities, brain atrophy, and lacunar infarctions fluid-attenuated inversion recovery sequence and T2-weighted images were applied. Regarding white matter integrity, a circular region of interest was situated within the cerebral white matter of the cortical lobes, that is, frontal, temporal, parietal, and occipital bilaterally, with ruling out the partial-voluming with CSF and gray matter. Quantitative measurements of ADC values with a commercially accessible software package were made. For every patient, three measurements were taken with obtaining the mean value for evaluation.
Outcome assessment
Effect of the drug (piracetam) can be measured by summation of the FFP of each parameter and each system separately, and then dividing them by their number:
[Table 1] and [Table 2] show that the mean age of group C was the highest, whereas group B was the youngest one. Male predominance was observed in the three groups. The mean duration of COPD process, mean duration of smoking, as well as mean duration of adherence of therapy without interruption were higher in the group B followed by group C and lastly the group A. The frequency of hospital admission in the last 5 years was higher in the control group followed by the high piracetam dose group, and lastly, the low-dose group. Significant statistical differences were detected among the three groups regarding the following parameters; sex, duration of COPD, frequency of hospital admission, duration of smoking, and smoking index (P<0.05).
[Table 3] shows that FFP of pulmonary functional parameters revealed a higher percentage parameters such as FEV1, FVC, PEFR, Pimax, Pemax, and MVV in group B than group A; however, the control group showed the lowest percentage in all parameters, with variable differences. Sniff nasal pressure was equivalent in group A and group B (22.01 and 22.61%, respectively). Diaphragmatic echography displayed a higher FFP in group B by 60% in both excursion and velocity than group A (18.23, 11.03% and 20.015, 12.25%, respectively). Control group was the lowest one in diaphragmatic echographic features, as described in [Figure 1]. Significant statistical differences were detected among the three groups regarding PEFR, Pemax, Sniff nasal inspiratory pressure, and diaphragmatic velocity, in addition to total FFP (P>0.05).
Table 3 Pulmonary functional, respiratory muscle strength, and radiological characteristics of studied groups
Figure 1 Arbitrage of pulmonary and neuropsychiatric characteristics of studied groups.From [Table 4], it could be declared that cognitive improvement was detected in group B by 62.5% followed by group A by 35.7% and lastly group C by 9%. Framingham stroke risk profile was higher in control group followed by group A and lastly group B. Regarding radiological features, the white matter hyperintensities and the multiple punctate lesions showed higher percentages in group A (71.42%) followed by group C (70%) and lastly group B (63%), but the higher percentage of improvement after therapy was found in group B by 35.71% than group A by 26.66% followed by group C by 7.14%. While speaking about initially confluent lesions, they showed a higher percentage in group B (36.36%) followed by group C (30%) and lastly group A (28.57%) but with a higher degree of improvement after therapy in group B by 56.26% than group A by 25% followed by group C by 8.33%. Concerning periventricular lesions, there was a higher percentage in group A (33.33%) before and after therapy followed by group B (25%) and lastly group C (22.5%), which deteriorated after therapy. Mild brain atrophy was prevalent in the three groups, being more in group C (85%) followed by group A (83.3%) and finally group B (72.72%); however, moderate atrophy was higher in group B followed by group A and lastly group C. The degree of improvement was favorable in group B by 31.25% than group A by 28.57% than group C by 5.88%. Regarding moderate atrophy, group B showed a higher improvement degree by 66.66% than group A by 28.57%. FFP of MRI ADC in different brain lobes was higher in group B than group A then group C, apart from temporal lobe, which was comparable between groups A and C, as described in [Figure 1]. Significant statistical differences were detected concerning white matter hyperintensities, periventricular lesions, and mild brain atrophy, as well ADC for frontal lobe only.
Table 4 Neurological functional and radiological characteristics plus MRI apparent diffusion coefficient pattern of studied groupsIn [Table 5], positive correlations were identified between MRI ADC with the duration of COPD process and the duration of smoking; however, a negative correlation was found with the duration of adherence to treatment, with significant statistical differences. Total pulmonary FFP was higher in the high-dose group B (28.12%) than in the low-dose group A (23.27%) than the control group C (5.68%). On the contrary, total neurological FFP was higher in the high-dose group B (29.11%) than the low-dose group A (15.7%) and lastly the control group C less than 1%. Significant statistical differences were detected among three group regarding total FFP in pulmonary and neurological evaluation, as described in [Table 3] and [Table 4] and in [Figure 2].
Table 5 Correlation between MRI apparent diffusion coefficient and the duration of smoking, the duration of disease and the duration of adherence to therapy Discussion The human CNS and the normal ventilatory system seem to have an optimal functional balance. Mild changes could have a major effect on both, either acute or chronic effects. Acute or chronic respiratory deficits lead to innumerable sequences of neurological, neuropsychological, and pulmonary signs and symptoms, which are the eventual concerns mainly from hypoxia and hypercapnia [18].
The neurons can adjust their activity in reaction to hypoxia by lowering their metabolic rate, so reduce the synthesis of adenosine triphosphate through oxidative phosphorylation, but this feature is not universal. These changes are owing to modification in signaling pathways, in neuromodulators and their receptors (nitric oxide, opioids, P substance, catecholamines, gamma-aminobutyric acid, and glutamate) in addition to consequences of the genomic background [19].
The thalamus, hypothalamus, pons, and medulla constitute the sites responsible for controlling sympathetic and respiratory activities. Once they are activated, they produce enhancement of respiratory system and sympathetic activities [20].
Mild hypoxia can cause the augmentation of cerebrospinal fluid by two-fold and lowers PaCO2 mostly by neurogenic components arising from the brain stem [21].
While the delivery of oxygen to the CNS is relatively resumed after exposure to chronic hypoxia, the same feature is deficient in the mitochondria. Oxygen delivery to the tissues decreases because the power that guides diffusion of oxygen from the capillaries to the tissues is the PaO2 gradient [22].
Piracetam affects vascular and neuronal functions and has a direct effect on cognitive function without acting as a sedative or stimulant. Piracetam is categorized as a positive allosteric modulator of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, despite being very weak in clinical practice [23].
It is hypothesized to work on ion carriers, enhancing neuron excitability. Piracetam improves the action of the neurotransmitter acetylcholine using muscarinic cholinergic receptors that are linked to memory processes [24]. Piracetam by other means, might induce cell membrane permeability together with modulation of ion channels (i.e. Na+, K+) [25]. Enhancement of oxygen consumption in the brain induced by piracetam occurs by connection to adenosine triphosphate metabolism, and via increase the activity of adenylate kinase in brains. An additional effect of piracetam is carried out by increasing the synthesis of cytochrome b5 [26], which is a modality of the mechanism of electron transport in mitochondria with augmentations of the permeability of its outer membrane to some intermediates of the Krebs cycle [26],[27].
In our study, high-dose piracetam group showed a higher percentage concerning duration of COPD process, duration of smoking, and the duration of adherence to therapy, whereas the low-dose group showed higher percentage in the frequency of hospital admission.
Our findings in this work stated that high-dose piracetam group revealed high FFP percentage than low-dose group concerning functional respiratory parameters (FEV1, PEFR, Pemax, MVV, diaphragmatic excursion, and velocity) than FVC, Pimax, and Sniff nasal pressure, which was approximate or fairly showed a slight increase as in Pimax. The explanation for these findings could not be attributed to the direct effects of drug high dose on respiratory nerve centers rather than increase muscle endurance and tolerance. Moreover, piracetam, as most studies postulated, has vasoactive properties related to vasodilation and furthermore increases cerebral cellular uptake of oxygen that restores ischemic brain centers and optimizes their functions and neuronal tract integrity with neuromodulatory mechanisms. Diaphragmatic muscle potency enhancement regarding velocity and excursion can be ascribed to neuronal cell regeneration rather than muscle fiber intensification. Group C showed minimal fractional progress that did not exceed 10% at most pulmonary variables. These improvements may be related to nutritional factors and also the fluctuation of differential measurements between times.
Our research detected that FFP regarding MRI ADC evaluation showed a higher percentage in high-dose group than low-dose group in all lobes, that is, frontal and parietal and temporal and occipital lobes, denoting universal increased in blood perfusion, although the cumulative reduction in ADC was not marked in all lobes. The temporal lobe showed equal percentages in low and control groups, but the occipital lobe showed deterioration not progress in the control group.
In our study, neurological cognitive evaluation of cases showed that group B revealed higher fractional progress than group A. Although Framingham stroke risk was higher in group A than group B. Radiological evaluation of patients brought out that white matter hyperintensities including punctate and confluent lesions were dominant in high-dose group and showed greater improvement and progress than other two groups, whereas periventricular lesions showed a higher percentage of fractional progress in group A than the other two groups. Fractional progress of brain atrophy in its moderate form was prevalent in group B than other two groups, whereas progress in mild form was close together in both groups A and B, whereas the C group showed almost no progress. MRI ADC values were favorable in their progress in group B than the other two groups but with minimal differences, making it less advisable as an indicator in the assessment.
We found a positive correlation between MRI ADC values and duration of COPD process plus the duration of smoking duration, but there was a negative correlation with duration of adherence with treatment. The total pulmonary FFP of piracetam was higher in high-dose group (28.12%) followed by a low-dose group (23.27%), and finally, the control group (5.68%). On the contrary, neurological FFP was higher in high-dose group (29.11%) followed by low-dose group (15.7%) than the control group less than 1%.
A pilot study done by Olaya et al. [28] revealed that in 12 patients who were given piracetam for 45 days were accompanied by an increase in blood flow in eloquent cortex, mainly Heschl’s gyrus and Wernicke’s, besides Broca’s areas, in the treatment group versus the placebo one. In contrast, the placebo group showed increased perfusion just in the inferior part of the left precentral gyrus. These alterations provided a biologically plausible mechanism for the effect of piracetam on the language improvement found by a study conducted by Huber et al. [29].
Other uses of piracetam in pulmonary practice included treatment fetal distress during labor, and managing breath-holding spells with less understudied mechanism [30].
Along with a meta-analysis on human studies, piracetam improves cognition in general when supplemented by cases with cognitive declines, like that related to aging. Supplementation of piracetam to healthy people experiences little to no cognitive benefit or advantage on longevity, except for older people due to cellular membrane fluidity enhancement. Piracetam has an effective property as aspirin, preventing blood clotting, with beneficial effect on cardiovascular issue [31].
In recent decades, research on COPD and OSAS demonstrated the presence of cognitive impairment caused by mild to moderate hypoxia and/or hypercapnea [32] and also patients exposed to artificially induced hypoxia and high altitude climbers [33]. Moderate to severe cognitive impairment had been described in 42% of patients with COPD (n=203) and in 14% of controls [34]. Disorders in the form of memory impairment, attention disturbance, verbal language loss, difficulties in abstract thinking, and the dysexecutive syndrome were identified, whereas visual attention can be somewhat well-preserved [35]. Reduction of FEV1 and FVC were predictive parameters of cognitive impairment in COPD [36].In another study, white matter lesions mainly caused by small artery cerebrovascular disease and periventricular as well as subcortical lesions were associated with cognitive deficits [37]. Most of these lesions arise from endovascular cholesterol deposition and owing to its local damaging problems. One of the main difficulties encountered in their research was the way to deal with vascular risk factors [38],[39].
MRI techniques were used to measure functional and microstructural brain changes in patients with COPD. White matter integrity and gray matter activation showed to be dissimilar between patients with COPD and age-matched healthy control cases. A lot of white matter lesions in patients with COPD on average 46% of their white matter skeleton presented a proof of microstructural damage, but no cerebral atrophy was found [40]. Exposure to cigarette smoke was linked to microstructural integrity deficit [41]. In COPD cases, factors such as FEV1 and arterial saturation showed no relationships with the extent of white matter damage [42]. In Wersching et al. [43] study, they supposed mechanisms of white matter changes to include systemic inflammation, hemodynamic instability, oxidative stress, and high C-reactive protein, which was linked with reduced white matter integrity irrespective of cardiovascular risk factors. Patients with COPD showed worsen cognitive ability, except for episodic memory, which was equivalent to controls. This concluded that cognitive dysfunction in COPD might be precipitated by disturbance of gray matter activation and white matter integrity [44].
Our study, through its course, was faced by multiple hazards and few limitations. Our hazards were found to be related to loss of follow-up owing to COPD, disabilities, or mortalities related to it. Moreover, adverse effects of piracetam in high dose like nervousness, insomnia, and excitability added more load on cases. Limitations in our work were encountered in the classification of COPD grades and subtypes of hypoxemia and hypercapnia, which was difficult owing to case to case and time to time variability in each case, also, presence of occult vascular or neurological disease, which was not known to the patient or treated before the presence of hemorrhagic disorders and renal or hepatic impairment and hypothyroid disorders.
ConclusionOral piracetam as a cerebral vasoactive agent might have a direct central boosting effect evidenced by enhanced spirometric parameters with improved cognitive level with low dose but with high dose. It enhanced both spirometric and respiratory muscle strength parameters and diaphragmatic echography with brain MRI changes.
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Conflicts of interest
There are no conflicts of interest.
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