Transient cerebral ischaemic attacks (TIAs) account for 13–15% of all acute cerebrovascular disorders (Vereshchagin N.V. et al., 1997; Shalkevich V.B. et al., 1997).
At present, pathogenetic treatment and prevention of TIA are based on antiplatelet agents, vasoactive drugs and nootropics; other neuroprotective agents, including antihypoxants and antioxidants, are also used during the first days after an attack (Vereshchagin N.V. et al., 1997; Evstigneev V.V. et al., 1998). Nevertheless, treatment and prevention outcomes cannot be considered satisfactory because stroke risk is high during the first month (up to 8–10%) and first three years (one third of patients) after TIA (Vereshchagin N.V. et al., 1997; Cillessen J.P. et al., 1993; Laloux P. et al., 1995). Despite pathogenetic drug therapy, recurrent TIA risk also remains high: approximately 20% in the first month and more than 50% in the first year.
Marked, prolonged disturbances of cerebral blood-flow autoregulation and CNS function persist for up to a month or longer after TIA. Drug therapy cannot activate the TIA patient’s own sanogenetic mechanisms.
We propose intermittent normobaric hypoxic therapy (INH) for treatment and prevention of TIA.
Indications
TIA in the carotid and vertebrobasilar territories associated with arterial hypertension and atherosclerosis of extracranial and intracranial cerebral vessels, 7–15 days after disease onset.
Required equipment
1. A Bio-Nova-204 hollow-fibre membrane gas-separation unit made by Bio-Nova, to produce a normobaric hypoxic gas mixture with adjustable oxygen concentration.
2. A Bion B-002 pulse oximeter to monitor oxygen saturation of arterialized blood (SaO₂).
3. A stopwatch to determine heart rate (HR).
4. A manometer to monitor blood pressure (BP).
5. An Intra-view ultrasound Doppler system made by Rimed Ltd., Israel.
Method of treatment
First stage
Before the INH course, patients undergo the usual examination, including assessment by a neurologist and a physician, to establish indications and detect contraindications. The work-up includes electrocardiography, chest fluoroscopy and a complete blood count; women are examined by a gynaecologist. If there are no contraindications, every patient undergoes a hypoxic tolerance test before INH: inhalation of the hypoxic mixture for 10 minutes. Before testing, explain that the patient will breathe air with reduced oxygen content, and may remove the mask independently and resume atmospheric-air breathing if any unpleasant sensation occurs, without waiting for the physician’s instruction.
During the test, a Bion B-002 pulse oximeter continuously records arterialized-blood oxygen saturation (SaO₂); heart rate and respiratory rate are determined. BP is measured before the test and at minutes 4 and 9. Signs of increased sensitivity to oxygen deficiency include increased sweating; increased pallor of skin and mucosae; a pulse increase of more than 30 beats/min; bradycardia below 60 beats/min; a BP increase of more than 30 mmHg; and pronounced dyspnoea with a respiratory-rate increase of more than 15/min.
The method is contraindicated if these changes occur during the first 60–90 seconds of hypoxic-mixture breathing. In some cases, however, these symptoms except bradycardia reflect an emotional reaction to the hypoxia procedure and resolve spontaneously a few minutes after mask removal. Such reactions should not be regarded as contraindications to hypoxic therapy. Bradycardia below 60 beats/min in response to hypoxia should sometimes be considered a manifestation of sick sinus syndrome.
Second stage
At 7–15 days after TIA, a course of 12–15 INH sessions, one daily, is given alongside pathogenetic drug therapy. This includes antiplatelet treatment with aspirin 125 mg/day, a nootropic, piracetam 1.2 g/day, and in some cases vasoactive agents, Cavinton 15 mg/day or cinnarizine 75 mg/day. Antihypertensive treatment is given when indicated.
Hypoxic gas is breathed in a cyclic, fractionated regimen: 5 minutes breathing a mixture of 10–12% oxygen in nitrogen at normal atmospheric pressure, followed by 5 minutes breathing atmospheric air containing 20.9% oxygen, forming one cycle. A session comprises six cycles of hypoxic-mixture breathing, giving a total hypoxic exposure of 30 minutes. The adjustable normobaric hypoxic mixture is produced by a Bio-Nova-204 hollow-fibre membrane gas-separation unit. During INH, a Bion B-002 pulse oximeter monitors SaO₂, while HR and BP are recorded.
The first INH session is supervised by a physician. Subsequent sessions are monitored by nursing staff.
Cerebral blood-flow autoregulation is known to be a major sanogenetic mechanism in ischaemic brain injury. In addition to clinical examinations, we recommend transcranial Doppler ultrasound (TCD) to assess hypoxia tolerance, autoregulation and treatment effectiveness objectively. Autoregulation is quantified by the cerebrovascular reactivity (CVR) index: the difference in linear blood-flow velocity in the relevant basal cerebral artery during a functional test divided by its resting baseline value, expressed as a percentage. Functional tests induce vasodilation or vasoconstriction through changes in cerebral arterial and/or arteriolar tone and address different autoregulatory mechanisms: neurogenic, myogenic and humoral (Evstigneev V.V. et al., 1997; Yonas H. et al., 1998).
A common test uses a 30-second breath hold after expiration, reflecting humoral autoregulation: cerebral arteries and arterioles dilate in response to endogenous CO₂ accumulation in blood. Bilateral TCD is performed in the middle or posterior cerebral arteries according to the affected territory. TCD is conducted before treatment, after the sixth or seventh INH procedure, and after completion of the course, at 12–15 sessions.
The proposed INH treatment alongside pharmacotherapy has a fairly high clinical effectiveness. By the middle of the course, patients feel better; headache, dizziness, swaying sensations and unsteadiness while walking diminish or disappear. BP normalizes in many patients.
Our findings indicate that, in the great majority of TIA patients receiving INH alongside pathogenetic drug therapy with antiplatelet agents and nootropics, clear clinical improvement is accompanied by a steady rise in CVR index (Table 1).
Table 1. CVR index during a 30-second breath hold
| Treatment | Patients | Baseline, % | Mid-course, % | End of course, % |
|---|---|---|---|---|
| Pharmacotherapy | 10 | 9,3 ± 2,88 | 12,2 ± 2,57 | 14,7 ± 4,95 |
| INH plus pharmacotherapy | 16 | 9,1 ± 3,23 | 15,8 ± 3,68 | 21,1 ± 3,91* |
* Significant difference versus baseline, p < 0.05.
As the table shows, CVR index does not change significantly by the end of drug-only treatment, but increases more than twofold with INH plus pharmacotherapy.
Comparison of CVR index at mid-course (5–7 sessions) and after completion in patients receiving INH plus pharmacotherapy showed that hypoxia’s therapeutic action increased reactivity by the end of treatment to more than twice baseline and one quarter above the intermediate value. This supports the need for 12–15 INH sessions for complete therapy and rehabilitation after TIA.
TIA is a particular type of paroxysmal, short-lived condition in which clinical signs sometimes disappear before treatment begins. Pathogenetic treatment and prevention should therefore be considered together, with absence of recurrent ischaemic episodes apparently the main favourable outcome. Table 2 presents follow-up data on recurrent TIAs during the first month after the event in patients receiving INH plus pharmacotherapy and those receiving pathogenetic medication alone.
The drug-only group had five recurrent TIAs during the first month, whereas no recurrence occurred in the INH-plus-pharmacotherapy group. These findings support proposing INH as an effective pathogenetic method of preventing recurrent TIA.
Table 2. Recurrent TIAs during the first month
| Treatment | Patients | Recurrent TIAs |
|---|---|---|
| Pharmacotherapy | 10 | 5 |
| INH plus pharmacotherapy | 16 | 0 |
Including the treatment period.
The proposed INH treatment was not only clinically effective but also well tolerated. No adverse reactions occurred during the INH course in the patients we observed (see Appendix).
According to published evidence, INH’s favourable effects include increased red-cell count and consequently haemoglobin concentration, changes in haemoglobin’s oxygen-transport properties, more efficient blood respiratory function, increased pulmonary ventilation and improved pulmonary respiration. This is reflected by a greater alveolar-ventilation share of minute ventilation and increased oxygen diffusion from alveoli to blood (Meerson F.Z., 1993; Agadzhanyan N.A. et al., 1997). Blood supply increases; cerebral microcirculation improves through expansion of its microvascular bed; conditions for microcirculation in the heart, liver and reproductive organs improve. Oxygen diffusion into tissues with activated metabolism is substantially improved. The most informative indicators of effective hypoxic adaptation are improved mental and physical performance, higher maximal workload and work volume during high-intensity exercise, increased maximal oxygen uptake and a reduced functional cost of the workload.
A method of preventing TIA in the vertebrobasilar territory using hypobaric chamber hypoxic therapy is known (Shalkevich V.B., 1988). INH nevertheless has several advantages over hypobaric chamber therapy (Meerson F.Z., 1993; Agadzhanyan N.A. et al., 1997):
1. INH either completely avoids adverse reactions to hypoxic adaptation or substantially reduces the damaging effects of hypoxia.
2. While retaining the training effect of hypoxic adaptation, INH halves total hypoxic exposure per session compared with hypobaric therapy: 30 versus 60 minutes.
3. INH has a pronounced training effect on cerebral blood-flow autoregulation, haemoglobin oxygen transport, the respiratory function of blood and pulmonary respiration.
4. INH is more accessible to routine healthcare than hypobaric chamber therapy. With inhalational anaesthesia equipment it can be used even at central district hospital level.
5. INH avoids several disadvantages of hypobaric chamber therapy: adverse effects of a rarefied atmosphere, possible barotrauma, baroreceptor excitation, claustrophobia and others.
Thus, INH alongside pharmacotherapy can be recommended for broad use in neurological practice for treatment and prevention of TIA.
Possible complications and their management
Possible complications of INH treatment after TIA include clinical symptoms indicating oxygen deficiency. All patients undergo a hypoxic tolerance test before INH: inhalation of the hypoxic mixture for 10 minutes.
The proposed INH treatment is well tolerated. No adverse reactions occurred during the INH course in the patients we observed.
The Stange test can help select the optimal breathing regimen according to individual compensatory and adaptive capacity. This timed breath-holding test after inspiration is a simple, sufficiently informative indicator of compensatory reserves. If breath-hold time is up to 10 seconds, limit uninterrupted hypoxic-mixture breathing, that is one cycle, to 2 minutes. For a 10–20-second breath hold, extend the cycle to 3 minutes; for 20–30 seconds, to 4 minutes; and for more than 30 seconds, to 5 minutes. Perform the Stange test before INH and immediately after the course. Longer maximum breath-holding indicates a positive treatment effect.
We also recommend measuring it at mid-course to establish the dynamics of change.
In patients with cardiovascular pathology, recording an ECG during the hypoxic test is advisable as a control for objective assessment of hypoxia tolerance.
Contraindications
1. Acute infectious diseases and exacerbations of chronic inflammatory processes.
2. Acute noninfectious diseases in their acute phase, including myocardial infarction, spontaneous pneumothorax, status asthmaticus, hypertensive crisis and others.
3. Thromboembolism of branches of the pulmonary artery.
4. Conditions requiring intensive care, including shock, coma and carbon monoxide poisoning.
5. Decompensated chronic diseases, including chronic renal failure requiring haemodialysis.
6. Grade III arterial hypertension and unstable angina.
7. Congenital abnormalities of the heart and great vessels.
8. Acquired valvular heart disease and myocardial or pericardial diseases in the decompensated stage.
9. Individual intolerance of oxygen deficiency.
Appendix: clinical examples
Case 1. Patient S., a woman aged 48, was admitted to the medical rehabilitation department of Vitebsk Regional Clinical Hospital, case record No. 1249, on 26 January 2001. She reported intermittent attacks of dizziness, swaying, numbness of the right side of the face, double vision and a veil before her eyes lasting about 30 minutes. She had been ill for 5–6 years with 8–10 such attacks, most recently on 18 January 2001. From 18 to 25 January she was treated in the neurology department of Polotsk City Hospital. Despite antiplatelet, neuroprotective and vasoactive treatment, she continued to report intermittent headaches, dizziness and BP fluctuations; hypertension had been present for 8–9 years.
Examination found no focal neurological signs. BP was 160–170/90–100 mmHg. Clinical blood and urine tests and blood biochemistry were normal. ECG showed left ventricular hypertrophy. Doppler ultrasound of extracranial and intracranial cerebral vessels found no haemodynamically significant flow abnormality; flow was symmetrical. Diagnosis: TIA in the vertebrobasilar territory on 18 January 2001 associated with arterial hypertension. Bilateral transcranial Doppler examination of the posterior cerebral arteries was performed according to the affected territory. Before treatment, CVR during a 30-second breath hold was 7.6% on the right and 6.1% on the left. She received 14 INH sessions alongside basic pathogenetic medication, including antihypertensive treatment.
Mid-course CVR in the right and left posterior cerebral arteries was 10.5% and 9.3%; after completion, 17.9% and 19.3%. She felt better after two sessions. BP normalized after five sessions to 130–140/80–90 mmHg. No recurrent TIA occurred during treatment. She was discharged on 16 February 2001 in satisfactory condition without complaints.
Case 2. Patient G., a man aged 47, was admitted to the same rehabilitation department on 5 February 2001, case record No. 1608. He reported predominantly occipital headache, noise in his head, cardiac-region pain and intermittent BP rises. During a hypertensive episode with headache he developed weakness and numbness of the right limbs lasting 30–40 minutes. From 26 January to 4 February he was treated in the neurology department of Postavy Central District Hospital. Hypertension had been present for about 20 years, with continuous antihypertensive medication. Examination showed mild Romberg unsteadiness with satisfactory coordination tests.
Clinical blood and urine tests and biochemistry were normal. ECG showed left ventricular hypertrophy and clockwise rotation of the heart around its longitudinal axis; fundoscopy revealed narrowed retinal arteries. Doppler ultrasound showed asymmetry of linear flow velocity in the middle cerebral arteries, with a 25–30% reduction in the left middle cerebral artery. Diagnosis: TIA in the left carotid territory on 26 January 2001 associated with arterial hypertension and cerebral atherosclerosis. Bilateral TCD of the middle cerebral arteries was performed according to the affected territory. Before treatment, CVR during a 30-second breath hold was 10% on the right and 7% on the left.
He received 15 INH sessions alongside basic pathogenetic medication, including antihypertensive treatment. At mid-course the CVR indices, reported in the source as right and left posterior cerebral arteries, were 28.3% and 13.4%; after completion, 32.9% and 18.6%. Headaches disappeared by mid-course, and BP normalized by the end. No recurrent TIA occurred during treatment. He was discharged on 26 February 2001 in satisfactory condition, reporting occasional noise in his head.
These cases clearly demonstrate the high clinical effectiveness of the proposed treatment and prevention method for TIA, its positive effect on cerebral blood-flow autoregulation and the absence of adverse effects.
References
Full main-text translation of: Н.Н. Белявский, В.И. Кузнецов, С.А. Лихачев. Способ лечения и профилактики транзиторных церебральных ишемических атак с помощью интервальной нормобарической гипокситерапии. Инструкция по применению № 6–0102, 9 апреля 2002 г. Витебский государственный медицинский университет. 14 с.
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