Introduction
Type 1 diabetes in children is an important medical problem, with incidence increasing by an average of 2.82% annually [1]. Its significance lies in early disability and reduced quality of life from complications, particularly diabetic peripheral polyneuropathy (DPN) and diabetic-foot risk [2]. Chronic hyperglycaemia initiates metabolic and vascular abnormalities causing segmental demyelination and axonal degeneration [3]. Oxidative stress plays a leading role: excess free radicals impair endothelial function and reduce endoneurial blood flow, causing endoneurial hypoxia and DPN [4, 5]. Altered circulating neurotrophic factors may also contribute, indicating depleted reserves and nerve-fibre demyelination [6].
These mechanisms highlight the need for new pathogenetically directed DPN treatments. Respiratory training combining hypoxia and hypercapnia is promising. Recent studies found greater neuroprotection from their combination than either alone [7, 8]. Stimulation of angiogenesis through increased vascular endothelial growth factor (VEGF) expression is one mechanism and may be decisive for repairing nerve-fibre injury [9, 10]. Hypercapnia also has a demonstrated antioxidant effect [11]. Benefits have been described in children with ADHD [12, 13] and facial neuritis [14]. Alongside stabilised function, improved well-being, mood and school performance positively affect children’s quality of life [15].
The study aimed to assess respiratory hypercapnic-hypoxic training in combined treatment of polyneuropathy caused by type 1 diabetes in children.
Materials and methods
The study at the endocrinology department of Altai Regional Children’s Clinical Hospital followed 50 children with type 1 diabetes: 31 girls and 19 boys.
All received basal–bolus insulin with short-acting NovoRapid and long-acting Levemir using Paradigm 722, 712 and 715 pumps (Medtronic MiniMed, USA) or Accu-Chek Spirit and Combo (Roche Diagnostics GmbH, Germany).
Inclusion required DPN verified clinically and by electroneuromyography (ENMG). Exclusions were diabetic nephropathy; acute or chronic metabolic acidosis including ketoacidosis; liver disease; hypocortisolism or hypothyroidism; central or peripheral nervous system disease, including epilepsy, migraine, ADHD and neural amyotrophy diagnosed in two diabetic girls; and previous traumatic brain injury. Other diabetic complications included microalbuminuria in 8% of each group (p>0.05) and nonproliferative retinopathy in 16% of intervention and 12% of comparison patients (p>0.05).
Simple randomisation using random-number tables formed age- and sex-comparable groups (p>0.05): intervention, 25 children, 15 girls and ten boys aged 12.9±1.8 years; comparison, 25, 16 girls and nine boys aged 13.2±2.0. Both received standard vascular treatment—ten intravenous infusions of 2% pentoxifylline, 100 mg/day—neurotrophic treatment—ten infusions of 20% piracetam, 30–50 mg/kg/day, then oral 400 mg twice daily for two months—and B vitamins: 1.0 mL intravenous B6 and B12, ten injections, then Neuromultivit one tablet daily for 20 days. Intervention children additionally received hypercapnic-hypoxic respiratory training.
Hypercapnic hypoxia was produced with the Carbonic respiratory trainer using adjustable added dead space. Moving a shutter varies alveolar gas concentration by changing added dead space smoothly from 500 to 1,000 mL. All children used a constant 500 mL and trained 20 minutes daily throughout their 14–16-day hospital stay.
Carbohydrate metabolism assessment comprised daily glycaemic profiles at 03:00, 06:00, 08:00, 11:00, 13:00, 16:00, 18:00, 21:00 and 24:00; mean amplitude of glycaemic excursions on the first and final treatment days; and admission glycated haemoglobin, HbA1c, measured routinely.
Table 1 presents disease duration and HbA1c as M±SD. HbA1c reflects metabolic compensation [2–4]: below 7.6% is optimal/compensated, 7.6–9% suboptimal/subcompensated and above 9% decompensated. Groups were also comparable on these measures.
DPN presence and severity were assessed by accepted criteria [16]. Pain, burning, paraesthesia and numbness were quantified using Total Symptom Score, TSS.
Neurological deficit was quantified by NIS-LL, Neuropathy Impairment Score–Lower Limbs. Muscle strength was tested through hip, knee, ankle and toe-joint flexion/extension: normal strength scored zero, 25% loss one, 50% two, 75% three, and paralysis four. Knee and Achilles reflexes and pain sensitivity were also scored; the sum evaluated treatment response. Clinical and ENMG absence of neuropathy defined DPN-0. ENMG abnormalities with up to two NIS-LL points but no neuropathic complaints defined DPN-1. DPN-2 required ENMG changes, NIS-LL above two and typical sensory phenomena. DPN impairing social or occupational adaptation was stage 3 [3–6, 16].
Device source: V.P. Kulikov and N.N. Yakushev, Device for producing hypoxic hypercapnia, Russian patent 2301081, 20 June 2007, Bulletin 17; registration FSR 2009/05033 of 10 June 2009. The original cites http://bd.patent.su/2301000-2301999/pat/servl/servlet5f37.html as accessible on 30 December 2016.
Objective ENMG assessment was performed on admission and discharge at day 14–16 with Nicolet EDX (USA), following standard practice [17]. Bilateral median, ulnar, peroneal and tibial motor fibres were studied for conduction velocity, m/s, motor M-response amplitude, mV, and residual latency, ms.
Statistical analysis used Statistica 6.0, StatSoft, USA. Shapiro–Wilk tested normality. Most datasets were nonnormal, so between-group comparisons used Mann–Whitney. Power was 80%, β≤0.2; significance p<0.05. Data are median with 25th/75th percentiles or mean M±SD.
Legal representatives gave voluntary informed consent before examinations and treatment. The ethics committee of Altai Regional Children’s Clinical Hospital approved the study.
Results and discussion
Safety assessment: no significant adverse events occurred during hypercapnic-hypoxic training in combined DPN treatment. Patients reported no new weakness, malaise, appetite loss, headache, nausea, somnolence or worsening limb pain/paraesthesia. On the first two days, glucose immediately after training at 13:00 rose to 15.0±2.3 mmol/L in intervention versus 9.6±4.2 in comparison (p<0.05). By 18:00 it was 12.9±3.2 versus 13.2±3.7 (p>0.05). On day three, 13:00 values equalised: 9.5±1.2 versus 9.8±2.3 (p>0.05). The study was thus safe for children’s life and health. An endocrinologist remained beside each patient throughout every daily session and supervised it. Post-discharge questionnaires consequently described greater physician attention and a more comfortable hospital stay than previously.
Effectiveness assessment: HbA1c of 10.6±1.1% in intervention and 11.3±1.3% in comparison showed metabolic decompensation, above 9%. Only 08:00 glucose changed significantly during treatment: baseline 13.1 mmol/L [10.2;15.6] versus 12.0 [8.7;16.9], and post-treatment 9.2 [6.2;11.8], p<0.01, versus 11.7 [6.8;15.2]. Between-group differences at other times were nonsignificant. Training significantly lowered fasting glucose, whereas comparison baseline-to-final changes were nonsignificant.
Daily glycaemic variability decreased in all children by treatment end, but group-level differences were nonsignificant. Mean excursion amplitude was 5.5±2.2 before and 3.7±1.8 mmol/L after intervention (p>0.05), and 5.9±3.4 versus 3.8±2.8 in comparison (p>0.05).
Initially, intervention included 22 DPN-2 and three DPN-3 children; comparison included 23 and two, respectively (p>0.05). Neuropathic symptoms—pain, burning, paraesthesia and numbness—declined in both groups. TSS fell from 4.5±2.1 to 1.6±0.5 with intervention and 5.7±3.2 to 2.5±1.1 in comparison, both p<0.05; post-treatment between-group differences were nonsignificant. NIS-LL differed significantly between groups after treatment (p<0.05): intervention fell from 5.2±1.1 to 3.1±0.4 and comparison from 6.1±1.6 to 4.5±0.5, both p<0.05. TSS based on complaints is more subjective than NIS-LL [16]. Severity shifted from severe/moderate to slight/absent, DPN-2/3 to DPN-0/1 [3–6,16]. Afterwards DPN-0 occurred in four versus two (p<0.05), DPN-1 in 20 versus 18 (p>0.05), DPN-2 in one versus three (p<0.05), and DPN-3 remained only in two comparison patients.
Table 2 shows ENMG changes. Intervention reduced residual latency except in the ulnar nerve and increased velocity in every motor nerve. Median-nerve latency decreased 6% and velocity rose 14%; tibial values changed by −28%/+13% and peroneal by −26%/+7%. M-response amplitude increased 29% in tibial and 20% in peroneal stimulation. Comparison improved less and with lower significance: only peroneal latency, −26%, and ulnar latency, −2%, decreased significantly. Ulnar velocity increased 9% with intervention but decreased 7% in comparison; comparison median motor velocity rose 16%. Comparison amplitudes did not change significantly. Overall ENMG improvements were greater with training.
One of our clinical observations illustrates these findings.
Clinical case
Patient P., a 12-year-old boy, had diabetes since 2010, a six-year history. Diagnosis: decompensated type 1 diabetes; complications: post-injection abdominal and thigh lipodystrophy. Associated diagnosis: diabetic polyneuropathy 2, N2b-TSS 6.0.
Admission complaints were unstable glucose with hypo-/hyperglycaemia, pulling pains in arms and legs mainly at night, and glove-and-stocking paraesthesia and itching.
Disease began with ketonuria without acidosis. A long remission required only one daily long-acting insulin injection in the first year. Follow-up was regular, with planned admission twice yearly. Unstable diet accompanied hypo-/hyperglycaemic episodes. Metabolic compensation persisted until 2012, HbA1c 7.2–7.5%; 2012–2013 showed subcompensation, 7.8–8.0%; from 2014 decompensation, 9.4–9.6%. He monitored glucose regularly in a diary: fasting 5–16 mmol/L, occasional peaks to 21. Mild hypoglycaemia three or four times weekly was corrected with extra carbohydrate units. Blood count and urinalysis were unremarkable. First-day glycaemic variability was 6.3 mmol/L and 08:00 glucose 16.4. Physical and sexual development matched age.
Examination found dry skin, abdominal/thigh lipodystrophy, coffee-coloured leg patches, reduced brachioradial and Achilles reflexes and sensory impairment. Ophthalmology identified mixed retinal angiopathy. ENMG showed bilateral median, peroneal and tibial axonal/demyelinating neuropathy. Inpatient treatment: NovoRapid six units at 08:00, 13:00 and 18:00; Levemir 12 units at 08:00 and 11 at 21:00; ten infusions of 2% pentoxifylline 100 mg/day; ten infusions of 20% piracetam 1,500 mg/day, followed by oral 400 mg twice daily; B6/B12 1.0 mL intravenously, ten infusions; diet No. 9 with carbohydrate units 6+1/6+1/6+1. Carbonic training lasted 20 minutes daily for all 16 inpatient days, constant dead space 500 mL.
He attended diabetes education. His condition improved: excursion amplitude decreased to 2.5 mmol/L, pain and paraesthesia resolved, median/tibial ENMG normalised, and peroneal M-amplitude and velocity improved. Discharge 08:00 glucose was 6.6 mmol/L.
The figure shows M-responses during right median-nerve stimulation before and after training. Conduction velocity increased 1.7-fold and distal latency decreased 1.6-fold. These findings confirm correction of DPN manifestations; normal values were restored within two weeks of therapy initiation.
Discussion of mechanisms
Literature suggests that hypercapnic hypoxia can increase endoneurial blood flow by stimulating angiogenesis and VEGF expression [9,10]. This probably improved nerve nutrition, reduced neurological deficit and accelerated conduction in our trained children. Hypercapnia’s antioxidant effect may also contribute [11]. Hypercapnic hypoxia is also known to markedly reduce neurological deficits and motor-coordination disturbances [18].
These effects improved NIS-LL clinical manifestations and restored or improved motor-nerve neurophysiology during electrical stimulation. Both groups improved clinically and neurophysiologically, with more significant changes after respiratory training.
Adequate glucose control is the priority for maximising pathogenetic DPN treatment effectiveness in type 1 diabetes [19]. Two weeks of hypercapnic-hypoxic training reduced fasting glucose in the intervention group.
Many publications describe drugs with good clinical and electrophysiological DPN outcomes [3,4,20,21]. Balneotherapy, phototherapy, acupuncture, magnetic therapy, hyperbaric oxygen, electrophoresis, diadynamic currents and electrical stimulation are also widely used [22]. However, these additional methods are contraindicated in metabolic decompensation [22], limiting physiotherapy particularly in hospital, where patients commonly arrive decompensated, as here. Hypercapnic-hypoxic training meets paediatric type 1 DPN treatment principles: significant metabolic correction, pathogenetic action and safety. Equipment can be used in hospital, outpatient and home settings; it is affordable and simple to use.
Previously, hypercapnic hypoxia in combined paediatric peripheral facial-nerve treatment produced faster clinical improvement confirmed by ENMG and PedsQL [14,23]. A new application is Carbonic training in combined childhood diabetic DPN therapy, with good clinical and ENMG outcomes, shorter hospitalisation and lower economic burden, and stronger clinical/neurophysiological effects. Reduced objective neurological manifestations and significantly improved peripheral-nerve function in trained children suggest that hypercapnic hypoxia both acts independently on nerve fibres [9–11] and potentiates neurotrophic medication.
Conclusions
The study supports three conclusions. First, hypercapnic-hypoxic training contributes significantly to pathogenetic childhood type 1 diabetes treatment by lowering fasting glucose from 13.1 to 9.2 mmol/L, p<0.01. Second, it provides clinical benefit through lower NIS-LL deficit, p<0.05, and a shift from severe/moderate DPN to mild/absent manifestations, p<0.05. Third, one course of daily 20-minute sessions over 14–16 days increases conduction velocity in every motor nerve examined, p<0.01, reduces median, tibial and peroneal residual latency, p<0.01, and increases lower-limb M-response amplitude, p<0.05, indicating a significant nerve-fibre effect.
Conflict of interest
The authors declare no conflict of interest.
Table 1. Patient group characteristics (M±SD)
| Parameter | Intervention, n=25 | Comparison, n=25 | p |
|---|---|---|---|
| Mean age, years | 12,9±1,8 | 13,2±2,0 | >0,05 |
| Disease duration, years | 5,0±2,6 | 5,8±2,1 | >0,05 |
| HbA1c, % | 10,6±1,1 | 11,3±1,3 | >0,05 |
| Fasting glucose, mmol/L | 13,5±3,4 | 13,0±4,6 | >0,05 |
M±SD; p>0.05.
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Full main-text translation of: Смирнов К.В., Смирнова Ю.В., Куликов В.П., Назаркина О.М. Респираторные тренировки с гиперкапнической гипоксией — эффективная составляющая комплексной терапии полинейропатии у детей с сахарным диабетом 1-го типа. Журнал неврологии и психиатрии им. С.С. Корсакова. 2018;118(3):32–38.
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