2. Objetivos provisionales
6.7 Interés superior del niño
Patient A
A 26-year-old A-T patient was admitted with an acute respiratory syncytial virus (RSV) pneumonia. He had no history of respiratory infections. Preoperative lung function testing at
the age of 20 was indicative of restrictive pulmonary dysfunction (Table 1) and therefore it was decided to cancel a planned corrective operation.
On admission his chest X-ray showed a small bell-shaped thorax, a mild kyphoscoliosis and only moderate infiltrative shadowing in the left lower quadrant. Over the subsequent days he became progressively dyspnoeic and tachypnoeic (respiration 30 – 40/ min). On day 5 he was intubated and ventilated for respiratory failure. From the start of mechanical ventilation (Pressure Regulated Volume Control (PRVC), Servo 300â, Siemens) severe restrictive lung function was observed. High Peak Inspiratory Pressures (PIP; 45 - 50 cm H20) were required to achieve acceptable ventilation (PaCO2 6 – 8 kPa) and correlated with low tidal volumes (TV) (200 - 220mL). Calculated Crs (at PEEP 5 cm H20) was extremely low: 4.4 - 5.5 mL/cm H20 (Normal values > 50 – 100 mL/cm H20). Supportive therapy with restrictive fluid management, broad spectrum antibiotics, immunoglobulin substitution and corticosteroids was not effective. His pulmonary function gradually deteriorated and he died 53 days after start of mechanical ventilation of hypercapnic respiratory failure.
Patient B
In this patient a B-cell non-Hodgkin lymphoma in the epipharynx had been successfully treated with mitigated dosages of vincristine, methotrexate, doxorubicin and prednisone at the age of 16 years. Following treatment, complete agammaglobulinaemia persisted. Intravenous immunoglobulin substitution was started and no respiratory infections were observed over
Table 1. Results of pulmonary function tests of the three classical A-T patients (%; values as percentage of reference value for gender, age and height)
patient A B C gender M F M age (yrs) 20 17 20 21 10 12 BMI 18,9 15,4 18 17,5 12 11,2 volumes TLC-He (L) 1,86 1,96 TLC-HE as % of predicted 44 46 VC (L) 1,12 1,17 1,34 1,21 0,56 0,55 VC as % of predicted 47 42 43 38 36 22 RV (L) 1,25 0,51 0,76 RV as % of predicted 53 51 66 FEV1 (L) 0,85 0,95 1,09 1,21 0,41 0,5 FEV1/VC max(%) 76 81 81 100 73 91 pressures MEP (kPa) 2,8 3,63 MEP as % of predicted 33 43 MIP (kPa) 3,6 4,43 MIP as % of predicted 57 70
TLC-He = total lung capacity determined with helium, VC = vital capacity, RV = residual volume, FEV1 = forced expiratory volume in the first second, MEP = maximal expiratory mouth pressure, MIP = maximal inspiratory mouth pressure
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subsequent years. Because of the observed severe restrictive lung function in patient A, we evaluated her lung function (Table 1). From the age of 17 pulmonary function tests had shown progressive restrictive pulmonary dysfunction (Table 1). At the age of 22 she was seen at Emergency Department with haemorrhagic shock due to extensive bleeding from the urinary bladder. After intubation and volume resuscitation she was admitted to the ICU. The chest X-ray showed a small bell-shaped thorax, mild kyphoscoliosis and no pulmonary infiltrates. Pulmonary mechanics during ventilation (PRVC) showed severe pulmonary restriction: calculated Crs (at PEEP 8cm H2O) was 6.3 – 8.1 mL/cm H20 (TV 235 – 260 mL; PIP 40- 45 cm H20). Despite extensive pro-coagulant therapy and coiling of both internal iliac arteries, the bleeding from the bladder persisted. She developed progressive hypercapnia and died of respiratory failure 10 days after admission. At autopsy, histology of the lungs showed no micro-organisms, mild diffuse interstitial fibrosis and areas of non-necrotizing granulomatous inflammation.
Patient C
In this boy, lung function was assessed at the age 12 and showed severe restrictive pulmonary dysfunction (Table 1). The same year an EBV-positive lymphoma was diagnosed and successfully treated with rituximab. When he was 13 years old, he developed a B-cell lymphoma in the nasopharynx causing severe upper airway obstruction. Treatment with prednisone and rituximab resulted in a decrease of tumour size and relief of the inspiratory stridor. Subsequently however, progressive pulmonary dysfunction developed and ventilatory support was indicated. The chest X-ray showed minimal kyphoscoliosis, no pulmonary infiltrates or signs of ARDS. Because of his known restrictive lung function non-invasive positive pressure ventilation was started (Bipap® Vision, Respironics) in an attempt to avoid intubation. However, on day 2 he had to be intubated because of progressive respiratory distress. From the start of mechanical ventilation (PRVC, Servo 300, Siemens), volume pressure ratios indicated severe restrictive pulmonary function; high peak pressures (35 – 40 cm H20) correlated with low tidal volumes (TV 225 - 250 mL). Calculated Crs (at PEEP 5 cm H20) was 6.4 – 8.3 mL/cm H2O. He progressively developed hypercapnia and died on day 6 after admission to ICU for respiratory failure.
Discussion
This report shows restrictive lung dysfunction to be a common finding in A-T patients and a major risk factor for adverse outcome after start of mechanical ventilation. In adolescent wheelchair-bound A-T patients preadmission lung function is rarely assessed, because pulmonary dysfunction may not be clinically evident and lung function testing is difficult to perform in patients with neuromuscular dysfunction. In all patients in this study, ventilator volume-pressure ratios were compatible with severe pulmonary restriction. The estimated Crs values are only indicative as they were calculated from PRVC ventilator settings. Restrictive
pulmonary dysfunction was supported by data on pre-admission lung function testing (Table 1). Recently, reproducible lung function testing was shown to be feasible in adolescent A-T patients by McGrath-Morrow and co-workers.5 In line with our findings they found decreased
vital capacity (VC)% predicted values in most A-T adolescents. It was hypothesized that this could be explained by expiratory muscle weakness. In our study however, severe restrictive lung function was also observed in sedated A-T patients on high ventilator settings when neuromuscular dysfunction is only minimally involved in respiratory mechanics.
Our observations, combined with those previously reported1-6 indicate that the aetio-
pathogenesis of restrictive lung function in A-T is not fully understood. First, none of our patients suffered from recurrent or severe lung infections. Second, none of the chest
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radiographs showed signs of ILD. Third, histology of the lungs in patient B revealed only mild fibrosis, not characteristic for A-T. In this patient a side effect of earlier cytostatic therapy cannot be excluded, although drugs with known toxicity in A-T were avoided. Pulmonary restriction in A-T patients may be multifactorial and can be caused by a variety of disorders involving the extracellular matrix of the lung, its vascularization, or the tissues that surround the lung. In addition mechanical factors that lead to decreased chest wall compliance such as scoliosis, stiffening of the intercostal muscles and neuromuscular weakness, may contribute to restrictive pulmonary function. The patients in our study, however, had only mild scoliosis. Remarkably, they all had the small sized bell-shaped thorax known to be associated with a fixed maximal inspiratory position of the ribs and decreased chest wall compliance. Interestingly, the growth curves of all our adult patients with classical A-T lacked a puberty-associated growth spurt (Fig 1). This is in line with data of Schubert and co-workers who showed decreased IGF- 1 and IGFBP3 levels reflecting impaired somatic growth in A-T patients.7 Taken together, we
hypothesize that development of a small bell-shaped thorax with restricted rib expansion may play an important role in restrictive lung dysfunction in A-T patients. Severe pulmonary restriction in these patients may be of decisive importance in the choice of treatment and the ultimate course of the disease. Mechanical ventilation is a major risk for a complicated course and unfavourable outcome and may not be an option in certain adolescent A-T patients. Therefore, invasive diagnostic procedures or surgery in A-T patients, requiring mechanical ventilation, demand individual tailored and careful consideration. Unfortunately, to the best of our best knowledge, there are no data in the literature referring to mechanical ventilation and outcome in A-T patients. If mechanical ventilation is unavoidable, forced weaning and early extubation is imperative. Using this approach, several young adolescent A-T patients (n=3) in our institution were successfully extubated after procedural mechanical ventilation (n=12 episodes; total time on mechanical ventilation 30 min - 2 hr).
In conclusion, this series of three patients demonstrates that severe restrictive lung dysfunction is a common finding in adolescent A-T patients and a serious risk factor for adverse outcome after the start of mechanical ventilation. Preadmission lung function testing is essential for the optimal medical management of these patients.
References
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2. Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 1988;336:577-580.
3. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749-1753.
4. Crawford TO, Skolasky RL, Fernandez R, et al. Survival probability in ataxia telangiectasia. Arch Dis Child 2006;91:610-611.
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7 Schubert R, Reichenbach J, Zielen S: Growth factor deficiency in patients with ataxia telangiectasia. Clin Exp Immunol 2005;140:517-519.