A simple functional marker to predict the need for prolonged mechanical ventilation in patients with Guillain-Barré syndrome

About 30% of patients with Guillain-Barré syndrome (GBS) will require endotracheal intubation and mechanical ventilation (MV) [1, 2]. Predictors of the need for intubation and MV at the onset of the disease or at intensive care unit (ICU) admission have been extensively studied. Data from multicenter therapeutic trials comparing plasma exchange (PE) with intravenous immunoglobulins (IVIgs) could document that simple clinical and biological markers could accurately predict these needs. Inability to walk, inability to lift one's head, decreased vital capacity (VC), delay between onset of symptoms and hospital admission of less than 7 days, and high liver enzyme levels were found to have good predictive values [3–7].

Usually, tracheotomy is indicated in these patients when a long duration of MV is expected. However, immunotherapy using PE or IVIgs has changed the natural course of the disease. It decreases the duration of the plateau phase and hastens functional recovery [1–8]. Thus, early weaning from MV may obviate the need for tracheotomy. However, simple clinical predictors of the need for prolonged MV are lacking in these treated patients. Single-center studies have shown that older age and an underlying pulmonary disease were significant risk factors for prolonged MV, but accurate predictors have not been determined [8]. Thus, practically, after admission to the ICU for an acute respiratory failure, these patients receive PE or IVIgs during the first days of their stay. These treatments usually require 5 to 8 days to be completed and the same period of time is needed to evaluate their effect, delaying the decision to eventually perform tracheotomy. Delayed tracheotomy has been shown to increase the risk of severe local and infectious complications, especially ventilator-associated pneumonia [9–11]. On the other hand, when performed too early during the treatment period, tracheotomy may be useless or pose a higher risk.

For 20 years, during which time we participated in the multicenter trials of the French GBS Study Group, patients have been managed in our ICU by the same physicians and therapists in accordance with the same protocols of treatments and repeated functional assessments. To our knowledge, no study has been specifically dedicated to determine, just after completion of immunotherapy, the predictors of a long duration of MV. We designed the present study to search for simple functional markers that could predict the need for prolonged MV.

We included in the study all patients who both were referred to the 16-bed ICU of the Roger Salengro University Hospital (Lille, France) between January 1996 and March 2009 and fulfilled standard clinical diagnostic criteria for GBS. The diagnosis was always confirmed by electromyography (EMG), which was systematically performed during the first week after hospital admission. Patients were excluded if they had nonidiopathic GBS. Patients were transferred to our ICU from either an emergency department or a neurological ward. Reasons for admission were usually either a suspected or established acute respiratory failure due to neurological impairment of respiratory muscles.

Patients entering the ICU in acute respiratory distress or hypercapnia were intubated without delay. In the other cases, tracheal intubation was decided when VC measured at the bedside was less than 20% of the predicted value. Patients were ventilated in assist-controlled mode with repeated sequences of assisted spontaneous breathing under physiotherapist supervision. All patients were treated by immunotherapy with either polyvalent high-dose IVIgs or PE (four to six procedures). Each PE procedure allowed the exchange of 1.5 plasma mass, replaced by albumin or plasma substitutes. The IVIg treatment regimen was always 0.4 g/kg of body weight daily for 5 consecutive days. These treatments were completed within 8 days after admission. Additionally, during the ICU stay, patients received symptomatic treatments and nursing care, including systematic anticoagulation to prevent thrombosis, early enteral nutrition, and parenteral vitamins. Tight glucose control was not used.

Throughout the study, the same physicians assessed patients' neurological condition and the same physiologist (JFH) interpreted EMG data. Respiratory function was assessed by repeated spirometry performed at the bedside. Spirometric measurements were done by the same well-trained respiratory physiotherapists and included minute ventilation, respiratory frequency, VC, and maximal minute ventilation [12].

Weaning from MV was decided on the basis of the results of clinical assessment and sequential spirometric measurements. Weaning procedures followed the criteria and recommendations of the 8th and 21st French Consensus Conferences in ICU and Emergency Medicine [13, 14]. Weaning and extubation were usually decided when VC was greater than 20% of the predicted value and maximal minute ventilation was twice the minute ventilation, after a 3- to 6-hour trial of T-tube ventilation. The physicians in charge made the decision to perform tracheotomy on the basis of the patient's status, usually when no functional and respiratory improvement was observed within 10 days after completion of immunotherapy.

The following characteristics were prospectively collected for all patients: age, sex, severity of illness at admission as assessed by the Simplified Acute Physiology Score II (SAPS II), delays from GBS onset to hospital admission and ICU admission, and ICU length of stay. Neurological testing used the standardized data collection elaborated by the French Cooperative Group on Plasma Exchange in GBS [4]. The following data were noted: (a) weakness of the limbs, (b) deep tendon reflex abolition in the upper and lower limbs, (c) cranial nerve impairment, (d) weakness of trunk and respiratory muscles (VC level and ability to lift and hold one's head above the bed), (e) presence of paresthesia or impaired vibratory sensitivity in the limbs, and (f) cardiovascular autonomic dysfunction defined as an increase or decrease (40 mm Hg) in systolic blood pressure, spontaneous or induced bradycardia (heart rate decrease of greater than 20 beats per minute), or spontaneous tachycardia (increase to greater than 120 beats per minute without fever). Cerebrospinal fluid analysis and the following biochemical tests were performed in all patients at ICU admission: natremia, glycemia, creatine phosphokinase, liver enzyme, platelet count, prothrombin time, and C-reactive protein levels. Standard viral serology, including cytomegalovirus and Campylobacter jejuni, was realized. Clinical and laboratory data were collected daily until the plateau phase was recognized and thereafter when significant neurological changes were observed. To search for significant neurological improvement or worsening, changes in motor scores were analyzed for all patients between admission and completion of immune therapy. Neurological improvement or worsening was defined as the reappearance or the disappearance of a spontaneous perceptible movement in one of the items of the standardized neurological functional testing. The definite functional outcome was assessed by walking ability (independent ambulation, requiring assistance to walk, or bed-bound) at a follow-up medical consultation 4 to 6 months after discharge from the ICU. Data from electrophysiological testing were analyzed to classify GBS as acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), or AIDP with axonal involvement. Motor conduction block for sciatic nerves was defined as an at least 50% decrease in amplitude of the compound muscle action potential (CMAP) [15].

For the purpose of this study, we compared the patients according to the need of MV to verify whether our population was representative of most GBS cases and exhibited previously known prognostic markers. Then the group of ventilated patients (MV⁺ group) was specifically studied, and the data collected at ICU admission, at the end of immunotherapy, and 8 days after completion of immunotherapy were extracted for each patient. The following time periods were calculated: time from ICU admission to tracheal intubation, time from the end of specific treatment to MV weaning, duration of MV, and timing of tracheotomy. MV weaning was defined as definite extubation or, in tracheotomized patients, when spontaneous ventilation was obtained 24 hours daily. Finally, two subgroups were defined according to the duration of MV (≤ or >15 days) and all of their clinical and biological data were compared to seek for significant predictors of prolonged MV. Prospective collection of patients' data was approved by the ethics committee of our university hospital in 1996. Since this was a fully retrospective study with all patients' data rendered anonymous and according to French law, informed consent was not requested.

Our study shows that, in patients with GBS, a long duration of MV may be predicted by means of a simple functional marker. In our patients, the lack of foot flexion ability at the end of immunotherapy was significantly associated with an MV length of greater than 15 days. The sensitivity of this simple marker was enhanced by the results of EMG assessment; conversely, the association of a sciatic nerve conduction block with the lack of foot flexion seemed highly specific of a prolonged duration of MV. We think this result may help clinicians to decide whether or not tracheotomy should be performed after completion of immunotherapy.

The patients whom we have studied were representative of severe GBS. Demographic characteristics concerning age, sex ratio, and neurological presentation were in accordance with most published series [5–7, 10, 11]. Our study confirms the previously known early predictive factors of MV, including inability to lift one's head and a decrease in VC [4, 6, 8, 16, 17]. As expected, severe autonomic dysfunction and inability to lift one's head above the bed at ICU admission was were associated with an increased risk of MV requirement. In our study, comparison of SAPS II between ventilated and nonventilated patients showed a significantly higher physiological severity in patients needing MV, but there was no score difference according to the duration of MV.

Since the length of MV in these patients is hardly predictable, finding predictive factors of prolonged mechanical support would help their management. In a multicenter randomized study including medical ICU patients, Rumbak and colleagues [9] concluded that early tracheotomy in those projected to need MV for more than 14 days was associated with a reduction of acquired pneumonias, sedation, length of MV and stay in the ICU, and finally a reduction of hospital mortality. In the standard ICU setting, tracheotomized mechanically ventilated patients needing prolonged MV require less sedation, appear more comfortable, and achieve more autonomy earlier [18, 19]. Thus, knowledge of predictive factors of prolonged mechanical support could help clinicians to select GBS patients for early tracheotomy.

To our knowledge, the study by Lawn and Widjicks [8] is the only one that could determine criteria of prolonged MV in GBS patients. These authors described a score combining VC and maximal expiratory and inspiratory pressures, measured at admission and 12 days later. In their study, an improvement in this pulmonary functional score predicted an MV duration of less than 3 weeks. In our study, we did not sequentially measure VC and maximal pressures and consequently cannot compare our results with those of Lawn and Widjicks. We found that the lack of foot flexion ability observed at ICU admission and at the end of immunotherapy was significantly more frequent in patients who needed a prolonged duration of MV. Nearly 20% of these patients lost their foot flexion ability between days 1 and 10, giving confirmation that neurological status should be reassessed just after completion of immune therapy. Additionally, at that time, the combined observation of a sciatic nerve motor conduction block with the lack of foot flexion ability was significantly associated with a prolonged MV with 100% specificity. This should strongly argue in favor of performing tracheotomy when these two criteria are present. Durand and colleagues [7] found, in keeping with our findings, a significant association between respiratory failure and neurological impairment of inferior limbs. The authors showed that peripheral neurophysiological testing was helpful for assessing the risk of respiratory failure. The highest risk of respiratory failure was observed in patients who exhibited a decrease in the CMAP between the proximal and the distal common peroneal nerve. The cutoff point found by Durand and colleagues was a 20% decrease in CMAP. In our study, the diagnosis of motor conduction block of the sciatic nerve was considered for a 50% decrease. This higher severity could explain why it may represent a good predictor of prolonged MV in our study. However, there is no obvious link between the presence of a peripheral conduction block and prolonged diaphragmatic weakness. Severe demyelination is characterized by a pronounced decrease in motor nerve conduction velocities, increase in distal motor latencies, or presence of a conduction block [15]. In patients with GBS, the prolonged impairment of foot flexion is probably evidence of a severe neurological injury with either a major demyelination process or a secondary axonal loss. This feature will reflect a more diffuse neurological injury or an impaired process of nerve recovery affecting phrenic nerves as well.

Our study has clear limitations, which are linked mainly to its retrospective and monocentric design. Only patients with the more severe form of GBS were admitted to our ICU, and our results cannot be extended to less severe types of GBS. Despite these limitations, we think that our population accurately reflects most patients with severe GBS. The long recruitment period between 1996 and 2009 is unlikely to have biased our results, because during this time, procedures of immunotherapy for GBS did not change, and decisions of tracheal intubation, tracheotomy, and MV weaning were made by using the same criteria by the same physicians according to the results of standardized neurological monitoring. We found the same risk factors of MV requirement as reported in published data, giving confirmation of the similarity of our patients with populations of GBS included in preceding larger studies. However, owing to the low number of patients, the operating characteristics of the functional markers predicting the need for prolonged MV should be considered cautiously.

We conclude from our results that, at the end of immunotherapy, the lack of foot flexion ability associated with a sciatic nerve EMG conduction block may predict a long duration of MV and represent a strong argument to perform tracheotomy. These results should be confirmed by a prospective study or a comparable multicenter retrospective study.