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Abstract
Rationale: Intensive care unit (ICU)- and mechanical ventilation (MV)-acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear.
Objectives: To quantify the prevalence and coexistence of these two forms of ICU-acquired weakness and their impact on outcome.
Methods: In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H2O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48.
Measurements and Main Results: Seventy-six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (ρ = 0.26; P = 0.03) and TFdi (ρ = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45–0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76–0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay.
Conclusions: Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.
Critically ill patients can develop intensive care unit–acquired weakness and intensive care unit–acquired diaphragm dysfunction. Both have been associated with poor outcome and prolonged weaning from mechanical ventilation. Whether they are two aspects of the same entity or whether they have a different prevalence and prognostic impact remains unclear. Their respective prevalence and coexistence, risk factors, and outcome at time of liberation from mechanical ventilation are not known.
At the time of liberation from mechanical ventilation, in a nonselected population, diaphragm dysfunction is twice as frequent as limb muscle weakness. Diaphragm dysfunction is significantly associated with subsequent weaning failure and mortality.
It is well established that a substantial proportion of intensive care unit (ICU) patients develop limb muscle weakness, also called ICU-acquired weakness (ICU-AW) (1, 2). In turn, ICU-AW is associated with increased duration of mechanical ventilation (MV) and ICU stay (3–7). More recently, it has been shown that mechanically ventilated ICU patients may also experience acquired diaphragm dysfunction (8, 9) and atrophy (10), which may cause difficult weaning and increased duration of MV (11–13). Although ICU-acquired limb muscle and diaphragm weaknesses are increasingly described, data regarding their interrelationship and their respective risk factors and prognostic impact are scarce and they have only been investigated in selected populations (3, 4, 13). To some extent, ICU-AW and diaphragm dysfunction share similar mechanisms and could be two aspects of the same disease in mechanically ventilated patients submitted to bed rest and general muscle disuse (8, 9, 14). However, in contrast with limb muscles, the diaphragm contracts phasically and continuously throughout the subject’s lifetime. It is currently unknown whether MV has a similar impact on diaphragm and limb muscle strength.
The aim of the present study was to assess whether diaphragm dysfunction and ICU-AW are or not two distinct entities with their own specific prevalence and risk factors. In this purpose, we enrolled a nonselected population of medical ICU patients on the day of their first spontaneous breathing trial (SBT). Diaphragm function was assessed by both phrenic nerve stimulation and ultrasound, and limb muscle strength was assessed by a validated clinical tool.
The primary objective of the study was to quantify the respective prevalence of ICU-AW and diaphragm dysfunction. We also sought to determine the respective impact of ICU-AW and diaphragm dysfunction on weaning success and their association with clinical outcome. Some of the results of this study have been previously reported in abstract form (15).
Detailed methods are provided in the online supplement. The study was conducted over an 8-month period (December 1, 2014, to July 31, 2015) in a medical ICU. The study was approved by the Comité de Protection des Personnes Ile-de-France VI (ID RCB: 2014-A00715-42). Informed consent was obtained from all patients or their relatives.
Patients intubated and ventilated for at least 24 hours were eligible for inclusion in the study when they met the predefined readiness-to-wean criteria on daily screening (see online supplement) and were therefore deemed ready to undergo a first 30-minute SBT (16). Exclusion criteria were related to factors possibly interfering with tracheal pressure measurements in response to phrenic nerve stimulation (see online supplement), tracheostomy, and the impossibility to assess muscular strength in a limb because of immobilization or inability to follow simple orders.
Diaphragm strength was assessed in terms of the changes in endotracheal tube pressure induced by bilateral phrenic nerve stimulation during airway occlusion (Ptr,stim), as described elsewhere (see online supplement) (17, 18). Stimulations were delivered at the maximum intensity allowed by the stimulator (100%) known to result in supramaximal diaphragm contraction in most patients (8, 18–21).
Ultrasound assessment of the diaphragm was performed using a 4- to 12-MHz linear array transducer (Sparq ultrasound system; Philips Healthcare, Bothell, WA), using techniques described elsewhere (22, 23). Measurements were performed while patients were mechanically ventilated with a standardized pressure-support level targeting a tidal volume of 6–8 ml/kg of ideal body weight. Positive end-expiratory pressure was not modified during the measurements. In our unit, positive end-expiratory pressure is routinely set at around 5 cm H2O. Diaphragm thickness was measured at end-expiration (Tde) and end-inspiration (Tdi), and thickening fraction (TFdi) was calculated offline as (Tdi − Tde)/Tde. The maximal excursion of the diaphragm was also measured. Ultrasound measurements were performed by one of the authors (either B.-P.D. or M.D.) on at least three separate breaths, and the mean of the three measurements was reported.
Limb muscle strength was assessed by the Medical Research Council (MRC) score in patients screened for awakening and understanding (see online supplement). MRC scoring was performed jointly by the ICU physiotherapist and one of the investigators (B.-P.D. or M.D.).
Ptr,stim was used to identify two groups of patients based on the 11 cm H2O cutoff already described (8, 24). Patients with a Ptr,stim less than 11 cm H2O were considered to have diaphragm dysfunction. MRC score was used to identify two groups of patients based on the cutoff of 48 of 60 (14). Patients with an MRC score less than 48 were considered to have ICU-AW.
Demographic data, comorbidities, severity scores, organ dysfunction–related variables, physiologic data, blood gas data, medication exposure, duration of MV, ICU and hospital stay, and ICU and hospital mortality were prospectively recorded.
The SBT was performed after completion of diaphragm and limb muscle assessment. Patients were connected to the ventilator (pressure support level 7 cm H2O, zero end-expiratory pressure) for a 30-minute period. SBT was considered to have failed when criteria of clinical intolerance were present (see online supplement) (16). Otherwise, the SBT was considered to be successful and patients were extubated according to the decision of the attending physician. Patients who did not meet the predefined clinical intolerance criteria but who were not extubated after completion of the SBT were considered to be weaning failures. Successful weaning was defined as sustained spontaneous breathing without any form of ventilatory support 48 hours after extubation. Weaning failure was defined as patients failing the SBT, requiring reintubation or any form of ventilatory support (including noninvasive ventilation for postextubation acute respiratory failure, but not prophylactic noninvasive ventilation) during the 48 hours following extubation. In addition, simple, difficult, and prolonged weaning were defined according to the international weaning conference (16).
Continuous variables are expressed as median (interquartile range) or mean (SD) and categorical variables are expressed as absolute and relative frequency. Continuous variables were compared with Student’s t test or Mann-Whitney U test depending on distribution and categorical variables were compared with chi-square test or Fisher’s exact test depending on sample size. The prevalence of each category of the weaning classification (simple, difficult, and prolonged weaning) in patients with diaphragm dysfunction and ICU-AW was compared by a chi-square test. The Spearman correlation was used to test the relationship between MRC score and Ptr,stim and TFdi, respectively.
Multiple regression models were used to identify the effect of exposure pre-SBT variables on the incidence of diaphragm dysfunction, ICU-AW, and weaning failure. Finally, the associations of diaphragm dysfunction and ICU-AW on inclusion with duration of MV, length of ICU and hospital stay, and mortality were also assessed.
For all final comparisons, a P value less than or equal to 0.05 was considered statistically significant. Statistical analyses were performed with SPSS version 21 (IBM, Chicago, IL).
During the study period, 330 patients were admitted, 184 patients were ventilated for at least 24 hours, and 76 patients were consecutively enrolled in the study (Figure 1). Patient characteristics on inclusion are detailed in Table 1. Patients had received MV for a median of 4 (2–6) days at the time of inclusion. MRC score could be obtained in all patients. At inclusion, all the patients were ventilated with a mean level of pressure support of 10 ± 2 cm H2O and a mean level of positive end-expiratory pressure of 6 ± 1 cm H2O.
Figure 1. Study flowchart. ICU-AW = intensive care unit–acquired weakness; PEEP = positive end-expiratory pressure.
[More] [Minimize]| Men, n (%) | 52 (68) |
| Age, yr | 57 ± 16 |
| Body mass index, kg/m2 | 25 ± 6 |
| SOFA | 5 ± 3 |
| SAPS II | 43 ± 2 |
| Sepsis on admission, n (%) | 42 (55) |
| Duration of mechanical ventilation, d | 4 (2–6) |
| Reason for mechanical ventilation, n (%) | |
| Hypercapnic respiratory failure | 9 (12) |
| Hypoxemic respiratory failure | 22 (29) |
| Coma | 22 (29) |
| Shock | 23 (30) |
| Medical conditions, n (%) | |
| COPD | 17 (22) |
| Cirrhosis | 14 (18) |
| Diabetes | 14 (18) |
| Current smoking | 37 (49) |
| Ventilator parameters | |
| FiO2, % | 34 ± 5 |
| Pressure support level, cm H2O | 10 ± 2 |
| Tidal volume, ml/kg ideal body weight | 6.9 ± 1.9 |
| PEEP, cm H2O | 6 ± 1 |
| Clinical parameters | |
| Respiratory rate, breath/min | 23 ± 5 |
| Mean arterial pressure, mm Hg | 83 ± 17 |
| Heart rate, min−1 | 92 ± 18 |
| Blood gases | |
| pH | 7.43 ± 0.08 |
| PaCO2, mm Hg | 40 ± 9 |
| PaO2, mm Hg | 101 ± 34 |
| PaO2/FiO2 | 292 ± 104 |
| Lactate, mmol/L | 1.6 ± 0.7 |
At the time of their first SBT, 48 patients (63%) had diaphragm dysfunction, 26 (34%) had ICU-AW, and 16 (21%) had both (Figure 1). Table 2 displays the patients’ clinical characteristics according to the presence of diaphragm dysfunction or ICU-AW. Ptr,stim was similar in patients with and without ICU-AW (9.3 ± 6.6 vs. 10.5 ± 6.0 cm H2O, respectively) and MRC score was similar in patients with and without diaphragm dysfunction (47 ± 13 vs. 50 ± 11, respectively). There was a significant but very weak correlation between MRC score and Ptr,stim (ρ = 0.26; P = 0.03) and between MRC score and TFdi (ρ = 0.28; P = 0.01) (Figures 2A and 2B).
| Diaphragm Dysfunction | ICU-AW | |||||
|---|---|---|---|---|---|---|
| Yes (n = 48) | No (n = 28) | P Value | Yes (n = 26) | No (n = 50) | P Value | |
| Demographic data | ||||||
| Men, n (%) | 32 (67) | 20 (71) | 0.67 | 17 (65) | 35 (70) | 0.68 |
| Age, yr | 61 ± 13 | 51 ± 18 | 0.01 | 61 ± 12 | 56 ± 17 | 0.16 |
| Body mass index, kg/m2 | 25 ± 6 | 26 ± 4 | 0.75 | 24 ± 3 | 26 ± 6 | 0.08 |
| Medical conditions, n (%) | ||||||
| Heart failure | 10 (21) | 2 (7) | 0.11 | 3 (12) | 9 (18) | 0.46 |
| COPD | 10 (21) | 2 (7) | 0.11 | 2 (8) | 10 (20) | 0.16 |
| Cirrhosis | 8 (17) | 6 (21) | 0.76 | 9 (35) | 5 (10) | 0.01 |
| Diabetes | 9 (19) | 5 (18) | 0.92 | 5 (19) | 9 (18) | 0.90 |
| Current smoking | 25 (52) | 12 (43) | 0.44 | 12 (46) | 25 (50) | 0.75 |
| On admission | ||||||
| SOFA | 5 ± 3 | 5 ± 3 | 0.80 | 6 ± 3 | 5 ± 3 | 0.04 |
| SAPS II | 46 ± 23 | 37 ± 21 | 0.09 | 47 ± 23 | 41 ± 22 | 0.11 |
| Sepsis, n (%) | 25 (52) | 17 (61) | 0.46 | 11 (42) | 31 (62) | 0.10 |
| Reason for admission, n (%) | ||||||
| Hypercapnic respiratory failure | 7 (15) | 2 (7) | 0.47 | 1 (4) | 8 (16) | 0.15 |
| Hypoxemic respiratory failure | 17 (35) | 5 (18) | 0.12 | 10 (38) | 12 (24) | 0.20 |
| Shock | 17 (35) | 6 (21) | 0.30 | 9 (35) | 14 (28) | 0.60 |
| Coma | 7 (15) | 15 (54) | 0.001 | 6 (23) | 16 (32) | 0.42 |
| Duration of MV before inclusion, d | 5 (2–7) | 3 (1–5) | 0.04 | 6 (4–8) | 3 (1–5) | 0.01 |
| Medication exposure before inclusion, n (%) | ||||||
| Propofol | 27 (57) | 13 (46) | 0.36 | 9 (35) | 31 (63) | 0.02 |
| Neuromuscular blocker | 9 (19) | 2 (7) | 0.16 | 3 (12) | 8 (16) | 0.58 |
| Midazolam | 14 (30) | 11 (39) | 0.40 | 9 (35) | 16 (33) | 0.86 |
| Sufentanil | 26 (55) | 11 (39) | 0.18 | 12 (46) | 25 (51) | 0.69 |
| Corticosteroids | 6 (13) | 3 (11) | 0.79 | 5 (19) | 4 (8) | 0.16 |
| Diaphragm assessment | ||||||
| Ptr,stim, cm H2O | 6.4 ± 2.4 | 16.5 ± 5.5 | <0.001 | 9.3 ± 6.6 | 10.5 ± 6.0 | 0.42 |
| Tde, mm | 2.11 ± 0.54 | 2.20 ± 0.63 | 0.54 | 2.01 (0.50) | 2.21 (0.60) | 0.13 |
| Diaphragm dysfunction, % | — | — | 16 (62) | 32 (67) | 0.83 | |
| TFdi, % | 21 ± 9 | 40 ± 11 | <0.001 | 26 ± 14 | 29 ± 13 | 0.40 |
| Excursion, cm | 0.94 ± 0.46 | 1.10 ± 0.32 | 0.15 | 0.87 ± 0.42 | 1.06 ± 0.40 | 0.11 |
| Limb muscle assessment | ||||||
| MRC score | 47 ± 13 | 50 ± 11 | 0.35 | 34 ± 13 | 55 ± 4 | <0.001 |
| ICU-AW, % | 16 (33) | 10 (36) | 0.83 | — | — | |
| Ventilator settings at inclusion | ||||||
| Pressure support level, cm H2O | 10 ± 2 | 10 ± 2 | 0.59 | 10 ± 3 | 10 ± 2 | 0.94 |
| PEEP, cm H2O | 6 ± 1 | 6 ± 1 | 0.77 | 5 ± 1 | 6 ± 1 | 0.09 |
| Tidal volume, ml/kg IBW | 6.4 ± 1.7 | 7.7 ± 2.0 | 0.005 | 6.9 ± 1.9 | 7.0 ± 1.9 | 0.79 |
Figure 2. Correlation analysis between the Medical Research Council (MRC) score and either the change in tracheal pressure induced by bilateral phrenic nerve stimulation (Ptr,stim) (A) or the diaphragm thickening fraction (B). Dashed lines represent the cutoff of Ptr,stim to diagnose diaphragm dysfunction in the critically ill (−11 cm H2O) (8), the cutoff of diaphragm thickening fraction to diagnose diaphragm dysfunction (20%) (40), and the cutoff of MRC to diagnose intensive care unit–acquired weakness (48).
[More] [Minimize]Pre-SBT factors associated with diaphragm dysfunction were age and duration of MV before inclusion, whereas ICU admission for coma was inversely associated with diaphragm dysfunction (Table 2). Multivariate analysis showed that admission for coma (odds ratio [OR], 0.15; 95% confidence interval [CI], 0.05–0.44; P = 0.001) was inversely associated with diaphragm dysfunction (see Table E1 in the online supplement). Pre-SBT factors associated with ICU-AW were cirrhosis, duration of MV before inclusion, propofol exposure, and Sequential Organ Failure Assessment score at inclusion (Table 2). Multivariate analysis showed that longer duration of MV before inclusion (OR, 1.25; 95% CI, 1.05–1.48; P = 0.01) and cirrhosis (OR, 8.20; 95% CI, 1.82–37.00; P = 0.006) were independently associated with ICU-AW (see Table E2).
Thirty-three (43%) of the 76 patients presented weaning failure. In the weaning failure group, 26 patients were not extubated at the end of the SBT, whereas the endotracheal tube was removed but ventilatory support had to be resumed within 48 hours for 7 patients. Compared with patients with successful weaning, patients with weaning failure had significantly lower MRC score, lower Ptr,stim, lower TFdi, and lower diaphragm excursion (Table 3). In addition, patients in the failure group were older, had received MV for a longer duration before inclusion, and had a higher PaCO2. Diaphragm dysfunction was more frequent in patients with prolonged and difficult weaning than simple weaning, whereas the prevalence of ICU-AW was similar in the three categories of the weaning classification (Figure 3).
| Weaning Failure (n = 33; 43%) | Weaning Success (n = 43; 57%) | P Value | |
|---|---|---|---|
| Men, n (%) | 23 (70) | 29 (67) | 0.83 |
| Age, yr | 63 ± 12 | 54 ± 17 | 0.01 |
| Body mass index, kg/m2 | 26 ± 6 | 25 ± 5 | 0.19 |
| SOFA | 5 ± 2 | 5 ± 3 | 0.77 |
| SAPS II | 46 ± 23 | 40 ± 21 | 0.23 |
| MV before inclusion, d | 6 (4–10) | 3 (1–5) | <0.001 |
| Reason for MV, n (%) | |||
| Hypercapnic respiratory failure | 6 (18) | 3 (7) | 0.17 |
| Hypoxemic respiratory failure | 12 (36) | 10 (23) | 0.31 |
| Shock | 10 (30) | 13 (30) | 0.99 |
| Coma | 5 (15) | 17 (40) | 0.02 |
| Medical conditions, n (%) | |||
| Chronic heart failure | 4 (12) | 8 (19) | 0.44 |
| COPD | 8 (24) | 4 (9) | 0.08 |
| Cirrhosis | 9 (27) | 5 (12) | 0.23 |
| Diabetes | 7 (21) | 7 (16) | 0.77 |
| Current smoking | 17 (52) | 20 (47) | 0.81 |
| Physiologic variables | |||
| Mean arterial pressure, mm Hg | 82 ± 20 | 84 ± 15 | 0.60 |
| Heart rate, min−1 | 95 ± 17 | 89 ± 18 | 0.15 |
| Respiratory rate, breath/min | 24 ± 5 | 22 ± 5 | 0.08 |
| Ventilator settings | |||
| Pressure support level, cm H2O | 10 ± 3 | 10 ± 2 | 0.36 |
| PEEP, cm H2O | 6 ± 1 | 6 ± 1 | 0.68 |
| Tidal volume, ml/kg IBW | 6 ± 1 | 8 ± 2 | 0.001 |
| Diaphragm activity | |||
| TFdi, % | 19 ± 9 | 35 ± 12 | <0.001 |
| Excursion, cm | 0.82 ± 0.42 | 1.12 ± 0.37 | 0.01 |
| Tde, mm | 2.20 ± 0.60 | 2.10 ± 0.58 | 0.42 |
| Arterial blood gases | |||
| PaO2/FiO2, mm Hg | 256 (87) | 322 (108) | 0.01 |
| PaCO2, mm Hg | 43 ± 10 | 37 ± 7 | 0.02 |
| Diaphragm and limb function | |||
| Ptr,stim <11 cm H2O, n (%) | 31 (94) | 17 (40) | <0.001 |
| Ptr,stim, cm H2O | 5.9 ± 2.7 | 13.3 ± 6.2 | <0.001 |
| Score MRC <48, n (%) | 15 (46) | 11 (26) | 0.07 |
| MRC score | 43 ± 14 | 51 ± 10 | 0.01 |
Figure 3. Histogram showing the respective prevalence of intensive care unit (ICU)-acquired weakness and diaphragm dysfunction according to the international weaning classification categories. *P < 0.05 (chi-square test among three groups).
[More] [Minimize]In the three logistic regression models, each including Ptr,stim, TFdi, or excursion as markers of diaphragm function, Ptr,stim (OR, 0.60; 95% CI, 0.45–0.79; P < 0.001), TFdi (OR, 0.84; 95% CI, 0.76–0.92; P < 0.001), and EXdi (OR, 0.15; 95% CI, 0.02–0.94; P = 0.04) were independently associated with weaning failure (Figure 4; see Tables E3–E5). In the model including the MRC score, the MRC score was not independently associated with weaning failure (OR, 0.96; 95% CI, 0.91–1.02; P = 0.20) (see Table E6).
Figure 4. Forest plot showing the factors significantly associated with weaning failure: results of four multivariate logistic regressions, each separately including Ptr,stim, TFdi, EXdi, or MRC score. The Forest plot shows that an increase in the duration of mechanical ventilation before inclusion was independently associated with weaning failure in the four models. Diaphragm dysfunction was independently associated with weaning failure in the models including Ptr,stim (each 1-unit increase of Ptr,stim decreased the risk of weaning failure; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45–0.79; P < 0.001), TFdi (each 1-unit increase of TFdi decreased the risk of weaning failure; OR, 0.84; 95% CI, 0.76–0.92; P < 0.001), and EXdi (each 1-unit increase of EXdi decreased the risk of weaning failure; OR, 0.15; 95% CI, 0.02–0.94; P = 0.04). MRC score was not associated with weaning failure (OR, 0.96; 95% CI, 0.91–1.02; P < 0.20). In the model with EXdi, data were available for 58 of 76 patients. EXdi = diaphragmatic excursion; MRC = Medical Research Council score; MV = mechanical ventilation; Ptr,stim = endotracheal tube pressure induced by bilateral phrenic nerve stimulation during airway occlusion; TFdi = diaphragm thickening fraction.
[More] [Minimize]Table 4 displays the clinical outcomes of the patients according to the presence of diaphragm dysfunction and ICU-AW on inclusion. Diaphragm dysfunction was associated with difficult weaning, prolonged weaning, prolonged total duration of MV and ICU length of stay, and higher ICU and hospital mortality. ICU-AW was associated with longer total duration of MV and hospital length of stay.
| Overall Population (n = 76) | Diaphragm Dysfunction | ICU-acquired Weakness | |||||
|---|---|---|---|---|---|---|---|
| Yes (n = 48) | No (n = 28) | P Value | Yes (n = 26) | No (n = 50) | P Value | ||
| Difficult weaning, n (%) | 25 (33) | 23 (48) | 2 (7) | <0.001 | 11 (42) | 14 (28) | 0.30 |
| Prolonged weaning, n (%) | 8 (10) | 8 (17) | 0 (0) | 0.02 | 4 (15) | 4 (8) | 0.43 |
| Total duration of MV, d | 5 (2–10) | 7 (4–12) | 4 (1–6) | 0.04 | 7 (4–12) | 5 (1–7) | 0.04 |
| Length of ICU stay, d | 8 (4–15) | 10 (5–16) | 6 (3–10) | 0.05 | 9 (6–17) | 6 (3–14) | 0.17 |
| Length of hospital stay, d | 21 (9–30) | 23 (15–32) | 18 (6–29) | 0.09 | 26 (14–37) | 19 (8–28) | 0.008 |
| ICU mortality, n (%) | 8 (10) | 8 (17) | 0 (0) | 0.02 | 5 (19) | 3 (6) | 0.11 |
| Hospital mortality, n (%) | 12 (16) | 11 (23) | 1 (4) | 0.04 | 7 (27) | 5 (10) | 0.09 |
In a nonselected population of mechanically ventilated patients deemed ready to perform a SBT, we found that the prevalence of diaphragm dysfunction was twofold higher than the prevalence of ICU-AW, with only a small overlap between diaphragm dysfunction and ICU-AW; and that diaphragm dysfunction but not ICU-AW influenced the success of weaning.
This study is the first to report that the prevalence of diaphragm dysfunction at time of liberation from MV was almost twofold higher than the prevalence of ICU-AW. A recent study reported a prevalence of diaphragm dysfunction as high as 80% in patients with ICU-AW entering the weaning process (13). Interestingly, we found a similar proportion of diaphragm dysfunction in our patients with ICU-AW (16 of 26; 62%). The overall prevalence of diaphragm dysfunction observed in the present study was similar to that already described at the time of ICU admission (8). Ventilator-induced diaphragm dysfunction has been described in specific settings, such as brain-dead donors (25) and small cohorts of ICU patients (9, 26). Several factors, such as sepsis, which may be present at ICU admission and responsible for initial diaphragm weakness, might improve with time, whereas other factors, such as ventilator-induced diaphragm dysfunction, may subsequently come into play. However, the respective contributions of MV and diaphragm dysfunction present on admission on the diaphragm dysfunction observed at time of weaning from MV cannot be determined from the results of this study.
The correlation between diaphragm dysfunction and ICU-AW was weak and the overlap was small. Previous studies have reported a preferential involvement of the diaphragm compared with limb muscles in patients with sepsis (27) or in mice with pneumonia (28). Ventilator-induced muscle dysfunction seems to be specific to respiratory muscles, at least the diaphragm, compared with pectoralis major for example (25). Although diaphragm and limb muscles are both skeletal muscles and share similar cellular pathway (6, 29), they seem to differ considerably in terms of their vulnerability to MV and bed rest (30). Because this was not a mechanistic study, we can only speculate on the pathophysiologic significance of our findings. However, it is essential to determine whether diaphragm dysfunction and ICU-AW are two distinct entities to address their possible mechanisms.
Immobilization is the most common of the numerous factors that may induce muscle weakness (31). Although the spontaneous activity of limb muscles may often be dramatically decreased (e.g., during sleep), the diaphragm is characterized by a continuous contractile activity throughout the subject’s lifetime, which could explain why the diaphragm is more susceptible to even brief periods of inactivity. This hypothesis is only speculative, but our overall findings suggest that ICU-AW and diaphragm dysfunction are two distinct syndromes probably associated with different pathophysiologic pathways.
Diaphragm dysfunction was significantly associated with subsequent difficult and prolonged weaning, but ICU-AW was not, confirming the results of previous studies assessing diaphragm dysfunction with phrenic nerve stimulation or ultrasound (11–13). As also reported by Kim and colleagues (11), we found that the maximum excursion of the diaphragm was significantly different according to the outcome of the SBT. Moreover, we also report, for the first time, that TFdi was an independent variable of weaning failure in addition to Ptr,stim. Although ultrasound measurements were performed under pressure support, it was interesting to observe a marked difference in TFdi (21 ± 9% vs. 40 ± 11%) between patients with or without diaphragm dysfunction under a similar level of pressure support ventilation (10 ± 2 vs. 10 ± 2 cm H2O). This finding suggests that, despite the same level of support, there was a much lower contribution of the diaphragm in patients with diaphragm dysfunction than in patients without diaphragm dysfunction, as reflected by lower tidal volumes in patients with diaphragm dysfunction.
Although some patients with diaphragm dysfunction can be easily extubated, diaphragm dysfunction was present in almost all patients with weaning failure. In contrast, ICU-AW was not associated with weaning failure, but with a longer duration of MV. These findings could be explained by the small number of cases of ICU-AW diagnosed in our population. However, it is noteworthy that our patients were assessed after a relatively short period of MV compared with other studies focusing on ICU-AW that selected patients who had been ventilated for at least 7 days (3, 4, 32). MV is most often associated with bed rest, which may lead to peripheral muscle inactivity and therefore ICU-AW. Whether prolonged duration of MV, by promoting bed rest, leads to ICU-AW (33) or whether ICU-AW induces prolonged duration of MV remains unclear.
A major strength of our study is the inclusion of unselected mechanically ventilated ICU patients; we did not restrict inclusion to patients with severe ICU-AW or prolonged MV. Our cohort is therefore more likely to reflect the patients encountered in routine ICU practice. Another strength of our study is that we measured diaphragm function by magnetic stimulation of the phrenic nerve, which constitutes the gold standard but which is a fairly difficult technique, and ultrasound, which is easier to use in everyday practice.
Several limitations must be acknowledged. First, by using phrenic nerve stimulation as the reference technique to define diaphragm dysfunction (8, 13, 18), we excluded some eligible patients, in whom this technique was contraindicated. The cutoff of 11 cm H2O of Ptr,stim to define diaphragm dysfunction has been recommended in ICU patients (17, 24) and validated in this population by a previous study from our group (8). Because the supramaximal nature of phrenic nerve stimulation in terms of diaphragm contraction was not specifically confirmed, we therefore cannot absolutely rule out that incomplete recruitment of phrenic nerve fibers may have contributed to low twitch pressure in some cases. However, phrenic nerve stimulation was delivered at the maximum available intensity (100% of the output of paired 2.5-T biphasic stimulators), an intensity known to result in supramaximal stimulation in most patients (8, 18–21).
Second, we defined weaning failure in the presence of clinical intolerance or by the need for any ventilator support during the 48 hours after extubation. However, among the 43 successful patients, only one was reintubated between 48 hours and Day 7 after extubation. This patient had a Ptr,stim value of 17 cm H2O. We consequently consider that extending the duration of extubation failure in our population would not have changed our findings. In fact, weaning failure may not necessarily be directly induced by diaphragm dysfunction or ICU-AW, because several other causes could impair the weaning process (34, 35). Third, ICU-AW was determined using the MRC score and not with a dynamometer, such as the measure of the adductor pollicis muscle function by magnetic stimulation of the ulnar nerve (36). We found that MRC was validated in ICU patients by much more studies than dynamometer and was also less time consuming and technically demanding. Lastly, for obvious technical reasons, this was a single-center study in a medical ICU with a limited number of patients, which may limit the generalizability of our findings concerning the prevalence of diaphragm dysfunction in other settings.
In patients undergoing their first SBT, we report a high prevalence of diaphragm dysfunction, which was associated with a higher rate of weaning failure and mortality. In contrast, the prevalence of ICU-AW was lower and not strongly correlated with diaphragm dysfunction, but was associated with a longer duration of MV and a longer ICU stay. Because the respective risk factors of ICU-AW and diaphragm dysfunction were also different, our findings raise the hypothesis that the respective potential contributors of ICU-acquired muscle weakness may have different consequences on the diaphragm and peripheral muscles with respect to the length of ICU stay. The association between diaphragm dysfunction and weaning failure demonstrated by our study fuels the notion that diaphragm dysfunction should be the object of prevention and possibly specific interventions (37–39). This should be the target of specific research studies.
| 1. | Fan E, Cheek F, Chlan L, Gosselink R, Hart N, Herridge MS, Hopkins RO, Hough CL, Kress JP, Latronico N, et al.; ATS Committee on ICU-acquired Weakness in Adults; American Thoracic Society. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit–acquired weakness in adults. Am J Respir Crit Care Med 2014;190:1437–1446. |
| 2. | Stevens RD, Marshall SA, Cornblath DR, Hoke A, Needham DM, de Jonghe B, Ali NA, Sharshar T. A framework for diagnosing and classifying intensive care unit-acquired weakness. Crit Care Med 2009;37(Suppl. 19):S299–S308. |
| 3. | Garnacho-Montero J, Amaya-Villar R, García-Garmendía JL, Madrazo-Osuna J, Ortiz-Leyba C. Effect of critical illness polyneuropathy on the withdrawal from mechanical ventilation and the length of stay in septic patients. Crit Care Med 2005;33:349–354. |
| 4. | De Jonghe B, Bastuji-Garin S, Durand M-C, Malissin I, Rodrigues P, Cerf C, Outin H, Sharshar T; Groupe de Réflexion et d’Etude des Neuromyopathies en Réanimation. Respiratory weakness is associated with limb weakness and delayed weaning in critical illness. Crit Care Med 2007;35:2007–2015. |
| 5. | Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med 2014;371:287–288. |
| 6. | Batt J, dos Santos CC, Cameron JI, Herridge MS. Intensive care unit–acquired weakness: clinical phenotypes and molecular mechanisms. Am J Respir Crit Care Med 2013;187:238–246. |
| 7. | Hermans G, Van Mechelen H, Clerckx B, Vanhullebusch T, Mesotten D, Wilmer A, Casaer MP, Meersseman P, Debaveye Y, Van Cromphaut S, et al. Acute outcomes and 1-year mortality of intensive care unit–acquired weakness: a cohort study and propensity-matched analysis. Am J Respir Crit Care Med 2014;190:410–420. |
| 8. | Demoule A, Jung B, Prodanovic H, Molinari N, Chanques G, Coirault C, Matecki S, Duguet A, Similowski T, Jaber S. Diaphragm dysfunction on admission to the intensive care unit. Prevalence, risk factors, and prognostic impact: a prospective study. Am J Respir Crit Care Med 2013;188:213–219. |
| 9. | Jaber S, Petrof BJ, Jung B, Chanques G, Berthet J-P, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, et al. Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 2011;183:364–371. |
| 10. | Goligher EC, Fan E, Herridge MS, Murray A, Vorona S, Brace D, Rittayamai N, Lanys A, Tomlinson G, Singh JM, et al. Evolution of diaphragm thickness during mechanical ventilation: impact of inspiratory effort. Am J Respir Crit Care Med 2015;192:1080–1088. |
| 11. | Kim WY, Suh HJ, Hong S-B, Koh Y, Lim C-M. Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation. Crit Care Med 2011;39:2627–2630. |
| 12. | Jiang J-R, Tsai T-H, Jerng J-S, Yu C-J, Wu H-D, Yang P-C. Ultrasonographic evaluation of liver/spleen movements and extubation outcome. Chest 2004;126:179–185. |
| 13. | Jung B, Moury PH, Mahul M, de Jong A, Galia F, Prades A, Albaladejo P, Chanques G, Molinari N, Jaber S. Diaphragmatic dysfunction in patients with ICU-acquired weakness and its impact on extubation failure. Intensive Care Med 2016;42:853–861. |
| 14. | De Jonghe B, Sharshar T, Lefaucheur J-P, Authier F-J, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, et al.; Groupe de Réflexion et d’Etude des Neuromyopathies en Réanimation. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288:2859–2867. |
| 15. | Dubé B-P, Demoule A, Mayaux J, Reuter D, Prodanovic H, Similowski T, Dres M. Ultrasonographically diagnosed diaphragmatic dysfunction and weaning failure from mechanical ventilation in critically ill patients. Intensive Care Med Exp 2015;3:A454. |
| 16. | Boles J-M, Bion J, Connors A, Herridge M, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, Vieillard-Baron A, et al. Weaning from mechanical ventilation. Eur Respir J 2007;29:1033–1056. |
| 17. | Mills GH, Ponte J, Hamnegard CH, Kyroussis D, Polkey MI, Moxham J, Green M. Tracheal tube pressure change during magnetic stimulation of the phrenic nerves as an indicator of diaphragm strength on the intensive care unit. Br J Anaesth 2001;87:876–884. |
| 18. | Watson AC, Hughes PD, Louise Harris M, Hart N, Ware RJ, Wendon J, Green M, Moxham J. Measurement of twitch transdiaphragmatic, esophageal, and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit. Crit Care Med 2001;29:1325–1331. |
| 19. | Mills GH, Kyroussis D, Hamnegard CH, Polkey MI, Green M, Moxham J. Bilateral magnetic stimulation of the phrenic nerves from an anterolateral approach. Am J Respir Crit Care Med 1996;154:1099–1105. |
| 20. | Supinski GS, Callahan LA. Diaphragm weakness in mechanically ventilated critically ill patients. Crit Care 2013;17:R120. |
| 21. | Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Diaphragm strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154:1310–1317. |
| 22. | Matamis D, Soilemezi E, Tsagourias M, Akoumianaki E, Dimassi S, Boroli F, Richard J-CM, Brochard L. Sonographic evaluation of the diaphragm in critically ill patients: technique and clinical applications. Intensive Care Med 2013;39:801–810. |
| 23. | Goligher EC, Laghi F, Detsky ME, Farias P, Murray A, Brace D, Brochard LJ, Sebastien-Bolz S, Rubenfeld GD, Kavanagh BP, et al. Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity. Intensive Care Med 2015;41:642–649. |
| 24. | American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518–624. |
| 25. | Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 2008;358:1327–1335. |
| 26. | Hermans G, Agten A, Testelmans D, Decramer M, Gayan-Ramirez G. Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study. Crit Care 2010;14:R127. |
| 27. | Jung B, Nougaret S, Conseil M, Coisel Y, Futier E, Chanques G, Molinari N, Lacampagne A, Matecki S, Jaber S. Sepsis is associated with a preferential diaphragmatic atrophy: a critically ill patient study using tridimensional computed tomography. Anesthesiology 2014;120:1182–1191. |
| 28. | Divangahi M, Matecki S, Dudley RWR, Tuck SA, Bao W, Radzioch D, Comtois AS, Petrof BJ. Preferential diaphragmatic weakness during sustained Pseudomonas aeruginosa lung infection. Am J Respir Crit Care Med 2004;169:679–686. |
| 29. | Wollersheim T, Woehlecke J, Krebs M, Hamati J, Lodka D, Luther-Schroeder A, Langhans C, Haas K, Radtke T, Kleber C, et al. Dynamics of myosin degradation in intensive care unit-acquired weakness during severe critical illness. Intensive Care Med 2014;40:528–538. |
| 30. | de Jonghe B, Lacherade J-C, Sharshar T, Outin H. Intensive care unit-acquired weakness: risk factors and prevention. Crit Care Med 2009;37(Suppl. 10):S309–S315. |
| 31. | Andersen JL, Gruschy-Knudsen T, Sandri C, Larsson L, Schiaffino S. Bed rest increases the amount of mismatched fibers in human skeletal muscle. J Appl Physiol (1985) 1999;86:455–460. |
| 32. | De Jonghe B, Bastuji-Garin S, Sharshar T, Outin H, Brochard L. Does ICU-acquired paresis lengthen weaning from mechanical ventilation? Intensive Care Med 2004;30:1117–1121. |
| 33. | Llano-Diez M, Renaud G, Andersson M, Marrero HG, Cacciani N, Engquist H, Corpeño R, Artemenko K, Bergquist J, Larsson L. Mechanisms underlying ICU muscle wasting and effects of passive mechanical loading. Crit Care 2012;16:R209. |
| 34. | Perren A, Brochard L. Managing the apparent and hidden difficulties of weaning from mechanical ventilation. Intensive Care Med 2013;39:1885–1895. |
| 35. | Dres M, Teboul J-L, Monnet X. Weaning the cardiac patient from mechanical ventilation. Curr Opin Crit Care 2014;20:493–498. |
| 36. | Harris ML, Luo YM, Watson AC, Rafferty GF, Polkey MI, Green M, Moxham J. Adductor pollicis twitch tension assessed by magnetic stimulation of the ulnar nerve. Am J Respir Crit Care Med 2000;162:240–245. |
| 37. | Ahn B, Beaver T, Martin T, Hess P, Brumback BA, Ahmed S, Smith BK, Leeuwenburgh C, Martin AD, Ferreira LF. Phrenic nerve stimulation increases human diaphragm fiber force after cardiothoracic surgery. Am J Respir Crit Care Med 2014;190:837–839. |
| 38. | Hooijman PE, Beishuizen A, de Waard MC, de Man FS, Vermeijden JW, Steenvoorde P, Bouwman RA, Lommen W, van Hees HWH, Heunks LMA, et al. Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator. Am J Respir Crit Care Med 2014;189:863–865. |
| 39. | Doorduin J, Sinderby CA, Beck J, Stegeman DF, van Hees HWH, van der Hoeven JG, Heunks LMA. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med 2012;185:90–95. |
| 40. | McCool FD, Tzelepis GE. Dysfunction of the diaphragm. N Engl J Med 2012;366:932–942. |
*These authors contributed equally to this work.
Supported by the French Intensive Care Society (SRLF Bourse de Mobilité 2015, M.D.), 2015 Short Term Fellowship program of the European Respiratory Society (M.D.), 2015 Bernhard Dräger Award for advanced treatment of ARF of the European Society of Intensive Care Medicine (M.D.), Assistance Publique Hôpitaux de Paris (M.D.), Fondation pour la Recherche Médicale (20150734498, M.D.), and Mitacs Globalink Sorbonne Universités (M.D.). The clinical research of Département “R3S” is supported by the Investissement d'avenir ANR-10-AIHU 06 program of the French Government.
Author Contributions: M.D. and A.D. designed the study. M.D. coordinated the study. M.D., B.-P.D., J.M., D.R., and J.D. were responsible for patient screening, enrollment, and follow-up. M.D., B.-P.D., L.B., T.S., and A.D. analyzed the data. M.D., B.-P.D., L.B., T.S., and A.D. wrote the manuscript. All authors had full access to all of the study data, contributed to drafting the manuscript or critically revised it for important intellectual content, approved the final version of the manuscript, and take responsibility for the integrity of the data and the accuracy of the data analysis.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201602-0367OC on June 16, 2016
Author disclosures are available with the text of this article at www.atsjournals.org.
