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Trials of Miscellaneous Interventions to Wean From Mechanical Ventilation
Trials of Miscellaneous Interventions to Wean From Mechanical Ventilation* Deborah Cook, MD; Maureen Meade, MD; Gordon Guyatt, MD; Ron Butler, MD; Aziz Aldawood, MD; and Scott Epstein, MD
We found eight randomized controlled trials (RCTs) of miscellaneous interventions that were designed to facilitate the process of weaning from mechanical ventilation. The two RCTs of high-fat/low-carbohydrate enteral nutrition found favorable physiologic effects on CO2 production and respiratory quotient, rendering this type of nutrition potentially useful in patients with impaired ventilatory reserve; however, no conclusions can be made about the outcomes of the duration of ventilation and weaning success. The two RCTs of postextubation use of noninvasive ventilation are conflicting, showing potential short-term physiologic benefit in one study, but no benefit in terms of reintubation rates or other morbidity. These RCTs are less promising than other applications of noninvasive ventilation such as those in patients with COPD exacerbations. One RCT showed no improvement in success of weaning with exogenous growth hormone administration. In the setting of very frequent baseline blood gas analyses, one RCT of oximetry and capnography was associated with significantly fewer blood gas analyses. Biofeedback to enhance safe and rapid weaning showed a dramatically lower duration of ventilation in one RCT that did not report the weaning methods used. One RCT of preextubation acupuncture showed lower rates of laryngospasm in the acupuncture group. Overall, these studies were underpowered for clinically important outcomes. Multidisciplinary, patient-centered, holistic, and non-pulmonary approaches to weaning may provide additional safe, effective adjunctive methods of hastening liberation from mechanical ventilation. (CHEST 2001; 120:438S– 444S) Key words: acupuncture; biofeedback; capnography; enteral nutrition; growth hormone; mechanical ventilation; meta-analysis; noninvasive ventilation; oximetry; systematic reviews; weaning Abbreviations: CPAP ⫽ continuous positive airway pressure; EVLW ⫽ extravascular lung water; Fio2 ⫽ fraction of inspired oxygen; IMV ⫽ intermittent mandatory ventilation; NPPV ⫽ noninvasive positive-pressure ventilation; PBVI ⫽ pulmonary blood volume index; RCT ⫽ randomized controlled trial; V˙e ⫽ minute ventilation; Vt ⫽ tidal volume
factors unrelated to ventilator management M yriad may influence the process of liberation from me-
chanical ventilation.1 These factors include malnutrition and other chronic illnesses such as cardiac disease that are present prior to the ICU admission, increased work of breathing during weaning, and psychological distress. The holistic approach to caring for patients with respiratory failure in the ICU has prompted investigators to study a 438S
variety of nontraditional weaning strategies unrelated to the mode of ventilation. These interventions are diverse and, often, nontechnologic, and they may be either directly or only indirectly related to the respiratory system. For example, the thermal effect of nutrition increases CO2 production in healthy patients and in those experiencing disease states. CO2 production may be determined in part by the composition of enteral or parental nutrition, which in turn may affect the weaning process.2 Other strategies to help achieve the goal of the safe and timely discontinuation of mechanical ventilation may involve devices and computers to monitor or drive the process of discontinuation,3 pharmacologic approaches to hasten it, and noninvasive ventilation to prevent extubation failure.4,5 Alternative strategies may focus on the provision of physiologic or psychological support during weaning.6 The objective of this systematic review is to examine the experimental evidence arising from randomized trials about miscellaneous interventions such as these designed to facilitate the process of weaning from mechanical ventilation.
Materials and Methods We have previously described the general methods of our systematic reviews, and, thus, we outline only the most relevant steps below. Eligibility Criteria For this section on miscellaneous interventions influencing the weaning process, we included only published randomized controlled trials (RCTs) of interventions not addressed in earlier sections in this supplement. Studies reporting both clinical and physiologic outcomes were included. We excluded interventions whose influence on the duration of ventilation already has been summarized in a recent systematic review (eg, sedation in the ICU7). Search for Relevant Studies To identify relevant studies, we searched MEDLINE, Excerpta Medica Database, HEALTHStar, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Controlled Trials Registry, and the Cochrane Data Base of Systematic Reviews from 1971 to 1999, and we examined the reference lists of all included articles. Data Abstraction and Assessment of Methodological Quality Data abstraction and methodological quality assessment were performed in duplicate by two members of a team of five *From the Department of Medicine (Drs. Cook, Meade, Guyatt, and Aldawood), McMaster University, Hamilton, Ontario, Canada; the Department of Anesthesia (Dr. Butler), University of Western Ontario, London, Ontario, Canada; and the Department of Medicine (Dr. Epstein), New England Medical Center, Tufts University, Boston, MA. This article is based on work performed by the McMaster University Evidence-based Practice Center, under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0017), Rockville, MD. Correspondence to: Deborah J. Cook, MD, McMaster University, Faculty of Health Sciences Center, Department of Clinical Epidemiology & Biostatistics, 1200 Main St West, Hamilton, Ontario, Canada; e-mail: [email protected] Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
respiratory therapists and five intensivists. The design features of RCTs that we abstracted included the following: the method of randomization and whether randomization was concealed; the definitions of weaning, extubation, and reintubation; the extent to which groups were similar with respect to important prognostic factors; whether investigators conducted an intention-to-treat analysis; whether patients, clinicians, and those assessing outcome were blind to allocation; the extent to which the groups received similar cointerventions; and reporting of the reasons for study withdrawal. Statistical Analysis We present both binary and continuous outcome variables. Differences in means, relative risks, and their 95% confidence intervals are reported. We did not pool results across studies due to the diverse interventions incorporated in this review.
Results Eight randomized trials are included (Table 1), two of which address the composition of enteral nutrition,8,9 two of which address postextubation noninvasive ventilation,10,11 and four of which evaluate other interventions.12–15 Results are reported in Table 2.
Composition of Enteral Nutrition The biological rationale for the high-fat/low-carbohydrate intervention tested in the following two RCTs is that the lower respiratory quotient might improve gas exchange and facilitate weaning from mechanical ventilation in patients with limited ventilatory reserve. In a randomized, double-blind trial,8 20 medical ICU patients were
allocated to one of the following: (1) a high-fat/lowcarbohydrate enteral feeding solution (Pulmocare; Ross Products; Columbus, OH [17% protein, 55% fat, and 28% carbohydrates]); (2) isocaloric feeds (Ensure Plus; Ross Products [17% protein, 30% fat, and 53% carbohydrates]). Nutritional requirements were calculated at 1.5 times the basal metabolic rate. Cointervening carbohydrate loading in IV dextrose or oral medication was avoided. Eligible patients had COPD, asthma, pneumonia, or neurologic disease. Patients with nephrotic syndrome, hepatic failure, and diabetes were excluded. Patients received mechanical ventilation using intermittent positive-pressure ventilation. Weaning was started when the patient’s respiratory rate was ⬍ 30 breaths/min, minute ventilation (V˙ e) was ⬍ 12 L/min (if their Pao2 at the fraction of inspired oxygen [Fio2] was ⬎ 60 mm Hg), when their Paco2 was 38 to 45 mm Hg, and when their pH was ⱖ 7.3. The study was terminated as soon as patients were able to tolerate 3 h of spontaneous breathing. Patients were comparable at baseline with respect to basic demographics and the preintervention duration of ventilation (approximately 64 and 70 h, respectively). Only one patient in the high-fat group developed delayed gastric emptying (feeds were held for 2 h, but recommenced with no further problem). The Paco2 decreased significantly in the high-fat feeding group just prior to weaning but increased slightly in patients receiving the isocaloric feed (p ⫽ 0.003), whereas there was no difference in Pao2 and tidal volume (Vt) or respiratory rate. The time from feeding commencement to successful weaning was significantly shorter in the high-fat group
Table 1—Methodological Characteristics of RCTs of Miscellaneous Interventions Study/yr
Population
Al Saady et al8/1989 20 patients in a medicalsurgical ICU who could be fed enterally van den Berg9/1994 32 adults with COPD, pneumonia, or neurological illness who could be fed enterally 75 patients postcoronary Gust et al10/1996 artery bypass Jiang et al11/1999 93 patients recovering from acute respiratory failure in a respiratory ICU Niehoff et al12/1988 24 mechanically ventilated adults in a surgical ICU Pichard et al13/1996 20 adults with acute respiratory failure, mechanically ventilated ⱖ 7 d Holliday and 40 adults in a Hyers14/1990 multidisciplinary ICU Lee et al15/1999 76 postoperative patients
Method of Randomization
Concealment
Weaning Criteria Extubation Reintubation Reported Criteria Reported Criteria Reported
Not clear
Not reported
Yes
Yes
No
Randomization table
Not reported
Yes
No
No
Not clear
Not reported
Yes
No
No
Not clear
Not reported
No
Yes
Yes
Not clear
Not reported
Yes
No
No
Not clear
Not reported
Yes
Yes
No
Randomization table Not clear
Not reported
No
No
No
Not reported
No
Yes
No
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Table 2—Results of RCTs of Miscellaneous Interventions* Study/yr Al Saady et al /1989† Continuous variables
Outcome
Results
Effect Magnitude
p Value
8
Change‡ in RR Change in Vt Change in Paco2 Change in Pao2 Duration of mechanical ventilation from the time that feed starts, h
van den Berg9/1994† Continuous variables
Respiratory quotient V˙ e during weaning
Binary variables Gust et al10/1996¶ Continuous variables
Spontaneous breathing for 3 h on CPAP Change in PBVI from end of the Tpiece trial to 90 min EVLW from end of T-piece trial to 90 min
Int Int Int Int Int Int Int Int Int Int
1: 2: 1: 2: 1: 2: 1: 2: 1: 2:
0.10 ⫾ 0.60 0.20 ⫾ 2.40 40.20 ⫾ 50.50 46.10 ⫾ 75.60 1.00 ⫾ 0.70 0.20 ⫾ 0.80 0.60 ⫾ 2.10 0.50 ⫾ 3.80 86.10 ⫾ 17.80 148.70 ⫾ 36.70
Int Int Int Int Int Int
1: 2: 1: 2: 1: 2:
0.72 ⫾ 0.02 0.86 ⫾ 0.02 8.80 ⫾ 0.90 10.50 ⫾ 0.80 12/14 patients 13/16 patients
Int Int Int Int Int Int Int Int Int
1: 2: 3: 1: 2: 3: 1: 2: 3:
17 ⫾ NE 8 ⫾ NE 17 ⫾ NE 0.1 ⫾ NE 0.4 ⫾ NE 1.6 ⫾ NE 0/25 patients 0/25 patients 0/25 patients
Binary variables
Reintubation
Jiang et al11/1999# Binary variables
Reintubation
Int 1: 13/47 patients Int 2: 7/46 patients
Niehoff et al12/1988** Continuous variables
ABG analyses performed
Int Int Int Int Int Int Int Int Int Int
1: 2: 1: 2: 1: 2: 1: 2: 1: 2:
5.90 ⫾ 2.70 10.50 ⫾ 1.80 18.80 ⫾ 2.04 19.70 ⫾ 1.90 0/12 patients 1/12 patients 0/12 patients 0/11 patients 0/12 patients 1/12 patients
Cumulative duration of mechanical support during weaning, h Nonextubation at day 12
Int Int Int Int
1: 2: 1: 2:
235.60 ⫾ 55.66 245.40 ⫾ 46.49 7/10 patients 7/10 patients
Change in Pimax
Int Int Int Int Int Int Int Int
1: 2: 1: 2: 1: 2: 1: 2:
12 ⫾ NE 6 ⫾ NE 120 ⫾ NE 51 ⫾ NE 4.41 ⫾ NE 2.67 ⫾ NE 20.60 ⫾ 8.90 32.60 ⫾ 17.60
Duration of mechanical ventilation, h Binary variables
Nonextubation Reintubation Combined end points
Pichard et al13/1996‡‡ Continuous variables Binary variables Holliday and Hyers14/ 1990§§ Continuous variables
Change in Vt Change in V˙ e, L/min Duration of mechanical ventilation, d
⫺0.10 (⫺1.71–1.51)§
0.90
⫺5.90 (⫺63.73–51.93)§
0.84
0.80 (0.13–1.47)§
0.02
0.10 (⫺2.68–2.88)§
0.94
⫺62.60 (⫺88.87–⫺36.33)§
⬍ 0.01
⫺0.14 (⫺0.16–⫺0.12)§
⬍ 0.01
⫺1.70 (⫺2.35–⫺1.05)§
⬍ 0.01
1.05 (0.75–1.46)㛳
0.78
Int Int Int Int Int Int Int Int Int
0§ ⫺8§ 8§ 0.7§ 1.0§ ⫺0.3§ 1.00㛳 1.00㛳 1.00㛳
1.00 1.00 1.00
1.76 (0.79–3.91)㛳
0.16
1 2 1 1 2 1 1 2 1
vs vs vs vs vs vs vs vs vs
3: 3: 2: 3: 3: 2: 3: 3: 2:
⫺4.60 (⫺6.49–⫺2.71)§
⬍ 0.01
⫺0.90 (⫺2.52–0.72)§
0.27
0.33 (0.01–7.45)㛳
0.49
1.00㛳
1.00
0.33 (0.01–7.45)㛳
0.49
⫺9.80 (⫺54.75–35.15)§
0.67
1.00 (0.57–1.77)㛳
1.00
6 69 1.74 ⫺12.00 (⫺20.64–⫺3.36)§
0.01
(table continues)
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Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
Table 2—Continued Study/yr
Outcome
Results
Effect Magnitude
p Value
Binary variables
Nonextubation
Int 1: 2/20 patients Int 2: 3/16 patients
0.58 (0.13–2.57)㛳
0.47
Lee et al15/1998㛳㛳 Binary variables
Laryngospasm
Int 1: 2/38 patients Int 2: 9/38 patients
0.26 (0.07–0.99)㛳
0.05
*Values given as mean ⫾ SD, unless otherwise indicated. RR ⫽ respiratory rate; Combined end point ⫽ nonextubation plus reintubation; NE ⫽ no estimate of variance was available or calculable; ABG ⫽ arterial blood gas; Pimax ⫽ maximal inspiratory pressure. †Int 1 ⫽ intervention 1 (high-fat/low-carbohydrate feed); Int 2 ⫽ intervention 2 (isocaloric feed). ‡“Change” for this variable signifies the change measured from the start of feeding to the start of weaning. §Values given as differences in means (95% confidence interval). 㛳Values given as relative risk (95% confidence interval). ¶Int 1 ⫽ intervention 1 (nasal bilevel pressure ventilation for 30 min); Int 1 ⫽ intervention 2 (CPAP for 30 min); Int 3 ⫽ intervention 3 (routine chest physiotherapy for 10 min plus oxygen by nasal cannula). #Int 1 ⫽ intervention 1 (nasal bilevel pressure ventilation for 30 min); Int 2 ⫽ intervention 2 (oxygen therapy by nasal prongs and chest physiotherapy). **Int 1 ⫽ intervention 1 (pulse oximetry and capnography); Int 2 ⫽ intervention 2 (periodic arterial blood gas analysis). ‡‡Int 1 ⫽ intervention 1 (recombinant growth hormone therapy); Int 2 ⫽ intervention 2 (no recombinant growth hormone therapy). §§Int 1 ⫽ intervention 1 (relaxation biofeedback); Int 2 ⫽ intervention 2 (no relaxation biofeedback). 㛳㛳Int 1 ⫽ intervention 1 (acupuncture); Int 2 ⫽ intervention 2 (control group).
than the isocaloric feeding group (86.1 ⫾ 17.8 h vs 148.7 ⫾ 36.7 h, respectively). In a second randomized unblinded enteral nutrition trial,9 32 medical ICU patients were allocated to (1) a high-fat/low-carbohydrate enteral feeding solution (Pulmocare; Ross Products [17% protein, 55% fat, and 28% carbohydrates]) or (2) isocaloric feeds (Ensure Plus; Ross Products [17% protein, 30% fat, ad 53% carbohydrates]). Nutritional requirements were calculated as per the previous trial. Patients were eligible if they had COPD, neurologic disease, or pneumonia without COPD. Patients were excluded if they had renal failure, hepatic failure, diabetes mellitus, or respiratory failure “without a prospect of weaning from the ventilator.” Patients received mechanical ventilation using volume control. Weaning was started using continuous positive airway pressure (CPAP) when patients were afebrile, in hemodynamically stable condition, required positive end-expiratory pressure of ⬍ 10 cm H2O on Fio2, and when their bicarbonate level was ⬍ 28 mmol/L. CPAP continued for a maximum of 3 h until patients were too dyspneic or tired too continue; specific failure criteria were not reported. Rest periods lasted for 4 to 6 h between CPAP trials. The study was terminated when patients were able to tolerate 3 h of spontaneous breathing. Adherence to the feeding regimens was successful in all but one patient in each group, in whom feeding was discontinued because of gastric distention. Patients were comparable at baseline with respect to illness severity and nutritional status. There were similar numbers of COPD patients in each arm of the study; however, in the high-fat group, 10 of 11 patients with COPD received mechanical ventilation for acute or chronic respiratory failure, vs 5 of 13 patients in the isocaloric feeding group. The respiratory quotient was significantly lower in patients receiving the high-fat/low-carbohydrate feed compared with the isocaloric feed (0.72 ⫾ 0.02 vs
0.86 ⫾ 0.02, respectively; p ⬍ 0.01). The V˙ e during weaning was also lower (8.8 ⫾ 0.9 vs 10.5 ⫾ 0.8, respectively; p ⬍ 0.01). A similar proportion of patients in both arms of the study had a successful 3-h trial of spontaneous breathing on CPAP (12 of 14 patients vs 13 of 16 patients, respectively; p ⫽ 0.74).
Postextubation Noninvasive Ventilation The hypothesis of this RCT is that functional residual capacity after spontaneous breathing with a T-piece may be better restored with noninvasive positive-pressure ventilation (NPPV) and CPAP than with spontaneous breathing and physiotherapy, thereby minimizing pulmonary edema and extubation failure. In a randomized unblinded trial of 75 cardiac surgery patients,10 three postextubation interventions were evaluated after 10 to 14 h of controlled ventilation and 30 min of T-piece breathing. Patients were extubated, then randomized to the following: (1) NPPV (n ⫽ 25) involving bilevel pressure ventilation using the spontaneous timed mode (S/T) via nasal mask with an inspiratory positive airway pressure of 10 cm H2O, an expiratory positive airway pressure of 5 cm H2O, and 10 L/min oxygen via nasal mask for 30 min; (2) CPAP at 7.5 cm H2O and Fio2 at 0.5 for 30 min (n ⫽ 25); and (3) chest physiotherapy for 10 min and oxygen via nasal mask at 6 L/min for 30 min (n ⫽ 25). Left ventricular function and inotropic support were comparable across groups. Cardiac surgical, anesthetic, and preextubation ICU management for the entire cohort are well-described. No patients were unavailable for follow-up, and the analysis was intention-to-treat. All three groups had the following increases in pulmonary blood volume index (PBVI) over time: bilevel pressure ventilation, 17 mL/m2; CPAP, 9 mL/m2; and chest physiotherapy, 17 mL/m2. Following 30 min of each intervention, however, PBVI in the bilevel pressure ventilation group was CHEST / 120 / 6 / DECEMBER, 2001 SUPPLEMENT
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significantly lower than that in the other two groups (p ⬍ 0.05). Extravascular lung water (EVLW) increased significantly from extubation through the 30-min intervention to 90 min following extubation in the chest physiotherapy group, compared to the other two groups (p ⬍ 0.05). All patients in each group underwent sustained extubation. In the second randomized trial by Jiang and colleagues,11 NPPV was evaluated among 93 extubated patients, 56 of whom were electively extubated and 37 of whom underwent unplanned extubations. Patients were randomized to either (1) bilevel pressure ventilation delivering inspiratory positive airway pressure of 12 cm H2O and expiratory positive airway pressure of 4 cm H2O by face mask, which was temporarily removed for suctioning and eating, for up to 72 h or (2) oxygen therapy. All patients had blood gas values measured 1 to 3 h after extubation. Bilevel pressure ventilation was terminated, and patients were intubated if their blood gas levels deteriorated, or if labored breathing or hemodynamic stability developed. Extubation failure was defined as the need for reintubation as judged by the attending physician. Patients had similar preextubation blood gas levels. Seven of 46 patients in the oxygen therapy group underwent reintubation, whereas 13 of 47 patients in the bilevel pressure ventilation group underwent reintubations (not significantly different). Postextubation management, with or without NPPV, therefore did not influence outcome; however, compared with the elective extubation patients (6 of 56 patients), the unplanned extubation patients were more likely to be reintubated (14 of 37 patients).
Oximetry and Capnography The rationale for this study12 was that arterial blood gas analysis may not be needed often if continuous monitoring of oxygenation and ventilation is provided during weaning. This trial was not designed to test the accuracy or utility of oximetry and capnography (which has been evaluated in the technology-assessment literature) but to evaluate its utility as a weaning adjunct. In a randomized unblinded trial, 24 postoperative cardiac patients were allocated to (1) pulse oximetry and capnography or (2) to periodic arterial blood gas measurements. Intermittent mandatory ventilation (IMV) was used for weaning, but stepwise decrements were not specified. Patients in the oximetry-and-capnography group had arterial blood gas measurements taken on ICU admission, just before extubation, and if their arterial oxygen saturation was at ⬍ 95% or their end-expiratory Pco2 was ⬍ 26 mm Hg or ⬎ 40 mm Hg, and as clinically indicated. The blood-gas group was weaned from ventilatory support if Paco2 was at 35 to 45 mm Hg, pH was at 7.35 to 7.45, Pao2 was ⱖ 70 mm Hg, and respiratory rate was ⱕ 30 breaths/min. There were fewer blood gas analyses performed in the oximetry-and-capnography group (5.9 ⫾ 2.7 vs 10.1 ⫾ 1.8 analyses, respectively; p ⬍ 0.01). The duration of ventilation was similar (18.8 ⫾ 2.0 h vs 19.7 ⫾ 1.9 h, respective442S
ly). One patient in the blood-gas group did not get extubated and was excluded from analysis. No patients required reintubation.
Growth Hormone The catabolism of critical illness, and the functional and structural neuromuscular abnormalities that occur in mechanically ventilated patients have prompted investigators to study the influence of growth hormones on weaning from mechanical ventilation. In a randomized double-blinded trial, 20 patients requiring ventilation for ⬎ 7 days were allocated to either (1) 0.43 IU recombinant growth hormone/kg/d administered subcutaneously for 12 days or (2) normal saline solution.13 Patients were excluded if they had known myopathy, neuropathy, or a risk factor for neuromuscular abnormalities. Weaning began for all patients when the following conditions occurred: V˙ e ⬍ 10 L/min; vital capacity, ⬎ 1 L; Pao2 ⱖ 60 with Fio2 ⱕ 0.4; or if a T-piece trial was tolerated for 30 min. Weaning began with synchronized IMV, and pressure support was added when spontaneous breathing developed and was gradually lowered. At a pressure support of 10 cm H2O, patients underwent a T-piece trial. After 12 h of spontaneous breathing, patients were extubated. Parenteral nutrition was provided for the first 48 h, at which time enteral nutrition was instituted. After 12 days, the growth-hormone group had higher levels of growth hormone, insulin-like growth hormone factor-1, and insulin. Fat-free mass was increased in the treated group compared to the untreated group. The cumulative duration of weaning for ⬎ 12 days was similar (235.6 ⫾ 17.6 h vs 245.4 ⫾ 14.7 h, respectively). A similar proportion of patients continued to receive mechanical ventilation at 12 days (7 of 10 and 7 of 10, respectively).
Relaxation Biofeedback To induce anxiolysis and to minimize muscle fatigue, the effect of relaxation biofeedback on respiratory mechanics and weaning was tested by Holliday and Hyers.14 In an unblinded randomized trial, 40 patients ventilated for ⱖ 7 days were allocated to either (1) relaxation biofeedback or (2) a control group. The biofeedback group received a multifaceted intervention, which consisted of communication (ie, the patient was asked about feelings, breathing, and sleeping, and was encouraged), Vt feedback (ie, auditory and visual feedback on a computer screen containing data on the patient’s Vt compared to a threshold Vt), and computerized visual feedback of frontalis muscle tension by electromyogram, for 30 to 50 min per day on CPAP (5 cm H2O) 5 days per week until study termination. Cointerventions during the weaning process are not well-described. Four patients who had been randomized to the control group died and were not included in the analysis. Within-group changes in maximal inspiratory pressure, Vt, and V˙ e were no different. The duration of ventilation was 12 days shorter in the biofeedback group than in the control group (20.6 ⫾ 8.9 days vs 32.6 ⫾ 17.6 days, respectively; p ⫽ 0.01). Nonextubation rates were Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
the same. The undisclosed weaning protocol using T-piece or IMV in this unblinded study, which found a 12-day difference in the duration of ventilation, makes interpretation difficult; moreover, the generalizability of this technologically complex intervention also is limited.
Acupuncture The potential benefit of acupuncture in averting largyngospasm was tested in 76 children who had undergone surgery and who had been randomized to receive either acupuncture with bloodletting at the Shao Shang acupoint on both thumbs just prior to extubation or to a control group.15 Patients undergoing oropharyngeal surgery were not enrolled. Laryngospasm was defined as occurring within 2 min of extubation, and was characterized by stridor, silence due to total closure of the vocal cords, and cyanosis. Among the patients in the acupuncture group, 2 of 38 (5.3%) developed laryngospasm, whereas 9 of 38 (23.7%) in the control group developed laryngospasm. No patients required reintubation.
Discussion This systematic review was conducted to summarize the approaches to weaning from mechanical ventilation that are not only focused on traditional ventilator strategies. Some of these strategies are physiologically based interventions such as low-carbohydrate enteral nutrition, while others reflect more unconventional approaches such as biofeedback and acupuncture. The two RCTs of high-fat/low-carbohydrate enteral nutrition enrolled a total of 52 patients. One study8 found a significant decrease in Paco2, while the other9 found a significantly lower respiratory quotient and V˙ e in patients receiving the high-fat feeds. The time from feeding commencement to successful weaning was significantly shorter in the high-fat group than in the isocaloric feeding group,8 but in the unblinded study9 the rate of successful 3-h spontaneous breathing trials was the same. High-fat feeds appear to have favorable physiologic effects on CO2 production and may be useful in patients with impaired ventilatory reserves. However, these studies were underpowered for clinically important outcomes, and their results require confirmation or refutation. Future RCTs in this area should enroll large numbers of difficult-to-wean COPD patients and should measure both physiologic and clinically important outcomes, such as the duration of mechanical ventilation. The influence of enteral vs parenteral nutrition on weaning success and the duration of ventilation in patients receiving long-term ventilation would be useful.16 The total calories may be as important as the composition of enteral feeding. Feasible but accurate methods to measure caloric needs also are needed. The two RCTs of patients after extubation that evaluate NPPV have conflicting results. The study by Gust et al10 in patients following coronary artery bypass grafting tested the following three strategies: NPPV; CPAP; and chest physiotherapy. All three groups had an increase in PBVI over time, but PBVI was lower in the NPPV group after 30
min, and the level of EVLW was higher following extubation in the chest physiotherapy group. Although these physiologic responses potentially have important clinical implications in some patients, all patients in this trial achieved successful extubation. In the randomized trial by Jiang et al,11 patients who were managed using NPPV after extubation did not have lower reintubation rates than did patients managed with oxygen therapy alone. The two small trials of NPPV postextubation that are included in this systematic review generate results that are less promising than other studies demonstrating the effectiveness of NPPV to prevent the initial intubation in patients with an exacerbation of COPD.17 However, it will be very challenging to detect a possible benefit of NPPV application following extubation, since the vast majority of patients who are extubated, including those who extubate themselves, do not require reintubation. Thus, trials of NPPV postextubation should focus on patients either at the highest risk of the need for reintubation or on those patients showing early signs of postextubation distress. The four other miscellaneous interventions provide us with insight into some nonpulmonary approaches to weaning. The double-blind trial of 12 days of recombinant growth hormone failed to show any significant improvement in the rate or success of weaning.13 Future research might include more chronic and difficult-to-wean patients, in whom the effect might be greater. However, a multicenter RCT18 showed that growth hormone therapy was associated with increased ICU mortality, seriously questioning the ethics of future investigations using this hormone. In the RCT of oximetry and capnography to monitor patients during weaning,12 approximately half as many blood gas analyses were performed compared to the control arm. However, the control patients were already getting approximately one blood gas analysis every 2 h. Such a dramatic benefit is unlikely to be seen in practice today, since this baseline blood gas frequency is highly atypical except for unstable or very difficult-to-wean patients. The hypothesis that biofeedback could enhance safe and rapid weaning is attractive, although the feasibility of this approach is questionable in clinical practice. The study by Holliday and Hyers14 showed a dramatic difference of 12 days in the duration of ventilation; however, the weaning methods were not described in this unblinded study, and it is possible that the estimated treatment is slightly inflated. One component of this multimethod intervention that could have been responsible for some of the benefit was actually a behavioral technique of positive verbal reinforcement. Encouragement has been shown to favorably influence functional health outcomes such as those for the 6-min walk test in ambulatory patients with severe COPD.19 Depending on a patient’s alertness, motivation, and sense of self-efficacy, strategies such as classic biofeedback, operant conditioning, or the behavioral approach used in this study could prove to be effective if studied in suitable populations. Multidisciplinary, patient-centered, holistic medicine is more embraced in the ICU today than in the past. Nontraditional medicine is increasingly subject to hypothCHEST / 120 / 6 / DECEMBER, 2001 SUPPLEMENT
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esis-driven investigation.20 In the future, we may read more research reports on less technologic and more nonpulmonary approaches to weaning from mechanical ventilation. These may suggest additional safe and effective adjunctive methods of hastening liberation from mechanical ventilation. The data included in this systematic review and a more comprehensive discussion of the original articles are included in an Evidence Report of the Agency for Healthcare Research and Quality.21
References 1 Manthous CA, Schmidt GA, Hall JB. Liberation from mechanical ventilation: a decade of progress. Chest 1998; 114: 886 –901 2 Dark DS, Pingleton SK, Kerby GR. Hypercapnia during weaning: a complication of nutritional support. Chest 1984; 88:141–143 3 Randolph AG, Clemmer TP, East TD, et al. Evaluation of compliance with a computerized protocol: weaning from mechanical ventilator support using pressure support. Comput Methods Programs Biomed 1998; 57:201–215 4 Meduri GH, Turner RE, Abou-Shala N, et al. Noninvasive positive pressure ventilation via face mask: first line intervention in patients with acute hypercapnic and hypoxemic respiratory failure. Chest 1996; 109:179 –193 5 Gilbert G, Gruson D, Portel L, et al. Noninvasive pressure support ventilation in COPD patients with postextubation hypercapnic respiratory insufficiency. Eur Respir J 1998; 11:1349 –1353 6 MacIntyre NR. Psychological factors in weaning from mechanical ventilator support. Respir Care 1995; 40:277–281 7 Ostermann ME, Keenan SP, Seiferling RA, et al. Sedation in the intensive care unit: a systematic review. JAMA 2000; 283:1451–1459 8 Al-Saady NM, Blackmore CM, Bennett ED. High fat, low carbohydrate, enteral feeding lowers Paco2 and reduces the period of ventilation in artificially ventilated patients. Intensive Care Med 1989; 15:290 –295 9 van den Berg B, Bogaard JM, Hop WCJ. High fat, low carbohydrate, enteral feeding in patients weaning from the
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ventilator. Intensive Care Med 1994; 20:470 – 475 10 Gust R, Gottschalk A, Schmidt H, et al. Effects of continuous CPAP and bi-level positive airway pressure (BiPAP) on extravascular lung water after extubation of the trachea in patients following coronary artery bypass grafting. Intensive Care Med 1996; 22:1345–1350 11 Jiang JS, Kao SJ, Wang SN. Effect of early application of biphasic positive airway pressure on the outcome of extubation in ventilator weaning. Respirology 1999; 4:161–165 12 Niehoff J, DelGuercio C, LaMorte W, et al. Efficacy of pulse oximetery and capnography in postoperative ventilatory weaning. Crit Care Med 1988; 16:701–705 13 Pichard C, Kyle U, Chrevrolet JC, et al. Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized controlled study. Crit Care Med 1996; 24:403–413 14 Holliday JE, Hyers TM. The reduction of weaning time from mechanical ventilation using tidal volume and relaxation biofeedback. Am Rev Respir Dis 1990; 11:1214 –1220 15 Lee CK, Chien TJ, Hsu JC, et al. The effect of acupuncture on the incidence of postextubation laryngospasm in children. Anaesthesia 1998; 53:910 –924 16 Heyland DK, MacDonald S, Keefe L, et al. Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA 1998; 280:2013–2019 17 Keenan SP, Gregor J, Sibbald WJ, et al. Noninvasive positive pressure ventilation in the setting of severe, acute exacerbations of chronic obstructive pulmonary disease: more effective, less expensive. Crit Care Med 2000; 28:2094 –2102 18 Takala J, Ruokonen E, Webster N, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341:785–792 19 Guyatt GH, Pugsley SO, Sullivan M, et al. Effect of encouragement on walking test performance. Thorax 1984; 39:818 – 822 20 Fontanarosa PF, Lundberg GD. Alternative medicine meets science. JAMA 1998; 280:1618 –1619 21 Criteria for weaning from mechanical ventilation. Evidence Report/Technology Assessment No. 23 from the Agency for Healthcare Research and Quality: AHRQ Publication No. 01-E010
Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
We found eight randomized controlled trials (RCTs) of miscellaneous interventions that were designed to facilitate the process of weaning from mechanical ventilation. The two RCTs of high-fat/low-carbohydrate enteral nutrition found favorable physiologic effects on CO2 production and respiratory quotient, rendering this type of nutrition potentially useful in patients with impaired ventilatory reserve; however, no conclusions can be made about the outcomes of the duration of ventilation and weaning success. The two RCTs of postextubation use of noninvasive ventilation are conflicting, showing potential short-term physiologic benefit in one study, but no benefit in terms of reintubation rates or other morbidity. These RCTs are less promising than other applications of noninvasive ventilation such as those in patients with COPD exacerbations. One RCT showed no improvement in success of weaning with exogenous growth hormone administration. In the setting of very frequent baseline blood gas analyses, one RCT of oximetry and capnography was associated with significantly fewer blood gas analyses. Biofeedback to enhance safe and rapid weaning showed a dramatically lower duration of ventilation in one RCT that did not report the weaning methods used. One RCT of preextubation acupuncture showed lower rates of laryngospasm in the acupuncture group. Overall, these studies were underpowered for clinically important outcomes. Multidisciplinary, patient-centered, holistic, and non-pulmonary approaches to weaning may provide additional safe, effective adjunctive methods of hastening liberation from mechanical ventilation. (CHEST 2001; 120:438S– 444S) Key words: acupuncture; biofeedback; capnography; enteral nutrition; growth hormone; mechanical ventilation; meta-analysis; noninvasive ventilation; oximetry; systematic reviews; weaning Abbreviations: CPAP ⫽ continuous positive airway pressure; EVLW ⫽ extravascular lung water; Fio2 ⫽ fraction of inspired oxygen; IMV ⫽ intermittent mandatory ventilation; NPPV ⫽ noninvasive positive-pressure ventilation; PBVI ⫽ pulmonary blood volume index; RCT ⫽ randomized controlled trial; V˙e ⫽ minute ventilation; Vt ⫽ tidal volume
factors unrelated to ventilator management M yriad may influence the process of liberation from me-
chanical ventilation.1 These factors include malnutrition and other chronic illnesses such as cardiac disease that are present prior to the ICU admission, increased work of breathing during weaning, and psychological distress. The holistic approach to caring for patients with respiratory failure in the ICU has prompted investigators to study a 438S
variety of nontraditional weaning strategies unrelated to the mode of ventilation. These interventions are diverse and, often, nontechnologic, and they may be either directly or only indirectly related to the respiratory system. For example, the thermal effect of nutrition increases CO2 production in healthy patients and in those experiencing disease states. CO2 production may be determined in part by the composition of enteral or parental nutrition, which in turn may affect the weaning process.2 Other strategies to help achieve the goal of the safe and timely discontinuation of mechanical ventilation may involve devices and computers to monitor or drive the process of discontinuation,3 pharmacologic approaches to hasten it, and noninvasive ventilation to prevent extubation failure.4,5 Alternative strategies may focus on the provision of physiologic or psychological support during weaning.6 The objective of this systematic review is to examine the experimental evidence arising from randomized trials about miscellaneous interventions such as these designed to facilitate the process of weaning from mechanical ventilation.
Materials and Methods We have previously described the general methods of our systematic reviews, and, thus, we outline only the most relevant steps below. Eligibility Criteria For this section on miscellaneous interventions influencing the weaning process, we included only published randomized controlled trials (RCTs) of interventions not addressed in earlier sections in this supplement. Studies reporting both clinical and physiologic outcomes were included. We excluded interventions whose influence on the duration of ventilation already has been summarized in a recent systematic review (eg, sedation in the ICU7). Search for Relevant Studies To identify relevant studies, we searched MEDLINE, Excerpta Medica Database, HEALTHStar, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Controlled Trials Registry, and the Cochrane Data Base of Systematic Reviews from 1971 to 1999, and we examined the reference lists of all included articles. Data Abstraction and Assessment of Methodological Quality Data abstraction and methodological quality assessment were performed in duplicate by two members of a team of five *From the Department of Medicine (Drs. Cook, Meade, Guyatt, and Aldawood), McMaster University, Hamilton, Ontario, Canada; the Department of Anesthesia (Dr. Butler), University of Western Ontario, London, Ontario, Canada; and the Department of Medicine (Dr. Epstein), New England Medical Center, Tufts University, Boston, MA. This article is based on work performed by the McMaster University Evidence-based Practice Center, under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0017), Rockville, MD. Correspondence to: Deborah J. Cook, MD, McMaster University, Faculty of Health Sciences Center, Department of Clinical Epidemiology & Biostatistics, 1200 Main St West, Hamilton, Ontario, Canada; e-mail: [email protected] Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
respiratory therapists and five intensivists. The design features of RCTs that we abstracted included the following: the method of randomization and whether randomization was concealed; the definitions of weaning, extubation, and reintubation; the extent to which groups were similar with respect to important prognostic factors; whether investigators conducted an intention-to-treat analysis; whether patients, clinicians, and those assessing outcome were blind to allocation; the extent to which the groups received similar cointerventions; and reporting of the reasons for study withdrawal. Statistical Analysis We present both binary and continuous outcome variables. Differences in means, relative risks, and their 95% confidence intervals are reported. We did not pool results across studies due to the diverse interventions incorporated in this review.
Results Eight randomized trials are included (Table 1), two of which address the composition of enteral nutrition,8,9 two of which address postextubation noninvasive ventilation,10,11 and four of which evaluate other interventions.12–15 Results are reported in Table 2.
Composition of Enteral Nutrition The biological rationale for the high-fat/low-carbohydrate intervention tested in the following two RCTs is that the lower respiratory quotient might improve gas exchange and facilitate weaning from mechanical ventilation in patients with limited ventilatory reserve. In a randomized, double-blind trial,8 20 medical ICU patients were
allocated to one of the following: (1) a high-fat/lowcarbohydrate enteral feeding solution (Pulmocare; Ross Products; Columbus, OH [17% protein, 55% fat, and 28% carbohydrates]); (2) isocaloric feeds (Ensure Plus; Ross Products [17% protein, 30% fat, and 53% carbohydrates]). Nutritional requirements were calculated at 1.5 times the basal metabolic rate. Cointervening carbohydrate loading in IV dextrose or oral medication was avoided. Eligible patients had COPD, asthma, pneumonia, or neurologic disease. Patients with nephrotic syndrome, hepatic failure, and diabetes were excluded. Patients received mechanical ventilation using intermittent positive-pressure ventilation. Weaning was started when the patient’s respiratory rate was ⬍ 30 breaths/min, minute ventilation (V˙ e) was ⬍ 12 L/min (if their Pao2 at the fraction of inspired oxygen [Fio2] was ⬎ 60 mm Hg), when their Paco2 was 38 to 45 mm Hg, and when their pH was ⱖ 7.3. The study was terminated as soon as patients were able to tolerate 3 h of spontaneous breathing. Patients were comparable at baseline with respect to basic demographics and the preintervention duration of ventilation (approximately 64 and 70 h, respectively). Only one patient in the high-fat group developed delayed gastric emptying (feeds were held for 2 h, but recommenced with no further problem). The Paco2 decreased significantly in the high-fat feeding group just prior to weaning but increased slightly in patients receiving the isocaloric feed (p ⫽ 0.003), whereas there was no difference in Pao2 and tidal volume (Vt) or respiratory rate. The time from feeding commencement to successful weaning was significantly shorter in the high-fat group
Table 1—Methodological Characteristics of RCTs of Miscellaneous Interventions Study/yr
Population
Al Saady et al8/1989 20 patients in a medicalsurgical ICU who could be fed enterally van den Berg9/1994 32 adults with COPD, pneumonia, or neurological illness who could be fed enterally 75 patients postcoronary Gust et al10/1996 artery bypass Jiang et al11/1999 93 patients recovering from acute respiratory failure in a respiratory ICU Niehoff et al12/1988 24 mechanically ventilated adults in a surgical ICU Pichard et al13/1996 20 adults with acute respiratory failure, mechanically ventilated ⱖ 7 d Holliday and 40 adults in a Hyers14/1990 multidisciplinary ICU Lee et al15/1999 76 postoperative patients
Method of Randomization
Concealment
Weaning Criteria Extubation Reintubation Reported Criteria Reported Criteria Reported
Not clear
Not reported
Yes
Yes
No
Randomization table
Not reported
Yes
No
No
Not clear
Not reported
Yes
No
No
Not clear
Not reported
No
Yes
Yes
Not clear
Not reported
Yes
No
No
Not clear
Not reported
Yes
Yes
No
Randomization table Not clear
Not reported
No
No
No
Not reported
No
Yes
No
CHEST / 120 / 6 / DECEMBER, 2001 SUPPLEMENT
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Table 2—Results of RCTs of Miscellaneous Interventions* Study/yr Al Saady et al /1989† Continuous variables
Outcome
Results
Effect Magnitude
p Value
8
Change‡ in RR Change in Vt Change in Paco2 Change in Pao2 Duration of mechanical ventilation from the time that feed starts, h
van den Berg9/1994† Continuous variables
Respiratory quotient V˙ e during weaning
Binary variables Gust et al10/1996¶ Continuous variables
Spontaneous breathing for 3 h on CPAP Change in PBVI from end of the Tpiece trial to 90 min EVLW from end of T-piece trial to 90 min
Int Int Int Int Int Int Int Int Int Int
1: 2: 1: 2: 1: 2: 1: 2: 1: 2:
0.10 ⫾ 0.60 0.20 ⫾ 2.40 40.20 ⫾ 50.50 46.10 ⫾ 75.60 1.00 ⫾ 0.70 0.20 ⫾ 0.80 0.60 ⫾ 2.10 0.50 ⫾ 3.80 86.10 ⫾ 17.80 148.70 ⫾ 36.70
Int Int Int Int Int Int
1: 2: 1: 2: 1: 2:
0.72 ⫾ 0.02 0.86 ⫾ 0.02 8.80 ⫾ 0.90 10.50 ⫾ 0.80 12/14 patients 13/16 patients
Int Int Int Int Int Int Int Int Int
1: 2: 3: 1: 2: 3: 1: 2: 3:
17 ⫾ NE 8 ⫾ NE 17 ⫾ NE 0.1 ⫾ NE 0.4 ⫾ NE 1.6 ⫾ NE 0/25 patients 0/25 patients 0/25 patients
Binary variables
Reintubation
Jiang et al11/1999# Binary variables
Reintubation
Int 1: 13/47 patients Int 2: 7/46 patients
Niehoff et al12/1988** Continuous variables
ABG analyses performed
Int Int Int Int Int Int Int Int Int Int
1: 2: 1: 2: 1: 2: 1: 2: 1: 2:
5.90 ⫾ 2.70 10.50 ⫾ 1.80 18.80 ⫾ 2.04 19.70 ⫾ 1.90 0/12 patients 1/12 patients 0/12 patients 0/11 patients 0/12 patients 1/12 patients
Cumulative duration of mechanical support during weaning, h Nonextubation at day 12
Int Int Int Int
1: 2: 1: 2:
235.60 ⫾ 55.66 245.40 ⫾ 46.49 7/10 patients 7/10 patients
Change in Pimax
Int Int Int Int Int Int Int Int
1: 2: 1: 2: 1: 2: 1: 2:
12 ⫾ NE 6 ⫾ NE 120 ⫾ NE 51 ⫾ NE 4.41 ⫾ NE 2.67 ⫾ NE 20.60 ⫾ 8.90 32.60 ⫾ 17.60
Duration of mechanical ventilation, h Binary variables
Nonextubation Reintubation Combined end points
Pichard et al13/1996‡‡ Continuous variables Binary variables Holliday and Hyers14/ 1990§§ Continuous variables
Change in Vt Change in V˙ e, L/min Duration of mechanical ventilation, d
⫺0.10 (⫺1.71–1.51)§
0.90
⫺5.90 (⫺63.73–51.93)§
0.84
0.80 (0.13–1.47)§
0.02
0.10 (⫺2.68–2.88)§
0.94
⫺62.60 (⫺88.87–⫺36.33)§
⬍ 0.01
⫺0.14 (⫺0.16–⫺0.12)§
⬍ 0.01
⫺1.70 (⫺2.35–⫺1.05)§
⬍ 0.01
1.05 (0.75–1.46)㛳
0.78
Int Int Int Int Int Int Int Int Int
0§ ⫺8§ 8§ 0.7§ 1.0§ ⫺0.3§ 1.00㛳 1.00㛳 1.00㛳
1.00 1.00 1.00
1.76 (0.79–3.91)㛳
0.16
1 2 1 1 2 1 1 2 1
vs vs vs vs vs vs vs vs vs
3: 3: 2: 3: 3: 2: 3: 3: 2:
⫺4.60 (⫺6.49–⫺2.71)§
⬍ 0.01
⫺0.90 (⫺2.52–0.72)§
0.27
0.33 (0.01–7.45)㛳
0.49
1.00㛳
1.00
0.33 (0.01–7.45)㛳
0.49
⫺9.80 (⫺54.75–35.15)§
0.67
1.00 (0.57–1.77)㛳
1.00
6 69 1.74 ⫺12.00 (⫺20.64–⫺3.36)§
0.01
(table continues)
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Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
Table 2—Continued Study/yr
Outcome
Results
Effect Magnitude
p Value
Binary variables
Nonextubation
Int 1: 2/20 patients Int 2: 3/16 patients
0.58 (0.13–2.57)㛳
0.47
Lee et al15/1998㛳㛳 Binary variables
Laryngospasm
Int 1: 2/38 patients Int 2: 9/38 patients
0.26 (0.07–0.99)㛳
0.05
*Values given as mean ⫾ SD, unless otherwise indicated. RR ⫽ respiratory rate; Combined end point ⫽ nonextubation plus reintubation; NE ⫽ no estimate of variance was available or calculable; ABG ⫽ arterial blood gas; Pimax ⫽ maximal inspiratory pressure. †Int 1 ⫽ intervention 1 (high-fat/low-carbohydrate feed); Int 2 ⫽ intervention 2 (isocaloric feed). ‡“Change” for this variable signifies the change measured from the start of feeding to the start of weaning. §Values given as differences in means (95% confidence interval). 㛳Values given as relative risk (95% confidence interval). ¶Int 1 ⫽ intervention 1 (nasal bilevel pressure ventilation for 30 min); Int 1 ⫽ intervention 2 (CPAP for 30 min); Int 3 ⫽ intervention 3 (routine chest physiotherapy for 10 min plus oxygen by nasal cannula). #Int 1 ⫽ intervention 1 (nasal bilevel pressure ventilation for 30 min); Int 2 ⫽ intervention 2 (oxygen therapy by nasal prongs and chest physiotherapy). **Int 1 ⫽ intervention 1 (pulse oximetry and capnography); Int 2 ⫽ intervention 2 (periodic arterial blood gas analysis). ‡‡Int 1 ⫽ intervention 1 (recombinant growth hormone therapy); Int 2 ⫽ intervention 2 (no recombinant growth hormone therapy). §§Int 1 ⫽ intervention 1 (relaxation biofeedback); Int 2 ⫽ intervention 2 (no relaxation biofeedback). 㛳㛳Int 1 ⫽ intervention 1 (acupuncture); Int 2 ⫽ intervention 2 (control group).
than the isocaloric feeding group (86.1 ⫾ 17.8 h vs 148.7 ⫾ 36.7 h, respectively). In a second randomized unblinded enteral nutrition trial,9 32 medical ICU patients were allocated to (1) a high-fat/low-carbohydrate enteral feeding solution (Pulmocare; Ross Products [17% protein, 55% fat, and 28% carbohydrates]) or (2) isocaloric feeds (Ensure Plus; Ross Products [17% protein, 30% fat, ad 53% carbohydrates]). Nutritional requirements were calculated as per the previous trial. Patients were eligible if they had COPD, neurologic disease, or pneumonia without COPD. Patients were excluded if they had renal failure, hepatic failure, diabetes mellitus, or respiratory failure “without a prospect of weaning from the ventilator.” Patients received mechanical ventilation using volume control. Weaning was started using continuous positive airway pressure (CPAP) when patients were afebrile, in hemodynamically stable condition, required positive end-expiratory pressure of ⬍ 10 cm H2O on Fio2, and when their bicarbonate level was ⬍ 28 mmol/L. CPAP continued for a maximum of 3 h until patients were too dyspneic or tired too continue; specific failure criteria were not reported. Rest periods lasted for 4 to 6 h between CPAP trials. The study was terminated when patients were able to tolerate 3 h of spontaneous breathing. Adherence to the feeding regimens was successful in all but one patient in each group, in whom feeding was discontinued because of gastric distention. Patients were comparable at baseline with respect to illness severity and nutritional status. There were similar numbers of COPD patients in each arm of the study; however, in the high-fat group, 10 of 11 patients with COPD received mechanical ventilation for acute or chronic respiratory failure, vs 5 of 13 patients in the isocaloric feeding group. The respiratory quotient was significantly lower in patients receiving the high-fat/low-carbohydrate feed compared with the isocaloric feed (0.72 ⫾ 0.02 vs
0.86 ⫾ 0.02, respectively; p ⬍ 0.01). The V˙ e during weaning was also lower (8.8 ⫾ 0.9 vs 10.5 ⫾ 0.8, respectively; p ⬍ 0.01). A similar proportion of patients in both arms of the study had a successful 3-h trial of spontaneous breathing on CPAP (12 of 14 patients vs 13 of 16 patients, respectively; p ⫽ 0.74).
Postextubation Noninvasive Ventilation The hypothesis of this RCT is that functional residual capacity after spontaneous breathing with a T-piece may be better restored with noninvasive positive-pressure ventilation (NPPV) and CPAP than with spontaneous breathing and physiotherapy, thereby minimizing pulmonary edema and extubation failure. In a randomized unblinded trial of 75 cardiac surgery patients,10 three postextubation interventions were evaluated after 10 to 14 h of controlled ventilation and 30 min of T-piece breathing. Patients were extubated, then randomized to the following: (1) NPPV (n ⫽ 25) involving bilevel pressure ventilation using the spontaneous timed mode (S/T) via nasal mask with an inspiratory positive airway pressure of 10 cm H2O, an expiratory positive airway pressure of 5 cm H2O, and 10 L/min oxygen via nasal mask for 30 min; (2) CPAP at 7.5 cm H2O and Fio2 at 0.5 for 30 min (n ⫽ 25); and (3) chest physiotherapy for 10 min and oxygen via nasal mask at 6 L/min for 30 min (n ⫽ 25). Left ventricular function and inotropic support were comparable across groups. Cardiac surgical, anesthetic, and preextubation ICU management for the entire cohort are well-described. No patients were unavailable for follow-up, and the analysis was intention-to-treat. All three groups had the following increases in pulmonary blood volume index (PBVI) over time: bilevel pressure ventilation, 17 mL/m2; CPAP, 9 mL/m2; and chest physiotherapy, 17 mL/m2. Following 30 min of each intervention, however, PBVI in the bilevel pressure ventilation group was CHEST / 120 / 6 / DECEMBER, 2001 SUPPLEMENT
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significantly lower than that in the other two groups (p ⬍ 0.05). Extravascular lung water (EVLW) increased significantly from extubation through the 30-min intervention to 90 min following extubation in the chest physiotherapy group, compared to the other two groups (p ⬍ 0.05). All patients in each group underwent sustained extubation. In the second randomized trial by Jiang and colleagues,11 NPPV was evaluated among 93 extubated patients, 56 of whom were electively extubated and 37 of whom underwent unplanned extubations. Patients were randomized to either (1) bilevel pressure ventilation delivering inspiratory positive airway pressure of 12 cm H2O and expiratory positive airway pressure of 4 cm H2O by face mask, which was temporarily removed for suctioning and eating, for up to 72 h or (2) oxygen therapy. All patients had blood gas values measured 1 to 3 h after extubation. Bilevel pressure ventilation was terminated, and patients were intubated if their blood gas levels deteriorated, or if labored breathing or hemodynamic stability developed. Extubation failure was defined as the need for reintubation as judged by the attending physician. Patients had similar preextubation blood gas levels. Seven of 46 patients in the oxygen therapy group underwent reintubation, whereas 13 of 47 patients in the bilevel pressure ventilation group underwent reintubations (not significantly different). Postextubation management, with or without NPPV, therefore did not influence outcome; however, compared with the elective extubation patients (6 of 56 patients), the unplanned extubation patients were more likely to be reintubated (14 of 37 patients).
Oximetry and Capnography The rationale for this study12 was that arterial blood gas analysis may not be needed often if continuous monitoring of oxygenation and ventilation is provided during weaning. This trial was not designed to test the accuracy or utility of oximetry and capnography (which has been evaluated in the technology-assessment literature) but to evaluate its utility as a weaning adjunct. In a randomized unblinded trial, 24 postoperative cardiac patients were allocated to (1) pulse oximetry and capnography or (2) to periodic arterial blood gas measurements. Intermittent mandatory ventilation (IMV) was used for weaning, but stepwise decrements were not specified. Patients in the oximetry-and-capnography group had arterial blood gas measurements taken on ICU admission, just before extubation, and if their arterial oxygen saturation was at ⬍ 95% or their end-expiratory Pco2 was ⬍ 26 mm Hg or ⬎ 40 mm Hg, and as clinically indicated. The blood-gas group was weaned from ventilatory support if Paco2 was at 35 to 45 mm Hg, pH was at 7.35 to 7.45, Pao2 was ⱖ 70 mm Hg, and respiratory rate was ⱕ 30 breaths/min. There were fewer blood gas analyses performed in the oximetry-and-capnography group (5.9 ⫾ 2.7 vs 10.1 ⫾ 1.8 analyses, respectively; p ⬍ 0.01). The duration of ventilation was similar (18.8 ⫾ 2.0 h vs 19.7 ⫾ 1.9 h, respective442S
ly). One patient in the blood-gas group did not get extubated and was excluded from analysis. No patients required reintubation.
Growth Hormone The catabolism of critical illness, and the functional and structural neuromuscular abnormalities that occur in mechanically ventilated patients have prompted investigators to study the influence of growth hormones on weaning from mechanical ventilation. In a randomized double-blinded trial, 20 patients requiring ventilation for ⬎ 7 days were allocated to either (1) 0.43 IU recombinant growth hormone/kg/d administered subcutaneously for 12 days or (2) normal saline solution.13 Patients were excluded if they had known myopathy, neuropathy, or a risk factor for neuromuscular abnormalities. Weaning began for all patients when the following conditions occurred: V˙ e ⬍ 10 L/min; vital capacity, ⬎ 1 L; Pao2 ⱖ 60 with Fio2 ⱕ 0.4; or if a T-piece trial was tolerated for 30 min. Weaning began with synchronized IMV, and pressure support was added when spontaneous breathing developed and was gradually lowered. At a pressure support of 10 cm H2O, patients underwent a T-piece trial. After 12 h of spontaneous breathing, patients were extubated. Parenteral nutrition was provided for the first 48 h, at which time enteral nutrition was instituted. After 12 days, the growth-hormone group had higher levels of growth hormone, insulin-like growth hormone factor-1, and insulin. Fat-free mass was increased in the treated group compared to the untreated group. The cumulative duration of weaning for ⬎ 12 days was similar (235.6 ⫾ 17.6 h vs 245.4 ⫾ 14.7 h, respectively). A similar proportion of patients continued to receive mechanical ventilation at 12 days (7 of 10 and 7 of 10, respectively).
Relaxation Biofeedback To induce anxiolysis and to minimize muscle fatigue, the effect of relaxation biofeedback on respiratory mechanics and weaning was tested by Holliday and Hyers.14 In an unblinded randomized trial, 40 patients ventilated for ⱖ 7 days were allocated to either (1) relaxation biofeedback or (2) a control group. The biofeedback group received a multifaceted intervention, which consisted of communication (ie, the patient was asked about feelings, breathing, and sleeping, and was encouraged), Vt feedback (ie, auditory and visual feedback on a computer screen containing data on the patient’s Vt compared to a threshold Vt), and computerized visual feedback of frontalis muscle tension by electromyogram, for 30 to 50 min per day on CPAP (5 cm H2O) 5 days per week until study termination. Cointerventions during the weaning process are not well-described. Four patients who had been randomized to the control group died and were not included in the analysis. Within-group changes in maximal inspiratory pressure, Vt, and V˙ e were no different. The duration of ventilation was 12 days shorter in the biofeedback group than in the control group (20.6 ⫾ 8.9 days vs 32.6 ⫾ 17.6 days, respectively; p ⫽ 0.01). Nonextubation rates were Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support
the same. The undisclosed weaning protocol using T-piece or IMV in this unblinded study, which found a 12-day difference in the duration of ventilation, makes interpretation difficult; moreover, the generalizability of this technologically complex intervention also is limited.
Acupuncture The potential benefit of acupuncture in averting largyngospasm was tested in 76 children who had undergone surgery and who had been randomized to receive either acupuncture with bloodletting at the Shao Shang acupoint on both thumbs just prior to extubation or to a control group.15 Patients undergoing oropharyngeal surgery were not enrolled. Laryngospasm was defined as occurring within 2 min of extubation, and was characterized by stridor, silence due to total closure of the vocal cords, and cyanosis. Among the patients in the acupuncture group, 2 of 38 (5.3%) developed laryngospasm, whereas 9 of 38 (23.7%) in the control group developed laryngospasm. No patients required reintubation.
Discussion This systematic review was conducted to summarize the approaches to weaning from mechanical ventilation that are not only focused on traditional ventilator strategies. Some of these strategies are physiologically based interventions such as low-carbohydrate enteral nutrition, while others reflect more unconventional approaches such as biofeedback and acupuncture. The two RCTs of high-fat/low-carbohydrate enteral nutrition enrolled a total of 52 patients. One study8 found a significant decrease in Paco2, while the other9 found a significantly lower respiratory quotient and V˙ e in patients receiving the high-fat feeds. The time from feeding commencement to successful weaning was significantly shorter in the high-fat group than in the isocaloric feeding group,8 but in the unblinded study9 the rate of successful 3-h spontaneous breathing trials was the same. High-fat feeds appear to have favorable physiologic effects on CO2 production and may be useful in patients with impaired ventilatory reserves. However, these studies were underpowered for clinically important outcomes, and their results require confirmation or refutation. Future RCTs in this area should enroll large numbers of difficult-to-wean COPD patients and should measure both physiologic and clinically important outcomes, such as the duration of mechanical ventilation. The influence of enteral vs parenteral nutrition on weaning success and the duration of ventilation in patients receiving long-term ventilation would be useful.16 The total calories may be as important as the composition of enteral feeding. Feasible but accurate methods to measure caloric needs also are needed. The two RCTs of patients after extubation that evaluate NPPV have conflicting results. The study by Gust et al10 in patients following coronary artery bypass grafting tested the following three strategies: NPPV; CPAP; and chest physiotherapy. All three groups had an increase in PBVI over time, but PBVI was lower in the NPPV group after 30
min, and the level of EVLW was higher following extubation in the chest physiotherapy group. Although these physiologic responses potentially have important clinical implications in some patients, all patients in this trial achieved successful extubation. In the randomized trial by Jiang et al,11 patients who were managed using NPPV after extubation did not have lower reintubation rates than did patients managed with oxygen therapy alone. The two small trials of NPPV postextubation that are included in this systematic review generate results that are less promising than other studies demonstrating the effectiveness of NPPV to prevent the initial intubation in patients with an exacerbation of COPD.17 However, it will be very challenging to detect a possible benefit of NPPV application following extubation, since the vast majority of patients who are extubated, including those who extubate themselves, do not require reintubation. Thus, trials of NPPV postextubation should focus on patients either at the highest risk of the need for reintubation or on those patients showing early signs of postextubation distress. The four other miscellaneous interventions provide us with insight into some nonpulmonary approaches to weaning. The double-blind trial of 12 days of recombinant growth hormone failed to show any significant improvement in the rate or success of weaning.13 Future research might include more chronic and difficult-to-wean patients, in whom the effect might be greater. However, a multicenter RCT18 showed that growth hormone therapy was associated with increased ICU mortality, seriously questioning the ethics of future investigations using this hormone. In the RCT of oximetry and capnography to monitor patients during weaning,12 approximately half as many blood gas analyses were performed compared to the control arm. However, the control patients were already getting approximately one blood gas analysis every 2 h. Such a dramatic benefit is unlikely to be seen in practice today, since this baseline blood gas frequency is highly atypical except for unstable or very difficult-to-wean patients. The hypothesis that biofeedback could enhance safe and rapid weaning is attractive, although the feasibility of this approach is questionable in clinical practice. The study by Holliday and Hyers14 showed a dramatic difference of 12 days in the duration of ventilation; however, the weaning methods were not described in this unblinded study, and it is possible that the estimated treatment is slightly inflated. One component of this multimethod intervention that could have been responsible for some of the benefit was actually a behavioral technique of positive verbal reinforcement. Encouragement has been shown to favorably influence functional health outcomes such as those for the 6-min walk test in ambulatory patients with severe COPD.19 Depending on a patient’s alertness, motivation, and sense of self-efficacy, strategies such as classic biofeedback, operant conditioning, or the behavioral approach used in this study could prove to be effective if studied in suitable populations. Multidisciplinary, patient-centered, holistic medicine is more embraced in the ICU today than in the past. Nontraditional medicine is increasingly subject to hypothCHEST / 120 / 6 / DECEMBER, 2001 SUPPLEMENT
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esis-driven investigation.20 In the future, we may read more research reports on less technologic and more nonpulmonary approaches to weaning from mechanical ventilation. These may suggest additional safe and effective adjunctive methods of hastening liberation from mechanical ventilation. The data included in this systematic review and a more comprehensive discussion of the original articles are included in an Evidence Report of the Agency for Healthcare Research and Quality.21
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Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support