Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Non-invasive ventilation during persistent weaning failure. A randomized controlled trial.

Ferrer M, Esquinas A, Arancibia F, et al.

Am J Respir Crit Care Med. 2003;168(1):70-6 [abstract]

Reviewed by Lincoln Smith MD, Children's Hospital and Regional Medical Center, Seattle, WA

Review posted March 2, 2003

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I. What is being studied?:

The study objective:

To assess the efficacy of noninvasive ventilation (NIV) in patients with persistent mechanical ventilator weaning failure.

The study design:

Prospective, randomized, controlled trial conducted in two centers. Patients in whom the spontaneous breathing trial failed during 3 consecutive days were randomly allocated, using a computer-generated table for each center either for (1) extubation and NIV treatment (NIV group) or (2) reconnection to the ventilator and once-daily weaning attempts (conventional-weaning group).

Successful weaning was defined as the ability to sustain spontaneous breathing at least for 3 consecutive days. Extubation failure was defined as reintubation within 72 hours after extubation. Spontaneous breathing trial failure was defined as the presence and persistence of one of the following criteria:

1. respiratory frequency > 35/min;
2. arterial O2 saturation by pulse oximetry < 90% (80% in chronic respiratory failure) at FIO2 ≤ 0.4;
3. heart rate > 140 or < 50/min, or increases or decreases > 20% compared to mechanical ventilation;
4. systolic blood pressure > 180 or < 70 mmHg, or increases or decreases > 20% compared to mechanical ventilation;
5. decreased consciousness, agitation or diaphoresis; and,
6. thoracic-abdominal paradoxical movement.

Criteria for reintubation and performance of tracheostomy were predefined.

The patients included:

Orotracheally intubated patients who met criteria to proceed with a weaning attempt but had failed a once-daily 2 hour spontaneous breathing trial on a T-piece for three consecutive days.

In addition to improvement or resolution of the underlying cause of acute respiratory failure, criteria to proceed with a weaning attempt were:

1. correction of arterial hypoxemia (arterial O2 tension (PaO2) > 60 mm Hg at inspired O2 fraction (FIO2) ≤ 0.4 and positive end-expiratory pressure (PEEP) ≤ 5 cm H2O) receiving either assist-control or pressure-support ventilation;
2. no fever (≤ 38 C) or hypothermia (< 35 C);
3. blood hemoglobin concentration ≥ 90 g.L-1;
4. no need for vasoactive drugs; and
5. normal consciousness (Glasgow coma score ≥ 13) with no need for sedative agents.

The patients excluded:

1. facial or cranial trauma or surgery
2. recent gastric or esophageal surgery
3. tracheotomy
4. active upper gastrointestinal bleeding
5. excessive amount of respiratory secretions
6. lack of cooperation

The interventions compared:

Noninvasive ventilation using the S/T mode delivered continuously immediately after extubation at least during the first 24 hours after extubation. Then, NIV was gradually withdrawn if patients tolerated spontaneous breathing until they could permanently sustain spontaneous breathing. A face mask was used as the first choice, but a nasal mask was optionally used if patients did not tolerate the face mask.

Conventional weaning. Patients were reconnected to the ventilator and daily spontaneous breathing trials were performed until patients could be extubated. When needed, low doses of sedatives or opioids were used between the spontaneous breathing trials to manage anxiety or pain and to avoid fighting against the ventilator.

The outcomes evaluated:

Primary: the period (length) of invasive ventilation

Secondary: 1) incidence of complications associated with prolonged mechanical ventilation, and 2) survival

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Each of two centers had its patients randomly allocated to the treatment or control group.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. 43 consecutive patients were enrolled. 21 patients were enrolled in the NIV group and 22 patients in the Conventional-weaning group. No patients were withdrawn from the study. 43 patients were included in presentation of data. All patients were followed 90 days after entry into the protocol.

Were patients analyzed in the groups to which they were randomized?

Yes. There were no crossovers. (One Conventional group patient was placed on NIV after extubation to avoid reintubation; this patient was analyzed as a Conventional weaning subject.)

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No. The nature of the study makes it impossible to blind patients and health workers.

4. Were the groups similar at the start of the trial?

There was no statistically significant difference in group characteristics at entry into the study based on a comparison of age, sex, smoking or alcohol abuse, admission APACHE-II, duration of ICU stay, days of mechanical ventilation, number of co-morbidities, history of chronic pulmonary disorder or cause of mechanical ventilation. There was no statistical significance between respiratory rate, tidal volume, heart rate, mean blood pressure, or arterial blood gas results while mechanically ventilated nor during the third spontaneous breathing trial at entry. However, there is no data on co-morbidities at entry into the study nor are the ventilator settings presented.

5. Aside from the experimental intervention, were the groups treated equally?

Although the nature of the study makes blinding virtually impossible, the authors established predefined criteria for spontaneous breathing trial failure, weaning success, reintubation and tracheostomy. Aside from the experimental intervention the groups were treated according to the discretion of the ICU attendings. The authors note the use of sedatives and opioids in the conventional weaning group. Other differences that are likely to be present, but not explicitly stated include feeding regimens, and use of diuretics, steroids and neuromuscular blockers.

III. What were the results?

1. How large was the treatment effect?

The primary outcome was a reduction in duration of mechanical ventilation. Compared with the conventional-weaning group, the mean duration of invasive ventilation was reduced by 11 days (p = 0.003) in the NIV group.

Secondary outcomes included the following:

1. The total period of ventilatory support was reduced by 9 days (p = 0.012) in the NIV group
2. The ICU stay was reduced by 11 days (p = 0.002) in the NIV group
3. The hospital stay was reduced by 13 days (p = 0.026) in the NIV group
4. There were 13 patients who required tracheostomy in the conventional-weaning group, and 1 patient in the NIV group (p < 0.001)

Kaplan-Meier curve for patients successfully weaned from mechanical ventilation as defined by three days without ventilatory support, either invasive or noninvasive revealed a significantly increased (p = 0.002) probability of weaning success in the NIV group (log-rank test).

Complications:

1. Increased serious complications in the conventional-weaning group (p = 0.004)
2. Increased nosocomial pneumonia (p = 0.042) and septic shock (p = 0.045) in conventional-weaning group.
3. 8 patients in the conventional-weaning group were not extubated at the end of the study period because of complications
4. Mild/moderate nasal bridge ulceration in 6 (29%), difficult to clear respiratory secretions in 2 (10), and gastric distension in 1 (5%) in the NIV group.

Kaplan-Meier curves for survival within 90 days after entry in to the protocol - cumulative survival was significantly higher in the NIV group (p = 0.045) (log-rank test)

Cumulative survival probability after 90 days of randomization was higher in the NIV group (p = 0.044)

Following a conventional-weaning approach was the only independent factor significantly associated with decreased ICU survival (p = 0.035)

Age > 70, development of hypercapnea (PaCO2 > 45 during the spontaneous breathing trial at entry in to the study (both p = .003) were independent factors significantly associated with decreased 90 day survival.

Univariate Analysis of Relative Risk (RR), Absolute Risk Reduction (ARR) and Numbers Needed to Treat (NNT) for outcomes of Death and Tracheostomy for NIV compared to conventional weaning:

	RR	ARR	NNT
Death	23% (6-95%)	31% (7-56)	3 (2-14)
Tracheostomy	8% (1-56)	54% (32-77)	1.8 (1-3)

2. How precise was the estimate of the treatment effect?

Using multivariate analysis there was a 77% RRR for ICU death in the NIV group with an adjusted Odds Ratio from the multivariate analysis of 6.6 (increased risk of death in conventional group) (95% CI 1.1-38.8)

There was an overall 67% RRR (CI 95% 27-85%) for serious complications in the NIV group

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Possibly. The patient population is different than found in pediatrics. The predictability of success of NIV may change with the age of the patient and reason for intubation. There was a decreased 90 day survival (p = 0.003) of patients > 70 yr in the conventional weaning group. There was premorbid chronic lung disease in 76 and 77% of the patients in the NIV and Conventional Weaning groups respectively.

Pediatric patients would probably be less cooperative with NIV. The higher incidence of death due to septic shock/multiorgan failure in the conventional weaning group, and the overall increased mortality of approx 60% at 90 days post entry into the study are also likely representative of significant differences between the outcomes of adult and pediatric patients. A general decreased mechanical ventilator time in children may be significant (1).

2. Were all clinically important outcomes considered?

No. Long term follow up of pulmonary function would also be a clinically important outcome to consider.

3. Are the likely treatment benefits worth the potential harms and costs?

Based on this study, it appears that the potential reduction in morbidity and mortality, as well as cost of NIV, clearly favors its use in intubated adults failing spontaneous breathing trials.

References

1. Randolph AG, Wypij D, Venkataraman ST, et al; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial. JAMA. 2002 Nov 27;288(20):2561-8. [abstract]

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