Journal Club Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital 9/12/2010 Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital

Journal ClubNir Hus MD., PhD.

Ryder Trauma CenterJackson Memorial Hospital

9/12/2010

Nir Hus MD., PhD.Ryder Trauma Center

Jackson Memorial Hospital

Determann et al. Critical Care 2010,

14:R1Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial.



Established

•Mechanical ventilation has the potential to aggravate lung injury.

•Randomized controlled clinical trials confirmed the existence of ventilator-associated lung injury in patients with ALI or its more-severe form, ARDS.

•Reduced morbidity and mortality in the lower tidal-volume arm.



NOT Established

•Guidelines using lower tidal volume in critically ill patients WITHOUT ALI/ARDS.

•No randomized controlled trials guiding the best ventilator strategies in these patients.



ALI / ARDS definition:

• In 1994, the American-European Consensus Conference on ARDS defined both ALI and ARDS.

• ALI requires all four of the following features in patients who have a risk factor for ARDS and no history of chronic lung disease:

• Acute onset

• Bilateral infiltrates

• No evidence of elevated left atrial pressure (the pulmonary capillary wedge pressure is ≤18 mmHg if measured)

• A ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) of 201 to 300 mmHg

• ARDS -- All of the above except PaO2/FiO2 ≤200 regardless of the (PEEP)



Current Literature• Animal studies show that mechanical ventilation

with conventional tidal volume may aggravate, and/or may initiate lung injury (Carney et al., 2005 and Dreyfuss et al., 1998).

• One study (Hudson et al., 1995) - suggested that more side effects are seen in lower tidal-volume ventilation in patients at high risk for ALI / ARDS. While not appreciating a beneficial reduction in mortality / morbidity.

• Other studies by Michelet et al., Anesthesiology 2006 and Wrigge et al., Intensive Care Med 2005, challenged these findings.



Current Literature

•Other cohort studies suggest that mechanical ventilation with conventional tidal volumes (10 ml/kg) may cause or contribute to development of lung injury in critically ill patients who did not have ALI/ARDS at the onset of mechanical ventilation.



The Question

•Since, ALI/ARDS is characterized by a profound production of inflammatory mediators,.

•The hypothesis follows that conventional tidal volumes would contribute to a worse development of lung injury in comparison to low tidal volume ventilation.

•The injury may also be associated with an increase in the production of cytokines.



The Question•Mechanical ventilation with

conventional (10 ml/kg) vs lower tidal volume (6ml/kg)show a different cytokine patterns and if so,

•Can that pattern difference be associated with degree of lung injury leading to ALI / ARDS in critically ill patients without ALI at onset of mechanical ventilation.



Secondary end points

•Development of:

•Lung injury.

•Duration of mechanical ventilation.

•Mortality.



Materials and methods

• Duration: Jan. 2005 -- Dec. 2007.

• Location: The Netherlands.

• One academic 28 bed “closed ICU” style.

• One regional teaching hospital with 8 bed “open ICU” style. It did not include neurosurgery and cardiothoracic surgery patients

• The two ICUs had similar standards of practice in terms of mechanical ventilation and sedation protocols.




•Eligibility:

• Pt’s that did not meet the consensus criteria for ALI/ARDS and,

•Required mechanical ventilation for an anticipated duration of more than 72 hours and,

• Pt’s had to be randomized less than 36 hours past the onset of mechanical ventilation.




• Exclusion criteria:

• Age younger than 18 years,

• Participation in other clinical trials,

• Pregnancy,

• Increased uncontrollable intracranial pressure,

• COPD,

• Restrictive pulmonary disease (evidence of chronic interstitial infiltration on chest radiograph),

• Use of immunosuppressive agents (100 mg hydrocortisone / day was allowed),

• PE,

• Previous pneumonectomy or lobectomy,

• Previous randomization in this study.




•Written informed consent was obtained from the patient or closest relatives before entry in the study.





Cytokines•On the day of enrollment and on each

second day until the patient was weaned from the ventilator, a BAL was performed:

• Levels of tumor necrosis factor α (TNF-α),

• Interleukin-1β (IL-1β),

• Interleukin-6 (IL-6).

• Simultaneously, blood samples were taken from A-line for IL-6 measurements.



Ventilation:•volume-controlled mode.

•Predicted body weight was used to calculate tidal volume.

•Target tidal volume in the conventional group was 10 ml/kg of predicted body weight

•Patients from the intervention group were ventilated at tidal volumes of 6 ml/kg of predicted body weight.



Ventilation:

• In the 6 ml/kg group, the attending physician was allowed to increase the tidal volume size to 7 - 8 ml/kg if patients had severe dyspnea,

•Defined by increased respiratory rate more than 35/min.

•Levels of PEEP were set, together with the level of inspired oxygen (FiO2), depending of the PaO2 according to a local protocol.



Ventilation:• The ventilator was routinely (3 times/day)

switched to the pressure support mode.

• If the pressure support mode was tolerated, this mode was used for further mechanical ventilation.

• Toleration of pressure support mode was assessed at the discretion of the attending physician.

• The pressure support was adjusted to reach the target tidal volumes.



Ventilation:• The following exception was accepted:

• In case the attending physician preferred pressure-support ventilation in a patient randomized to the lower-tidal-volume group,

• and the applied tidal volume exceeded the target tidal volume because of high levels of pressure support,

• Such patients were kept in their original randomization group for the statistical analyses.



Ventilation:•For weaning:

•The pressure-support level had to be lowered stepwise to 5 cm H2O within 24 hours.

•If this was not possible because of severe dyspnea, then the pressure support had to be increased to maintain tidal-volume size based on randomization group



Ventilation:

•Pt’s that were reintubated within 28 days were restarted on the same tidal-volume protocol as before.



Ventilation:

•Lung injury was diagnosed if a patient met the consensus ALI/ARDS criteria.

•Protocol mandated mechanical ventilation with a tidal volume of 6 ml/kg in a pressure controlled mode for the remaining ventilation period.



Objective and outcomes

• The primary outcomes:

• Cytokine levels in blindly obtained bronchoalveolar lavage fluid and plasma.

• Development of lung injury (according to consensus criteria for ALI/ARDS.

• Secondary outcomes:

• Duration of mechanical ventilation,

• Mortality.



Sample size

•Based on previous study, IL-6 levels increased by +/-20% in ALI/ARDS pt.’s ventilated at 10ml/kg and decreased by +/-20% in pt.’s ventilated at 6ml/kg.

•For a two-sided significance level of 0.05 and a power of 80%, 49 patients had to be included in each group. The authors chose to study twice as many patients, resulting in a total of 200 patients.



Statistical analysis

•Baseline comparisons between groups were made with the Student t test, Mann-Whitney U test, χ2 test, or Fisher Exact test where appropriate.

•The relation between cytokine levels and development of ALI/ARDS was studied with a multivariate logistic regression analysis.



Pt. Accrual•The study design was built around an

accrual of 200 patients.

•But, after 150 patients were included, the trial was stopped.

•More patients had developed lung injury in the conventional tidal-volume group as compared with the lower tidal-volume group (10 patients (13.5%) versus two patients (2.6%); P = 0.01).





Demographics











•Patients whom lung injury did not develop, compared to patients in whom lung injury did develop had

•significantly higher baseline lavage-fluid levels of IL-6









Conclusions

•The study was stopped after the second interim analysis.

•Interim analyses were not planned at first and were not taken into account on the calculation of sample size! which is a significant limitation of the study.



Conclusions• The odds ratio of 5.1 for a tidal volume of 10 ml/kg

versus 6 ml/kg in the present study is in line with earlier findings of an odds ratio of 1.3 for each milliliter above 6 ml/kg by Wrigge et al., Anesth Analg 2004.

• However, the study did not find differences in either mortality or the number of ventilator-free days among 10ml/kg vs. 6ml/kg.

• Possibly lack of power and,

• The protocol required that if lung injury developed, tidal volumes were reduced to 6 ml/kg. This may have underestimated the effect of higher tidal volumes.



Conclusions• Both groups in the present study had comparable

prevalence of risk factors for ALI/ARDS.

• Mechanical ventilation at 10ml/kg tidal volumes was associated with:

• A delayed decrease in plasma IL-6 levels, and

• An increased frequency of lung injury after the initiation of mechanical ventilation.

• The benefit of the use of lower tidal volumes (6ml/kg)occurred without the need for additional sedation or vasopressor use and was not associated with altered requirements for higher PEEP or additional FiO2.



Conclusions•Conventional mechanical ventilation

was accompanied by an altered plasma cytokine profile but not an altered pulmonary cytokine profile.

•Plasma IL-6 levels decreased over time in both groups. The decrease was, however, more pronounced in patients ventilated with lower tidal volumes.



The End



Documents

Journal Club Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital 9/12/2010 Nir Hus MD., PhD. Ryder Trauma Center Jackson Memorial Hospital