Supplementary Appendix

Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008;359:2095-104. DOI: 10.1056/NEJMoa0708638.

1 Mechanical Ventilation Guided by Esophageal Pressure in Acute Lung Injury. Data Supplement Contents Appendix 1 Appendix 2 Appendix 3 Appendix 3 Appendix 4 Appendix 5 Table of individual subject data. Figures of individual values of PEEP and P plateau over time. Kaplan-Meier survival function for 6 month survival Sample tracings of esophageal and airway pressures in individual patients. BIDMC resuscitation protocol. Membership and role of the DSMB.

2 Appendix 1 Table of individual subject data. Patient No Group Gender Age Mortality 28d PrimaryDx PaO2/FiO2 1 Control Male 78 TRUE Perforated Colon 147 2 Control Male 34 FALSE Traumatic Brain Injury 143 3 Control Female 55 FALSE Bowel Obstruction 73 4 Control Female 64 FALSE Pneumonia 74 5 Control Female 78 FALSE Multiple Trauma 203 6 Control Male 30 TRUE Tylenol Overdose 105 7 Control Male 59 TRUE Septic Shock 247 8 Control Male 30 TRUE Sepsis 166 9 Control Female 83 TRUE Pneumonia 118 10 Control Male 79 TRUE Perforated Viscous 177 11 Control Female 57 FALSE Ischemic Bowel 115 12 Control Male 20 FALSE MVA Trauma 128 13 Control Male 41 FALSE Trauma / MVA 131 14 Control Male 37 FALSE Trauma / MVA 156 15 Control Female 23 TRUE Tylenol Overdose 74 16 Control Female 74 FALSE Large Bowel Obstruction 236 17 Control Male 20 FALSE Multiple Trauma 111 18 Control Male 25 FALSE Multiple Trauma 118 19 Control Female 40 FALSE Multi-Drug Overdose 135 20 Control Female 68 FALSE Small bowel Perforation 107 21 Control Male 78 FALSE Trauma/MVA 141 22 Control Male 51 TRUE Intraventricular Hemorrhage 87 23 Control Female 55 FALSE Perforated Colon 287 24 Control Male 38 FALSE Pneumonia 158 25 Control Female 18 FALSE Multiple Trauma 80 26 Control Female 75 FALSE Small Bowel Obstruction 224 27 Control Female 70 TRUE Ruptured AAA 230 28 Control Male 78 FALSE Small Bowel Obstruction 83 29 Control Female 23 TRUE Influenza 220 30 Control Male 20 FALSE Aspiration Pneumonitis 109

3 Patient No Group Gender Age Mortality 28d PrimaryDx PaO2/FiO2 31 Intervention Female 72 TRUE Pneumonia 186 32 Intervention Female 60 FALSE MVA Trauma 63 33 Intervention Male 31 TRUE Crohn's Disease 89 34 Intervention Female 90 FALSE Colon CA s/p Colectomy 97 35 Intervention Female 58 TRUE Pneumococcal Pneumonia 125 36 Intervention Male 37 FALSE Trauma 130 37 Intervention Male 67 FALSE Pneumonia 286 38 Intervention Female 41 TRUE End-Stage Liver Disease 141 39 Intervention Male 71 FALSE Sepsis 125 40 Intervention Male 22 FALSE Gunshot Wound Abdomen 85 41 Intervention Female 54 FALSE Panniculitis 146 42 Intervention Male 41 FALSE GI Bleed 204 43 Intervention Female 57 FALSE Ventral Hernia Repair 180 44 Intervention Female 51 FALSE Hypoxic Respiratory Failure 110 45 Intervention Female 38 FALSE Pneumonia 147 46 Intervention Male 54 FALSE Aspiration Pneumonitis 94 47 Intervention Male 35 FALSE Multiple Trauma 263 48 Intervention Male 73 FALSE Pancreatitis 95 49 Intervention Male 60 FALSE Smoke Inhalation 206 50 Intervention Female 83 FALSE Pneumonia 118 51 Intervention Male 48 FALSE Small Bowel Perforation 162 52 Intervention Male 44 FALSE Pancreatits 143 53 Intervention Male 48 FALSE Traumatic Brain Injury 180 54 Intervention Male 71 FALSE AAA Repair 81 55 Intervention Male 70 FALSE Pancreatitis 117 56 Intervention Female 38 FALSE Cholecystitis 144 57 Intervention Male 52 FALSE Multiple Trauma 162 58 Intervention Male 57 FALSE Sepsis 280 59 Intervention Male 42 FALSE Pancreatitis 122 60 Intervention Male 70 TRUE Cholangitis 145

4 Appendix 2 Individual values of PEEP and P plateau over time. 35 Conventional protocol PEEP, cmh2o 30 25 20 15 10 5 0 baseline 24 hours 48 hours 72 hours 35 EP protocol PEEP, cmh2o 30 25 20 15 10 5 0 baseline 24 hours 48 hours 72 hours

5 60 Conventional protocol Plateau pressure, cmh2o 50 40 30 20 10 0 baseline 24 hours 48 hours 72 hours 60 EP protocol Plateau pressure, cmh2o 50 40 30 20 10 0 baseline 24 hours 48 hours 72 hours

6 Appendix 3: Kaplan-Meier survival functions for comparison between esophageal pressure-guided vs. conventional ventilation protocols. Log-rank test, P=0.13

7 Appendix 4 Sample tracings of esophageal and airway pressures in individual patients. Below we present 5 representative cases from our study. For each of the patients the initial esophageal pressure tracings and their interpretation are shown. We then present the changes made to the ventilator settings based on the study group to which the patient was randomized. Finally we present the influence of these changes on the esophageal pressure and the estimated transpulmonary pressure. Immediately above are graphs of the PEEP and plateau pressures of these five patients presented separately from those in Appendix 2 to allow easier interpretation.

8 Case 1- This patient in intervention group was a 90 year old woman with peritonitis secondary to colonic perforation and colon cancer. The patient was on CMV with a tidal volume of 400 ml, FiO2= 0.6 and PEEP of 12. Baseline measurements indicate that the transpulmonary pressure at end-expiration is well below zero at -6 (solid arrow). At end-inspiration the patient s transpulmonary pressure was barely positive at +3 (dashed arrow). Case 1 at baseline. Following this measurement the PEEP was increased from 12 to 24 based on the intervention protocol (below) to bring the transpulmonary pressure at end-expiration to +4. At the same time the tidal volume was reduced to 320 ml or 6 ml/kg IBW. F I O 2 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9.1.0 P Lexp 0 0 2 2 4 4 6 6 8 8 10 10

9 A recruitment maneuver was performed per the protocol and 5 minutes later the following tracings were recorded. The transpulmonary pressure is now +4 at endexpiration (solid arrow). At end-inspiration (plateau) the patient's transpulmonary pressure is now +12 (dashed arrow). Case 1 at 5 minutes post-recruitment maneuver. Case 2- This patient in the control group was a 25 year old man with multiple trauma. The patient was on CMV with a tidal volume of 400 ml, FiO2= 0.9 and PEEP of 18. Baseline measurements indicate that the transpulmonary pressure was below zero at -4.6 at end-expiration (solid arrow). At end-inspiration the patient's transpulmonary pressure was positive at +5 (dashed arrow).

10 Case 2 at baseline. Following this measurement the PEEP is reduced from 18 to 14 based on the ARDSnet sliding scale (below). A PEEP of 14 was chosen rather than 16 as this combination of PEEP and FiO2 met the oxygenation goals. The tidal volume remained at 400 ml. F I O 2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20-24 A recruitment maneuver was performed per the protocol and measurements were then repeated 5 minutes later and the following tracings were recorded.

11 Case 2 at 5 minutes. The transpulmonary pressure at end-expiration remains below zero at -6 (solid arrow). At end-inspiration the patient s transpulmonary pressure was +4.4 (dashed arrow). The negative transpulmonary pressure at end-expiration suggests sub-optimal recruitment for this patient on ARDSnet settings. Case 3- This patient in the control group was a 34 year old man with traumatic brain injury. The patient was on CMV with a tidal volume of 600 ml, FiO2= 0.6 and PEEP of 15. Baseline measurements were made but were not interpretable due to the patient s active breathing efforts. These are recognized as an unstable pattern during both the endinspiratory hold (solid arrow) and the end-expiratory hold (dashed arrow). (The two-

12 second interruption after the solid arrow is an automatic purging event initiated by the recording device). Case 3 at baseline. Additional sedation was administered and the effects on the tracings are seen as the respiratory rate drops and the breathing pattern became more regular.

13 Case 3 after sedation. The baseline measurements were repeated after sedation. These second baseline measurements (below) indicate that the transpulmonary pressure at end-expiration was positive at +1.6 (solid arrow). At end-inspiration the patient s transpulmonary pressure was positive at +8.7 (dashed arrow). Based on the control group tables (ARDSnet scale) the patient's PEEP was dropped to 10. The tidal volume was reduced to 400 ml to bring it into line with ARDSnet recommendations (6 ml/kg IBW). F I O 2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20-24

14 Case 3 at the second baseline measurement after sedation. Case 3 at 5 minutes post-recruitment maneuver.

15 These new settings left this control group patient with a negative transpulmonary pressure, 1.2 at end-expiration (solid arrow). The negative end-expiratory transpulmonary pressure suggests sub-optimal recruitment for this patient Case 4- This patient in the intervention group was a 71 year old man with sepsis and multi-organ failure. The patient was on CMV with a tidal volume of 650 ml, FiO2 = 0.6 and PEEP = 5. Baseline measurements indicated that the transpulmonary pressure is 0 at end-expiration (solid arrow). At end-inspiration the patient s transpulmonary pressure was positive at +4 (dashed arrow). Case 4 at baseline. Following this measurement the PEEP was increased from 5 to 21 based on the sliding scale in order to bring the transpulmonary pressure at end-expiration to +2-4. At the same time the tidal volume was reduced to 540 ml to comply with 6 ml/kg IBW.

16 F I O 2 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9.1.0 P Lexp 0 0 2 2 4 4 6 6 8 8 10 10 On these settings, the transpulmonary pressure was +4 at end-expiration (solid arrow). At end-inspiration the patient s transpulmonary pressure was +10 (dashed arrow). Case 4 at 5 minutes post-recruitment maneuver. This case illustrates the important principle that increases in PEEP applied at the airway are not equal to the increases in the end-expiratory transpulmonary pressure due to chest wall stiffness and lung recruitment. In this case, the airway PEEP was increased from 5 to 21 in order to bring the transpulmonary pressure from 0 to +4.

17 Case 5- A 31 year old man in the intervention group suffering from a perforated colon, peritonitis, septic shock and multi-organ failure. The patient was on CMV with a tidal volume of 400 ml, FiO2= 0.7 and PEEP of 24. Baseline measurements indicate that the transpulmonary pressure was positive, +1 at endexpiration (solid arrow). At end-inspiration the patient's transpulmonary pressure was positive at +10 (dashed arrow). Case 5 at baseline. Following this measurement the FiO2 required a transpulmonary pressure at endexpiration to be +4 (below). PEEP was increased from 24 to 32 based on the sliding scale in order to achieve this. At the same time the tidal volume was increased to 450 ml to comply with 6 ml/kg IBW. F I O 2 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9.1.0 P Lexp 0 0 2 2 4 4 6 6 8 8 10 10

18 On these settings, the transpulmonary pressure was now +4 at end-expiration (solid arrow). The patient s plateau pressure was 50 cmh2o. However at end-inspiration the patient s transpulmonary pressure was only +15 (dashed arrow). The rationale of our protocol was to optimize the transpulmonary pressures and not the airway pressures. This case also again shows the unequal relationship between changes in the PEEP and transpulmonary pressure. Case 5 at 5 minutes post-recruitment maneuver. The patient continued to deteriorate due to multi-organ failure. After 18 hours on the protocol measurements were repeated due continued hypoxemia. These showed that the patient's transpulmonary pressures at end-inspiration and at end-expiration were unchanged to 12 and 4 respectively. At this point the patient's FiO2 was increased based

19 on the sliding scale, to 0.8. When this did not bring about an adequate response the PEEP was increased to bring the end-expiratory transpulmonary pressure to 6. F I O 2 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9.1.0 P Lexp 0 0 2 2 4 4 6 6 8 8 10 10 The patient stabilized again with an adequate PaO2. Measurements were repeated again at the 24 hour mark. As can be seen on the tracings below the end-expiratory (solid arrow) and end-inspiratory transpulmonary pressures are now 6 and 13, respectively (dashed arrow). These values require a PEEP of 32 and a plateau pressure of 52. Case 5- Additional measurements at 24 hours This patient died shortly after these measurements from refractory shock. There was no evidence of barotraumas at the time of death.

20 One interesting aspect of this patient s tracings is demonstrated below. At the second set of measurements the patient had unstable readings of esophageal pressure leading to difficulties in decision making. The balloon catheter was replaced and the original balloon was found to have a leak. The time axis on the tracing below has been compressed to illustrate the falling esophageal pressures (marked by brackets).

21 Appendix 5 BIDMC resuscitation protocol. Non-ventilator related care was standardized as much as possible in all patients. This included a standardized approach to resuscitation. This approach has been validated and previously published (Shapiro et al. Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med. 2006 Apr; 34 (4):1025-32.) This approach is outlined below.

22 Appendix 6 Membership and role of the Data Safety and Monitoring Board (DSMB) Members of the DSMB were Atul Malhotra MD and Alan Lisbon MD. These physicians participated in the conception and design of the study. They then withdrew from active participation in the study and were available to review adverse events (none) and all patient deaths. Following interim analysis of the data, the results were reported to the DSMB and they directed that recruitment be closed.