RETRACTED. Closed Loop Control of Inspired Oxygen Concentration in Trauma Patients

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1 Closed Loop Control of Inspired Oxygen Concentration in Trauma Patients Jay A Johannigman, MD, FACS, USAFR, Richard D Branson, MSc, RRT, Michael G Edwards, MD, FACS BACKGROUND: Transport of mechanically ventilated patients in a combat zone presents challenges, including conservation of resources. In the battlefield setting, provision of oxygen supplies remains an important issue. Autonomous control of oxygen concentration can allow a reduction in oxygen usage and reduced mission weight. METHODS: Trauma patients requiring ventilation and inspired oxygen concentration (FIO 2 ) 0.40 were evaluated for study. Patients were randomized to consecutive 4-hour periods of closed loop control or standard care. The system for autonomous control consisted of a ventilator, oximeter, and a portable computer. The computer housed the control algorithm and collected data every 5 seconds. The controller goal was to maintain pulse oximetry (SpO 2 )at94 2% through discrete changes of 1% to 5% every 30 seconds. Ventilator settings and SpO 2 were recorded every 5 seconds for analysis. RESULTS: Forty-five patients were enrolled in this study. Oxygen saturation was maintained in the 92% to 96% saturation range 33 36% of the time during clinician control versus 83 21% during closed loop control. Time spent at the target SpO 2 92% to 96% was minutes during closed loop control and minutes during clinician control (p 0.001). Hyperoxemia was more frequent during clinician control ( minutes) than during closed loop control ( minutes; p 0.001). There were no differences in the number of episodes of SpO 2 88%. Oxygen usage was reduced by 32% during closed loop control. CONCLUSION: Closed loop control of FIO 2 offers the opportunity for maximizing oxygen resources, reducing mission weight, and providing targeted normoxemia without increasing risk of hypoxemia in ventilated trauma patients. (J Am Coll Surg 2009;208: by the American College of Surgeons) Mechanical ventilation is commonly used to reverse hypoxemia and hypercarbia under direction of a physician or through protocol. In recent years, closed loop control of ventilation has been introduced to facilitate ventilator discontinuation or escalate therapy to maintain minute ventilation (V E ). 1-4 Closed loop control of oxygenation has been explored in neonates, where both hypoxemia and hyperoxia produce consequences, but has not been attempted in adults. 5-8 In an austere environment, such as the battlefield, oxygen supplies are limited assets that require substantial logistical resources for resupply and storage. In this setting, Disclosure Information: Nothing to disclose. Sponsored by Office of Naval Research grant N Presented at the Southern Surgical Association 120 th Annual Meeting, West Palm Beach, FL, December Received January 8, 2009; Accepted January 12, From the Department of Surgery, University of Cincinnati, Cincinnati, OH. Correspondence address: Jay A Johannigman, MD, Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, ML #0558, Cincinnati, OH jay.johannigman@uc.edu oxygen conservation is an important objective. Conventional teaching advocates administration of oxygen to trauma patients at the time of injury, even if the signs of hypoxemia are absent and administration of oxygen might have no therapeutic benefit. 9 Our group hypothesized that a closed loop controller for oxygen could provide appropriate oxygen saturation, prevent hypoxemia, and reduce oxygen consumption in trauma patients requiring mechanical ventilation. The purpose of this study was to evaluate the safety and efficacy of a closed loop oxygenation controller used during mechanical ventilation. The system was designed to monitor oxygen saturation through pulse oximetry (SpO 2 ), to adjust inspired oxygen concentration (FIO 2 ), and to maintain normoxemia (SpO %). METHODS Patients The study was conducted in the surgical and neurosurgical ICUs at the University Hospital Inc, in Cincinnati, OH by the American College of Surgeons ISSN /09/$36.00 Published by Elsevier Inc. 763 doi: /j.jamcollsurg

2 764 Johannigman et al Closed Loop Control of FIO 2 in Trauma Patients J Am Coll Surg Abbreviations and Acronyms FIO 2 inspired oxygen concentration PaO 2 arterial partial pressure of oxygen SaO 2 oxygen saturation SpO 2 pulse oximetry V E minute ventilation The study was approved by the University of Cincinnati Institutional Review Board, and an investigational device exemption was received from the Food and Drug Administration. This study was supported by funding provided by the Office of Naval Research. Written informed consent was obtained from the patient s legally authorized representative before any study-related procedures. Patients requiring mechanical ventilation after traumatic injury were screened for the study between September 2005 and February Inclusion criteria were a current FIO , age 18 to 55 years, presence of an indwelling arterial line, and ability to monitor SpO 2 accurately. Patients were excluded if they were likely to be ventilated 8 hours, had a diagnosis of brain death, were pregnant, or required hyperoxemia. Protocol The study protocol consisted of 2 randomly assigned 4-hour periods of observation, for a total study duration of 8 hours. During the control period, FIO 2 was set by the ICU team of physicians and respiratory therapists according to standard ICU protocol. FIO 2 management in the control period was to maintain SpO 2 94% and to reduce FIO 2 to nontoxic levels (FIO ). During the treatment period, FIO 2 was automatically adjusted by the controller to maintain an SpO 2 of 94 2%. Before airway suctioning, FIO 2 was increased to 1.0 for 2 to 3 minutes to avoid hypoxemia. All patients were ventilated using either continuous mandatory ventilation or synchronous intermittent mandatory ventilation using tidal volumes of 6 to 8 ml/kg of predicted body weight. All patients were ventilated with the same ventilator (Impact 754 Eagle; Impact Instrumentation Inc) modified for autonomous control of FIO 2 and data collection. The Impact 754 ventilator was used during this study because it is currently the device used by the military for mechanical ventilation in a deployed setting. During the study period, other ventilator parameters, including respiratory frequency, tidal volume, PEEP, inspiratory time, and inspiratory-to-expiratory ratio were held constant unless changes were required by the clinical condition. Every 2 hours, an arterial blood sample was drawn from indwelling lines for analysis of ph, blood gases, and oxygen saturation (SaO 2 ). Hemodynamic parameters at these time points were also recorded, including heart rate; systolic, diastolic, and mean arterial pressures; central venous pressure; pulmonary artery pressures, if available; and cardiac output. All ventilator parameters, including respiratory frequency, tidal volume, peak inspiratory pressure, PEEP, inspiratory time, and any ventilator alarms were collected to a portable computer every 5 seconds for later analysis. SpO 2 was monitored by the bedside monitor and by an oximeter (Masimo) integral to the ventilator and data collection system. SpO 2 and pulse rate were recorded to the computer every 5 seconds as well. Algorithm description The algorithm is a modified negative feedback controller that uses information about current FIO 2, current SpO 2, trend in SpO 2, and recent FIO 2 changes to maintain a target SpO 2 of 94 2%. These data allow the controller to manipulate FIO 2 in 1% to 5% increments every 30 to 60 seconds. A rule-based system controls algorithm behavior during periods of hypoxemia (defined as SpO 2 88% lasting 10 seconds). Under these conditions, the increase in FIO 2 is more rapid, with an increase to 1.0 if hypoxemia persists. End points Study end points included both efficacy and safety variables. Efficacy end points were to determine the amount of oxygen conserved with closed loop control of FIO 2 and the ability of the controller to maintain the desired SpO %. Oxygen use in liters per minute was calculated from set FIO 2 and current V E using the equation (V E * FIO 2 ) (1.0 to 0.21). The primary safety end point was prevention of hypoxemia, defined as the number and duration of episodes of hypoxemia (defined as SpO 2 88%). Efficacy of the controller was evaluated by determining the duration of time SpO 2 was between 92% and 96% during the study periods. Data analysis Computerized analysis was used to calculate the mean SpO 2 and the number of and duration of episodes of hypoxemia Table 1. Characteristics of Patients Enrolled in the Study Characteristic Age (y), mean SD Gender (men/women) 39/6 Injury Severity Score, mean SD Apache II, mean SD FIO 2 at study entry, mean SD PaO 2 /FIO 2 at study entry, mean SD FIO 2, inspired O 2 concentration; PaO 2, arterial partial pressure of oxygen.

3 Vol. 208, No. 5, May 2009 Johannigman et al Closed Loop Control of FIO 2 in Trauma Patients 765 Table 2. Blood Gas and Ventilator Data at the 2-Hour Time Points Variable Control T1 Control T2 Closed loop T1 Closed loop T2 ph PaCO 2 (mmhg) PaO 2 (mmhg) SaO 2 (%) * FIO 2 (%) PEEP (cmh 2 O) Respiratory rate (bpm) V T (ml) PIP (cmh 2 O) SBP (mmhg) DBP (mmhg) MAP (mmhg) HR (bpm) *p vs control T1 and control T2. p vs control T1 and control T2. p 0.05 vs control T1. p vs control T2. DBP, diastolic blood pressure; FIO 2, inspired oxygen concentration; HR, heart rate; MAP, mean arterial pressure; PaCO 2, arterial pressure of carbon dioxide; PaO 2, arterial partial pressure of oxygen; PIP, peak inspiratory pressure; SaO 2, oxygen saturation; SBP, systolic blood pressure; V T, tidal volume. (SpO 2 88%). The percentage of time during each study period with SpO 2 97%, 92% to 96%, 89% to 91%, and 88% was determined for each patient. Within-participant comparisons using a two-tailed, paired t-test were used when appropriate. Apvalue 0.05 was considered significant. Results are reported as mean 1 SD. RESULTS Eighty-one patients were screened during the study period, and 45 patients were enrolled. The most common reasons for failure to enroll patients included: no legally authorized representative to provide consent, failure to meet oxygenation criteria, and legally authorized representative declined subject participation. Characteristics of the patients are shown in Table 1. All patients completed the 8-hour data collection period, and there were no deaths. Twentytwo patients were randomized to start with the closed loop system and 23 patients were randomized to start with physician-set FIO 2. Arterial blood gas and ventilator data for the 2-hour time points are shown in Table 2. There were substantial differences in arterial partial pressure of oxygen (PaO 2 ), FIO 2, and SaO 2 during autonomous control of FIO 2 compared with clinician control of FIO 2. All other ventilatory and hemodynamic variables were unchanged. Table 3 demonstrates the duration of time in minutes at each level of SpO 2. The number of occurrences when the SpO 2 88% was slightly longer during the control period compared with closed loop control, but this difference was not statistically significant (Fig. 1). There was also no difference in the number of events with SpO 2 88%. Time spent at the target SpO 2 of 92% to 96% was minutes during closed loop control and minutes during clinician control (p 0.001). Hyperoxemia was more frequent during clinician control minutes than during closed loop control: minutes (p 0.001) (Fig. 2). Figure 3 depicts the percentage of time SpO 2 was in each of the 4 ranges. Oxygen usage was calculated from the current FIO 2 and minute ventilation (V E ) using the equation V E (FIO )/0.79. The mean oxygen use during manual control was 3.11 L/min compared with 2.10 L/min (p 0.001) during closed loop control. The mean savings in oxygen was 32.5% during closed loop control compared with the control period. DISCUSSION Our findings suggest closed loop control of FIO 2 resulted in more precise control of SpO 2, reduced oxygen usage, and provided comparable safety to clinician controlled Table 3. Comparisons of Mean Duration of Time in Minutes Spent at Each Oxygen Saturation Range During 4-Hour Periods Oxygen saturation range (%) Control period Closed loop period % % * % * *p versus control period.

4 766 Johannigman et al Closed Loop Control of FIO 2 in Trauma Patients J Am Coll Surg Figure 1. Mean duration in minutes with pulse oximetry (SpO 2 ) 88% and 89% to 91%. FIO 2 during a short period of ventilation in trauma patients. Oxygen usage was reduced by 32.5%, suggesting that closed loop control might reduce the mission requirement for oxygen during transport of mechanically ventilated casualties. SpO 2 was maintained in the desired range nearly three times more frequently during autonomous control. The slight difference in total duration of time at SpO 2 88% in the control group was not statistically significant. All of these findings have considerable implications, particularly in the deployed or austere setting. Transportation of military casualties requiring mechanical ventilation represents a unique set of circumstances. 10,11 During movement from the Level II battalion aid station to Level IIb forward surgical team and Level III combat surgical hospital, en route care represents challenges to technology, training, patient access, and visibility in an austere environment. En route care often occurs in a hypobaric environment, with limited visibility, limited caregiver mobility, and excessive noise and vibration. Limited space and the need for Figure 2. Mean duration in minutes with pulse oximetry (SpO 2 ) 92% to 96% and 97% caregiver safety limit the ability of the staff to monitor patients, recognize alarms, and visualize displays. Flights requiring rapid ascent and descent along with turbulence in low-light environments complicate these problems. Finally, the training and skill of the caregiver can vary, depending on location and tactical conditions. The spectrum of en route care provider can vary from a combat medic to advanced-skill physician. All of these considerations create an environment that severely taxes the clinician s situational awareness and increases the opportunity for adverse clinical events to occur (and remain) undetected. The substantial potential opportunities to improve patient safety while conserving resources are suggested by the results of this preliminary study, which demonstrated fewer periods of hypoxemia in the protocol group managed by the autonomous controller system. Autonomous control of FIO 2 during en route care offers the potential of solving many of the problems encountered in a military setting. Autonomous control Figure 3. Percentage of time spent in each range of pulse oximetry (SpO 2 ) for control and closed loop 4-hour periods.

5 Vol. 208, No. 5, May 2009 Johannigman et al Closed Loop Control of FIO 2 in Trauma Patients 767 can prevent hypoxemia by adjusting FIO 2 regardless of access to the patient and monitoring devices or skill set of the attendant. Autonomous control would provide the appropriate FIO 2, which, in many patients, will reduce oxygen use and simultaneously reduce the required mission weight and bulk of multiple oxygen tanks. Changes in oxygenation secondary to changes in cabin altitude would be continuously compensated. Presence of an autonomous controller provides the opportunity to increase monitoring and improve response time to patient conditions in an environment where patient situational awareness is often limited. Our study is the first to evaluate use of a closed loop FIO 2 /SpO 2 controller in civilian adult trauma care. The controller is designed to maintain SpO 2 at 94 2% by adjusting FIO 2. The gain of the adjustment is guided by the current SpO 2 and FIO 2 and the recent history of SpO 2 and FIO 2 changes. Presence of hypoxemia (SpO 2 88%) results in rapid correction by returning FIO 2 to 1.0. The goals of the controller are to provide appropriate oxygenation, prevent hypoxemia, and reduce oxygen usage. Results of this study suggest that the current algorithm is effective at meeting these conditions. There have been previous published attempts at closed loop control of FIO 2 during mechanical ventilation. To date, these attempts have been made in the neonatal ICU, where both hypoxemia and hyperoxemia carry consequences. In a series of investigations, 5,6 a microprocessor-controlled system using proportional-integral-derivative control to autonomously adjust FIO 2 using pulse oximetry was studied. In this series of lung model and animal experiments, the authors found that the controller was capable of restoring oxygen saturation to physiologic levels within 20 to 25 seconds. The authors concluded that the system was capable of correcting hypoxemia within seconds and preventing hyperoxia, eliminating artifacts, and minimizing oxygen exposure. In a similar study, Raemer and colleagues 7 also used a proportional-integral-derivative controller to adjust FIO 2 based on SpO 2 input in a series of animal experiments. Results from animal studies demonstrated that the response time to reach a stable SpO 2 after a change in FIO 2 was 50 to 70 seconds. Sun and colleagues 8 used a computer-assisted FIO 2 adjustment, but the system was open loop controlled, requiring the operator to make the FIO 2 changes. At present, there are no commercially available autonomous FIO 2 controllers for mechanical ventilation on the market. An emphasis of our design is on patient safety. During initial discussion of the algorithm, our investigative group was concerned to ascertain that lower oxygen saturation did not result in more frequent hypoxic events. In the current patient cohort, the number of desaturation events is not statistically different, and the duration of time with SpO 2 88% is lower with closed loop control, although this is not statistically significant (p 0.08). This potential liability was not demonstrated in the protocol group. In this limited number of patients, the algorithm for autonomous control responds to an SpO 2 88% lasting 15 seconds by increasing FIO 2 to 1.0. It is interesting to note that in many patients, an SpO 2 88% was never observed. Additional patients are required to fully test our hypothesis related to safety. We have also noted that despite considerable multiple trauma, many young healthy patients have a low oxygen requirement in the first 24 to 48 hours. This closely parallels the current conditions for transport of military casualties from the combat zone. Critical Care Air Transport Team movements of patients commonly occur within 24 hours of wounding. The total period of time of hypoxia did not vary between the autonomous control group and the standard care group, despite maintenance of an overall lower oxygen saturation state in the autonomous control group. This observation appears to support the feasibility of oxygen conservation without unduly compromising patient safety. Autonomous control of oxygen during transport appears to have promise in preventing hypoxemia and in conserving oxygen. These systems require only the addition of an oximeter to the ventilator and should not greatly impact cost. We continue to enroll patients in this trial in an effort to determine additional refinements. The longterm goal of the project would be to use low levels of FIO 2 such that compressed oxygen would be unnecessary. Ideally, an electrically (battery) powered ventilator and oxygen concentrator could be developed to maximize use. Information from the oximeter would define the required FIO 2. A closed loop controller could then dictate operation of the oxygen concentrator based on V E and required FIO 2. This system could operate at FIO , depending on V E and continue to operate as long as there was electricity. The major limitations of this study include the small number of patients and the short duration of observation. Additionally, although these civilian trauma patients are critically ill, they might not represent the needs of the military casualty. In summary, results of this initial clinical investigation suggest that use of autonomous oxygen control reduces oxygen use, effectively controls SpO 2, and prevents hypoxemia. Additional research in larger numbers of patients is required to substantiate these initial results.

6 768 Johannigman et al Closed Loop Control of FIO 2 in Trauma Patients J Am Coll Surg Author Contributions Study conception and design: Johannigman, Branson Acquisition of data: Johannigman, Branson Analysis and interpretation of data: Johannigman, Branson Drafting of manuscript: Johannigman, Branson, Edwards Critical revision: Johannigman, Branson, Edwards REFERENCES 1. Branson RD, Campbell RS, Davis K, Johannigman JA. Closed loop ventilation. Respiratory Care 2002;47: Johannigman JA, Barnes SA, Muskat P, et al. Autonomous control of oxygenation. J Trauma 2008;64[Suppl]:S295 S Johannigman JA, Barnes SA, Muskat P, et al. Autonomous control of ventilation. J Trauma 2008;64[Suppl]:S302 S Lellouche F, Mancebo J, Jolliet P, et al. A multicenter randomized trial of computer-driven protocolized weaning from mechanical ventilation. Am J Respir Crit Care Med 2006;174: Tehrani FT, Bazar AR. A feedback controller for supplemental oxygen treatment of newborn infants: a simulation study. Med Eng Phys 1994;16: Tehrani FT. A control system for oxygen therapy of premature infants. Proc IEEE Eng Med Biol Conf 2001;23: Raemer DB, Ji X, Topulos GP. FIx controller: an instrument to automatically adjust inspired oxygen fraction using feedback control from a pulse oximeter. J Clin Monit 1997;13: Sun Y, Kohnae IS, Starrt AR. Computer-assisted adjustment of inspired oxygen concentration improves control of oxygen saturation in newborn infants requiring mechanical ventilation. J Pediatr 1997;131: Stockinger ZT, Mcswain NE Jr. Prehospital supplemental oxygen in trauma patients: its efficacy and implications for military medical care. Mil Med 2004;169: Johannigman JA. Maintaining the continuum of en route care. Crit Care Med 2008;36[Suppl]:S377 S Barnes SA, Branson RD, Beck G, Johannigman JA. En-route care in the air: a snapshot of mechanical ventilation at 37,000 feet. J Trauma 2008;64[Suppl]:S129 S135. Discussion DR J DAVID RICHARDSON (Louisville, KY): I think this is an excellent study, and I certainly congratulate the authors on the ingenuity used to solve this problem. Those of you outside the trauma community may not know the tremendous role that Dr Johannigman has played in training people to take care of our combat injured. I get teary-eyed when I think about all the things that he has really done and how many lives that he s helped save all through his many efforts. So I think not only should the Southern be grateful to Dr Johannigman but really society in general should be grateful to him and the other dozens of military surgeons, many of whom are connected in one way or another with our member associations in the south. I have just three questions: Is this a technique that can be used in patients who are really superhypoxic, patients with stiff lungs and the like? Second, do you use it only in theater or is this something that you continue to use if you are doing long flights? Then thirdly, is this a technique that would have application for evacuation perhaps in this country in noncombat situations, is this a technique that could be used or would be useful, as you tended to indicate in your last slide, with a PE patient in routine ICU care? I really think it s an excellent study and thank you for the opportunity to discuss it. DR TIMOTHY C FABIAN (Memphis, TN): I rise to compliment the authors on really an interesting and very innovative technique of mechanical ventilation and congratulate Dr Johannigman on a fine presentation today. As in many important advances, the beauty of this approach is in its relative simplicity. Although this study was designed for austere environments associated with combat casualties, it appears to me to be the wave of the future for all mechanical ventilatory support. Appropriate levels of oxygenation were provided by the system of closed loop control of inspired oxygen concentration, avoiding significant periods of both hypoxia and hyperoxia. I would like to ask just a few questions. The authors acknowledge in the manuscript that this is a relatively small clinical trial. Is there in fact a potential risk for patients with severe traumatic brain injury of having progression with even short periods of hypoxia in the interval required for increasing FiO2 in the closed loop system? Further, could such a risk be reduced by decreasing the time required for Fi02 adjustment? Second, have you considered adding other parameters to the closed loop system? I didn t notice in your article, but today it sounds like you are thinking about using distending airway pressures and other things such as C02 analysis. I have insinuated that the closed loop control systems are probably the future of all mechanical ventilation. Are you aware of where this technology stands in the arena of commercial development as we speak? You state in the article that you continue to enroll patients in the trial in an effort to determine future refinements. Please update us to some degree on that. Thank you very much for this important advance which has practical value and which appears ready for near immediate application in both military and civilian environments. DR DAVID V FELICIANO (Atlanta, GA): It wasn t clear in the abstract, are you increasing Fi02 and flow simultaneously in the control area? Or is one favored over the other? Second, the saturation range that you use is obviously safe for patients with modest ARDS. If you take a patient in that saturation range and turn them on their side to rub their back or suction them, everybody who runs ICUs knows some of those patients go right off the cliffs. So I assume this was limited to patients as the FDA prescribed with modest respiratory distress. And that leads to the third question, can this controller work in the patient who is on super PEEP, very high pressure support and very high Fi02? Because what Dr Fabian is implying is that we are not smart enough to keep up with the second respiratory changes. And he s absolutely right. Can this controller do it?