Ace844

"stcommodore," Since you are having trouble with this topic and posting evidence to support or be against your claims let me add to the list of studies and information you should be reading in your quest for further EDUCATION, and add this to the extensive and growing compendium of evidence here. Please read this as well: (Delayed or Missed Diagnosis of Cervical Spine Injuries [Original Articles) Platzer, Patrick MD; Hauswirth, Nicole MD; Jaindl, Manuela MD; Chatwani, Sheila MD; Vecsei, Vilmos MD; Gaebler, Christian MD From the University of Vienna Medical School, Department for Traumatology, Vienna, Austria. Submitted for publication September 20, 2004. Accepted for publication August 10, 2005. Address for reprints: Patrick Platzer, MD, University of Vienna Medical School, Department for Traumatology, Waehringer Guertel 18-20, A-1090 Vienna, Austria; email: patrick.platzer@guix.at.] Abstract Background: Correct diagnosis of cervical spine injuries is still a common problem in traumatology. The incidence of delayed diagnosis ranges from 5 to 20%. The aim of this study was to analyze the frequency and reasons for delayed or missed diagnosis at this Level I trauma unit and to provide recommendations for optimal examination of patients with suspected cervical spine injuries. Methods: Analysis of clinical records showed 367 patients with cervical spine injuries who were admitted to this trauma department between 1980 and 2000. In all, 140 patients had an injury of the upper cervical spine (C1/C2), 212 patients had an injury of the lower cervical spine (C3–C7), and 15 patients had a combined injury of the upper and lower cervical spine. Results: The diagnostic failure rate was 4.9% (n = 18). Results showed several profound reasons for missed or delayed diagnosis. In eight patients (44%), radiologic misinterpretation was responsible for delay in diagnosis; in five patients (28%), incomplete sets of radiographs were responsible. In four cases (22%), the injury was missed because inadequate radiographs did not show the level of the injury; in one case (6%), the treating surgeon did not see the radiographs. Conclusion: For optimal examination of patients with suspected cervical spine injuries, we recommend establishing specific diagnostic algorithms including complete sets of proper radiographs with functional flexion/extension views, secondary evaluation of the radiographs by experienced staff, and further radiologic examinations (computed tomography, magnetic resonance imaging) if evaluation of standard views is difficult. -------------------------------------------------------------------------------- Failure to diagnose cervical spine injuries occurs with a frequency of 5 to 20%.1–3 The incidence of delayed or missed diagnosis at the cervical spine has been reduced in the last years by increased availability and accuracy of radiologic examination (computed tomography [CT] scan, magnetic resonance imaging [MRI]) as well as improved diagnostic algorithms at trauma departments. Nevertheless, incomplete sets of radiographs, radiologic misinterpretation, and trauma patients with multiple injuries are still common reasons for delays in correct diagnosis.1,2 However, the early detection of cervical spine injuries is essential because false or delayed diagnosis might lead to tragic consequences for the patients, ranging from neurologic deficits to complete tetraplegia.4,5 The aim of this study was to analyze the frequency of delayed or missed diagnosis of cervical spine injuries and the factors involved in these diagnostic failures, and to develop recommendations for appropriate clinical and radiologic examination of patients with suspected cervical spine injuries to avoid delays in diagnosis. PATIENTS AND METHODS This study retrospectively analyzed the clinical records of 367 patients with fractures and/or dislocations of the cervical spine that were admitted to the Level I trauma center at Vienna General Hospital, University of Vienna Medical School between January 1980 and December 2000. Collected data included parameters such as age, sex, mechanism of injury, level of injury, treatment, neurologic state, significant concomitant injuries, and alteration of mental state during initial examination. Delayed or missed diagnosis was defined as any injury identified after primary trauma evaluation. The patients were evaluated for cervical spine injuries corresponding to the diagnostic algorithm of this unit with physical examination and standard set of radiographs. The standard set of radiographs included an anteroposterior view, a lateral view, and an open-mouth view of the odontoid. Other series like oblique views, flexion-extension views, or swimmer's views were not used routinely. CT scan or MRI was ordered at the discretion of the trauma surgeon as indicated by the standard views (incomplete or inadequate radiographs) or by clinical suspicion because of persistent symptoms or neurologic deficits. RESULTS In all, 140 patients (38%) sustained an injury of the upper cervical spine (C1/C2), 212 patients (58%) an injury of the lower cervical spine (C3–C7), and 15 patients (4%) suffered from a combined injury of the upper and lower cervical spine. Clinical records showed several mechanisms of injury. The injuries resulted from car or motorcycle accidents in 44%, falls in 22%, jumps into shallow water in 15%, various sports activities in 8%, scuffles in 1%, and from other mechanisms in 9%. Fifty-three patients (14%) came in walking, 138 patients (38%) were brought in by ambulance, 66 patients (18%) by emergency car or emergency helicopter, and 110 patients (30%) were transferred from other hospitals. Forty-nine percent of the cervical spine injuries occurred isolated or combined with insignificant concomitant injuries (e.g., grazes, bruises, etc.) and 51% in combination with other severe injuries. In all, 222 patients (60%) were fully conscious during primary evaluation and examined both clinically and neurologically. Also, 145 patients (40%) had an alteration of their mental status so that clinical and neurologic evaluation was not reliable. The overall incidence of neurologic deficits was 38% (n = 140). One patient showed motor deficits, 14 patients incurred sensory deficits, and 58 patients had motor and sensory deficits. Sixty-seven patients (18%) showed a complete tetraplegia. In all, 185 patients (50%) were treated conservatively, 182 patients (50%) submitted to an operation, 325 patients (89%) were admitted to the ward, and 42 patients (11%) remained outpatients. One hundred twenty-four patients (34%) required intensive care treatment. The average duration at ICU was 15.3 days. Forty-nine patients (13%) died: 16 because of the cervical spine injury, nine as a result of multiple injuries, nine because of a severe brain injury trauma, and 15 patients because of other reasons. The analysis of clinical records revealed that 18 patients (4.9%) had delayed or missed diagnosis of their cervical spine injuries. The 18 diagnostic failures concerned 7 female and 11 male patients with an average age of 46.6 years (3.6–88.9 years). Seven delayed diagnoses occurred at the upper cervical spine, nine at the lower cervical spine, and two occurred in combined injuries of the upper and lower cervical spine (Fig. 1). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 1. Delayed diagnosis: distribution. -------------------------------------------------------------------------------- The missed injuries of the upper cervical spine consisted of five fractures of the odontoid process, one Jefferson fracture, and a slightly displaced fracture of C2. The missed injuries of the lower cervical spine comprised a fracture of C4, two displaced fractures of C5, two fractures of C6, one displaced fracture of C7, and three discoligamentous instabilities. In the two patients with combined injuries of the upper and lower cervical spine level, once a fracture of C2 and C3 was missed and once a fracture of the atlas and C5 was failed to diagnose. In eight cases (44%), delayed diagnosis was found to be the result of a misinterpretation of the standard radiographs (Fig. 2). Junior staff responsible for initial radiologic examination failed to diagnose the injuries. In six cases, correct diagnosis was made later on from the standard radiographs by more experienced senior surgeons following the control mechanism of the unit. Experienced staff evaluated all plain radiographs secondarily within 24 hours. In two cases, the injury was diagnosed after performing a CT scan because of continuous neck pain. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 2. Diagnostic failures: causes. -------------------------------------------------------------------------------- In five cases (28%), incomplete sets of radiographs were responsible for delayed diagnosis (Fig. 2). Three discoligamentous injuries were missed because no functional flexion/extension views were performed. One of the patients had an isolated discoligamentous injury. He was polytraumatized and unconscious as a result of a severe brain injury during primary examination. Clearing the cervical spine with complete sets of standard radiographs and CT scan did not show the extent of the injury. After regaining consciousness, the patient had a complete tetraplegia. Functional flexion/extension views and MRI were ordered showing the discoligamentous injury. The other two patients sustained discoligamentous injuries combined with fractures at the lower cervical spine. The fractures were diagnosed during primary radiologic examination, but the discoligamentous instabilities were missed. Finally, in both cases the discoligamentous injuries were identified by functional flexion-extension views after the spinal precautions were discontinued. In the other two cases with incomplete sets of radiographs, fractures were missed because only a lateral view of the cervical spine was performed during initial evaluation. Both patients were polytraumatized and primary examination focused on other severe injuries. Correct diagnosis was made after performing complete sets of standard radiographs in one case and by autopsy in the other case. In four cases (22%), the injury was missed because inadequate radiographs did not show the level of the injury (Fig. 2). All four delayed diagnosis occurred at the lower cervical spine level. Performing proper x-ray views was difficult because of degenerative spine disease, severe neck pain, or altered mental state. In two cases, correct diagnosis was made by a CT scan, in one case by tomography, and in another case after repeating standard radiographs. In one case (6%) of delayed diagnosis, the injury was missed because the treating surgeon did not see the radiographs (Fig. 2). The patient returned later on with increasing neck pain. Correct diagnosis could then be made by another surgeon who checked the initial radiographs. An appropriate clinical and neurologic evaluation of the patients was not possible in eight cases (44%). Five patients suffered from an altered mental state because of other severe injuries, two patients because of alcohol or drug usage. Six patients (33%) had other severe injuries that were focused on during initial evaluation. Immediate lifesaving measures for other injuries were necessary in three patients. Correct diagnosis was made by senior surgeons following the control mechanism of the unit in seven cases. In four cases, the injury was diagnosed by a CT scan, in three cases by performing functional flexion/extension views, and in two cases after repeating standard radiographs. Once the injury was diagnosed by a conventional tomography and once by an autopsy (Fig. 3). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 3. Correct diagnosis. -------------------------------------------------------------------------------- Seven (39%) of the 18 patients with delayed diagnosis remained outpatients after primary trauma evaluation. In four of them, correct diagnosis was made within 24 hours following the control mechanism of the unit. All four patients were informed to come in immediately. In the other three cases, correct diagnosis was made within a week after trauma, after patients had returned because of increasing neck pain and/or neurologic deficits. Eleven patients (61%) with delayed diagnosis of their cervical spine injuries were admitted to the ward because of other injuries. In eight cases, correct diagnosis was made during stationary treatment after patients had complained about increasing neck pain or after developed neurologic deficits. In five of them, correct diagnosis was made within a week after trauma; in three of them, correct diagnosis was made after 10 to 15 days. In three cases, correct diagnosis was made after patients had been discharged. All of them returned with increasing neck pain or neurologic symptoms. In two of them, correct diagnosis was made within a week after trauma; in one of them, it was made after three weeks. Complications attributed to delayed or missed diagnosis occurred in eight patients (44%), ranging from motor and/or sensory neurologic deficits to complete tetraplegia. Six patients had neurologic deficits during primary evaluation and developed progressive deficits subsequently. One patient returned with incipient neurologic deficits after being discharged. In one case, a polytraumatized and initially unconscious patient showed a complete tetraplegia after regaining consciousness. Finally, in six of those eight patients, we saw a complete recovery of neurologic function after change of treatment. In two patients, neurologic deficits resolved incompletely. A change of treatment was necessary in 15 patients (83%). Seven patients underwent operative treatment after correct diagnosis had been made. In two patients, anterior cervical fusion was performed; posterior cervical fusion was performed in five patients. Eight patients were treated conservatively either by a halo brace (n = 3) or a cervical collar (n = 5). Two patients (11%) died, but neither because of the cervical spine injury. DISCUSSION The incidence of delayed or missed diagnosis of cervical spine injuries is between 5 and 20%.1–3 Previous works have shown that common reasons for delays in diagnosis are radiologic misinterpretation, incomplete sets of radiographs, or inadequate radiographs.1,2 An inappropriate clinical and neurologic evaluation of the patients is another common problem for diagnostic pitfalls. This problem mainly appears in patients with an altered mental state or in patients with other severe injuries.4,5 The results of this retrospective study show an incidence of delayed diagnosis of 4.9%. Comparing to previous studies, the incidence rate at this trauma unit was relatively low, but the causes for delays in diagnosis appear not to have changed in the last 10 to 15 years. An analysis of causes demonstrate that we had three main reasons for delayed or missed diagnosis at the cervical spine: (1) lack of experience in evaluating the radiographs leading to misinterpretation, (2) inadequate radiographs, and (3) incomplete sets of radiographs. The most common cause of missed cervical spine injuries was a misinterpretation of the standard radiographs. In eight cases (44%), injuries were not detected because inexperienced junior staff responsible for initial radiologic examination failed to make the correct diagnosis. This requires establishing a policy for the department. More experienced senior surgeons are expected to evaluate all radiographs secondarily. In our patients, this helped to detect six primarily missed cervical spine injuries within 24 hours. Incomplete sets of radiographs ranked as the second most common cause of missed cervical spine injuries. This error was responsible for five (28%) of 18 delayed diagnosis. In three cases, discoligamentous injuries were missed because no functional flexion/extension views were performed during initial examination. The functional flexion/extension views were made delayed (after spinal precautions were discontinued) because the patients had complained about continuous neck pain or neurologic deficits. In all three patients, the functional flexion/extension views showed discoligamentous instability of the cervical spine that was missed primarily. We recommend performing functional flexion/extension views as obligate completion to a three-view cervical-spine series (anteroposterior, lateral, and open mouth) in awake patients after excluding unstable bony injuries in the standard series. In comatose patients, flexion-extension studies are potentially dangerous to the unprotected spinal cord. If functional flexion/extension views are performed, strict adherence to an established guideline, including repeated review of the cervical spine radiographs by an experienced reviewer as well as complete visualization of the entire cervical spine, is necessary to ensure safety of the patients. If this protocol is obtained and patient safety can be ensured, flexion/extension studies appear to be an effective method to detect occult discoligamentous injuries. In patients with a suspected injury in the standard series, flexion/extension views should be avoided until the extent of the injury can be measured by cervical CT scan. In two cases, bony injuries were missed because only a lateral view was made during initial examination in the trauma room. Both patients were severely injured and livesaving measures were focused on initially. Following several studies reporting that a lateral cervical spine view alone is associated with delays in diagnosis in 15% of patients with cervical spine injuries, we also recommend performing further standard radiographs to a complete three-view cervical-spine series after treatment of life-threatening injuries to improve sensitivity in detecting cervical spine injuries in these patients before they leave the trauma room.2,6–9 In four cases (22%), inadequate radiographs were responsible for delays in diagnosis. Injuries were missed either because the x-ray field did not show the level of the injury or because of the poor technical quality of the radiographs. All four delayed diagnosis occurred at the lower cervical spine, where it might be difficult to perform proper x-ray views. Particularly in patients with preexisting degenerative spine disease or severe neck pain, as we found it in this study, further radiologic examination (CT scan, tomography) might become necessary for complete visualization of the cervical spine. This helped in our cases to detect all four cervical spine injuries that were missed primarily. Severely injured patients as well as patients with an altered mental status pose a further diagnostic problem because clinical and neurologic evaluation is often not reliable.2,4,5 In eight cases (44%), an appropriate clinical and neurologic evaluation of the patients was not possible at all. Five patients had an altered mental status because of other serious injuries, three patients because of alcohol or drug abuse. Finally, we had four patients with neurologic deficits that were missed primarily. We recommend that patients with altered mental status should remain in cervical spine precautions until they are awake and alert.1 A cervical collar might be indicated until a careful clinical and neurologic evaluation of these patients is completed. Six patients (33%) had other serious injuries that were focused on during initial examination. Immediate lifesaving measures were necessary in three cases. Two patients only got a lateral view of the cervical spine and the injury was missed. In these cases, we recommend complete sets of cervical-spine radiographs before initial examination is completed and patients can leave the trauma room. As our results show, most errors leading to delayed or missed diagnosis of cervical spine injuries were fundamental and did not require advanced diagnostic technology. For optimal examination of patients with suspected cervical spine injuries, we recommend establishing a specific diagnostic algorithm including physical examination, standard radiographs, and further radiologic evaluation (CT scan, MRI) as indicated (Figs. 4 and 5). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 4. Diagnostic algorithm in alert patients. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 5. Diagnostic algorithm in patients with altered mental status. -------------------------------------------------------------------------------- For standard radiologic evaluation of the cervical spine, we recommend a three-view cervical spine series (anteroposterior, lateral, and open-mouth) followed by functional flexion-extension views. Some studies suggest that three-view cervical-spine series are limited and that improved sensitivity would be obtained with a five-view series (oblique views added) as “golden standard.”2,8 However, those reports were disapproved by other studies indicating that most “false-negative” three-view cervical spine series were interpreted retrospectively by other surgeons or radiologists as being abnormal.1,10 McDonald et al., for example, stated that a complete three-view cervical-spine series would miss significant fractures in less than 1% of patients.5 In patients with clinically suspected cervical spine injuries or significant trauma history, cervical spine precautions should be maintained until the radiographs are evaluated by experienced reviewers.1 Correct interpretations of cervical spine radiographs can be difficult, particularly for junior staff with lack of experience in evaluating those radiographs. Only experienced trauma surgeons should decide on a removal or a continuation of the spinal precautions. After excluding significant injuries in the three-view cervical-spine series, flexion-extension views might be obtained to detect suspected discoligamentous injuries. In responsive and awake patients, those studies should be considered as obligate completion to a three-view cervical-spine series, but in comatose or anesthetized trauma patients, passive flexion/extension views are not without risk for the spinal cord. In addition, previous studies report that flexion/extension studies are not routinely necessary to clear the cervical spine in unconscious patients because isolated discoligamentous injuries without fractures are a rare occurrence.11,12 However, other studies have introduced those views as a safe and effective method for detecting discoligamentous injuries after excluding significant bony injuries or an instability pattern in the standard radiographs.13,14 If functional flexion/extension views are to be obtained in unresponsive patients, strict adherence to established guidelines, including review of the cervical spine radiographs by a skilled reviewer as well as complete visualization of the entire cervical spine, is mandatory to ensure patient safety.13 To avoid delays in diagnosis by misinterpretation of the radiographs, experienced surgeons are required to evaluate all x-ray studies secondarily as soon as possible. This control mechanism is a certain policy of the department to detect suspected cervical spine injuries that were missed primarily. A careful physical examination should be obtained in alert patients.1,8 Severe neck pain, tenderness on palpation, spasm on active motion, or neurologic deficits are clinical signs referring to a suspected cervical spine injury.8 A meticulous physical examination of those patients is certainly helpful in determining the risk of a cervical spine injury, although it might not result in better compliance from the x-ray technicians in getting all the necessary views. Patients with altered mental state and significant history of trauma should remain in cervical spine precautions until they are awake and appropriate evaluation is possible.1 Further radiologic examination becomes necessary when indicated by the standard radiographs or by clinical suspicion. Computed tomography has become the most important area for improvement in cervical spine clearance using newer technology. We recommend the use of cervical CT scan by suggestion of an injury on the standard cervical-spine series or an incomplete visualization of the entire cervical spine in patients with significant history of trauma. A CT scan of the cervical spine is also obligate in patients with neurologic deficits and should be used more liberally in patients with preexisting cervical pathologic conditions and in patients with persistent symptoms. In patients with neurologic deficits but negative radiographs and CT scans, we perform MRI to detect suspected discoligamentous injuries. MRI poses as a further area using newer technology in cervical spine clearance and will become definitely more important by increased availability and decreased costs. SUMMARY In conclusion, most errors leading to delayed or missed diagnosis of cervical-spine injuries were fundamental (misinterpretation of radiographs, incomplete or inadequate cervical spine series). A three-view cervical-spine series including functional flexion/extension views should be obtained for radiologic evaluation. In patients with significant symptoms or trauma history, cervical spine precautions should be maintained until evaluation of the patients is completed and radiographs have been interpreted by skilled reviewers. Patients with altered mental status should also remain in cervical spine precautions until they are awake to complete evaluation. Further radiologic examination using cervical CT scan becomes necessary when indicated by the cervical spine series or by clinical suspicion. Combining a more meticulous physical examination, standard cervical spine series, and the more liberal use of cervical CT scan should improve the detection of cervical spine injuries. Regarding the fact that most errors leading to delayed or missed diagnosis were fundamental and did not require advanced diagnostic technology, an error rate of 4.9% appears to be improvable if a specific diagnostic algorithm with standard and supplemental diagnostic tools for cervical spine clearance is accepted and obtained. REFERENCES 1. Davis JW, Phreaner DL, Hoyt DB, et al. The etiology of missed cervical spine injuries. J Trauma. 1993;34:342–346. Bibliographic Links [Context Link] 2. Gerrelts BD, Petersen EU, Mabry J, et al. Delayed diagnosis of cervical spine injuries. J Trauma. 1991;31:1622–1626. Bibliographic Links [Context Link] 3. Reid DC, Henderson R, Saboe L, et al. Etiology and clinical course of missed spine fractures. J Trauma. 1987;27:980–986. Bibliographic Links [Context Link] 4. Alker GJ, OH YS, Leslie EV, et al. Postmortem radiology of head and neck injuries in fatal traffic accidents. Neuroradiology. 1975;114:611–617. [Context Link] 5. MacDonald RL, Schwartz MD, Mirich D, et al. Diagnosis of cervical spine injury in motor vehicle crash victims: How many x-rays are enough? J Trauma. 1990;30:392–397. Bibliographic Links [Context Link] 6. Doris PE, Wilson RA. The next logical step in the emergency radiographic evaluation of cervical spine trauma: The five-view trauma series. J Emerg Med. 1985;3:371–377. Bibliographic Links [Context Link] 7. Shaffer MA, Doris PE. Limitation of the cross table lateral view in detecting cervical spine injuries: A retrospective analysis. Ann Emerg Med. 1983;12:508–513. [Context Link] 8. Wales LR, Knopp RK, Morishima MS. Recommendations for evaluation of the acutely injured cervical spine: A clinical radiologic algorithm. Ann Emerg Med. 1980;9:422–428. Bibliographic Links [Context Link] 9. Committee on Trauma, American College of Surgeons. Chicago: Advanced Trauma Life Support, 1989:166–174. [Context Link] 10. Ross SE, Schwab CW, David ET, et al. Clearing the cervical spine: Initial radiologic evaluation. J Trauma. 1987;27:1055–1060. Bibliographic Links [Context Link] 11. Davis JW, Kaups KL, Cunningham MA, et al. Routine evaluation of the cervical spine in head-injured patients with dynamic fluoroscopy: a reappraisal. J Trauma. 2001;50:1044–1047. Ovid Full Text Bibliographic Links [Context Link] 12. Pasquale M, Marion DW, Domeier RM, et al. Practice management guidelines for trauma: EAST ad hoc committee on guideline development: identifying cervical spine instability after trauma. J Trauma. 1998;44:945–946. [Context Link] 13. Davis JW, Parks SN, Detlefs CL, et al. Clearing the cervical spine obtunded patients: the use of dynamic fluoroscopy. J Trauma. 1995;39:435–438. Ovid Full Text Bibliographic Links [Context Link] 14. Sees DN, Rodriquez-Cruz LR, Flaherty SF, et al. The use of bedside fluoroscopy to evaluate the cervical spine in obtunded trauma patients. J Trauma. 1998;45:768–771. Ovid Full Text Bibliographic Links [Context Link] Based on your lack of further responses in this thread I hope you actuallt read this far. For everyone else, I hope this helps, ACE844

(Inflammation and the Host Response to Injury @ a Large-Scale Collaborative Project: Patient-Oriented Research Core—Standard Operating Procedures for Clinical Care: III. Guidelines for Shock Resuscitation [surgical Glue Grant) Moore, Frederick A. MD; McKinley, Bruce A. PhD; Moore, Ernest E. MD; Nathens, Avery B. MD, PhD, MPH; West, Michael MD, PhD; Shapiro, Michael B. MD; Bankey, Paul MD, PhD; Freeman, Bradley MD; Harbrecht, Brian G. MD; Johnson, Jeffrey L. MD; Minei, Joseph P. MD; Maier, Ronald V. MD From the Department of Surgery (F.M., B.M.), University of Texas at Houston; Department of Surgery (E.M., J.L.), University of Colorado; Department of Surgery (A.N., R.M.), University of Washington; Department of Surgery (M.W., M.S.), Northwestern University; Department of Surgery (P.B.), University of Rochester; Department of Surgery (B.F.), Washington University; Department of Surgery (B.H.), University of Pittsburgh; Department of Surgery (J.M.), University of Texas at Southwestern; and the Inflammation and the Host Response to Trauma Large Scale Collaborative Research Program* *Additional participating investigators in the Large Scale Collaborative Research Agreement entitled, “Inflammation and the Host Response to Trauma” include Henry V. Baker, PhD., Timothy R. Billiar, MD, Bernard H. Brownstein, PhD, Steven E. Calvano, PhD, Irshad H. Chaudry, PhD, J. Perren Cobb, MD, Chuck Cooper, MS, Ronald W. Davis, PhD, Adrian Fay, PhD, Robert J. Feezor MD, Richard L. Gamelli, MD, Nicole S. Gibran, MD, Doug Hayden, MS, David N. Herndon, MD, Jureta W. Horton, PhD, John Lee Hunt, MD, Matthew Klein MD, Krzysztof Laudanski MD, MA, James A. Lederer, PhD, Tanya Logvinenko, PhD, John A. Mannick, MD, Carol L. Miller-Graziano, PhD, Michael Mindrinos, PhD, Lyle L. Moldawer, PhD, Grant E. O'Keefe, MD, MPH, Laurence G. Rahme, PhD, Daniel G. Remick, Jr. MD, David Schoenfeld, PhD, Robert L. Sheridan, MD, Geoffrey M. Silver, MD, Richard D. Smith, PhD, Scott Somers, PhD, Ronald G. Tompkins, MD, ScD. Mehmet Toner, PhD, H. Shaw Warren, MD, Steven E. Wolf, MD, Wenzhong Xiao, PhD, Martin Yarmush, MD, PhD, Vernon R. Young, PhD, ScD. Submitted for publication January 20, 2006. Accepted for publication April 19, 2006. Supported by a Large-Scale Collaborative Project Award (U54-GM62119) from The National Institute of General Medical Sciences, National Institutes of Health Address for reprints: Frederick A. Moore, MD, UTHSC – Houston Medical School, Department of Surgery, 6431 Fannin Street, MSB 4.264, Houston, TX 77030; e-mail: Frederick.A.Moore@uth.tmc.edu.] Shock frequently accompanies severe trauma. In addition to acute mortality, shock is a predominant risk factor for multiple organ dysfunction syndrome (MODS) and shock resuscitation is an obligatory early intervention. Because both under and over resuscitation contribute to the pathogenesis of MODS, the potential for MODS development can be minimized by developing a guideline to insure early consistent and appropriate resuscitative efforts. The challenges of this guideline include: a) early identification of high risk patients, implementation in environments that are suboptimal for monitoring resuscitation, c) early identification of resuscitation “non-responders” that require more aggressive interventions, and d) avoiding potentially harmful over zealous interventions. This guideline is based on the best available evidence and expert consensus discussions supported by the Inflammation and Host Response to Injury Large Scale Collaborative Project award from the National Institute of General Medical Sciences, and is being used in the funded clinical studies.1,2 The following section provides a brief overview of the rationale for specific guideline recommendations. This is followed by two algorithms that depict escalation in interventions and monitoring requirements in the subset of patients who do not respond to ongoing volume loading and/or blood transfusions. With multi institutional experience and critical analysis this resuscitation process may be further refined; at this time it is intended to serve as a template for interventional trials and to test the utility of new monitoring technology. This protocol was designed for blunt trauma patients who are presumed not to have a serious concomitant brain injury. Its purpose is to guide resuscitation as soon as feasible after arrival in the Emergency Department (ED) after control of active torso bleeding. Protocol Rationale Early Recognition of Shock in the Emergency Department Recognizing the presence of shock and assessing its severity are key factors in early identification of high risk patients. Shock often can be detected by simple physical examination findings in the ED resuscitation area. Diminished or absent peripheral (radial, pedal) or central (carotid, femoral) pulses, decreased capillary refill associated with pallor or cool clammy extremities may all denote the presence of shock and hypovolemia. The initial blood pressure (BP) measurement should be performed using a manual cuff because automatic cuff BP measurement devices may overestimate systolic BP (SBP) in hypovolemic trauma patients.3 A SBP < 90 mm Hg and/or a heart rate (HR) > 130 bpm is generally considered to be indicative of shock. Some patients (especially the young) compensate for hypovolemia and maintain a normal SBP even in the face of significant ongoing hemorrhage although this is often associated with tachycardia. Additionally, because acute massive blood loss may paradoxically trigger a vagal-mediated bradycardia, the traditional inverse correlation between increased HR and decreased effective blood volume may not hold in the early resuscitation period.4 The initial hemoglobin concentration ([Hb]) is notoriously misleading because there has not been sufficient time for influx of interstitial fluid into the intravascular space and the patient has not yet been volume resuscitated. Therefore, it is important to measure the [Hb] again after the initial 2 L of crystalloid loading, a decrease greater than 2 g/dL is grounds for concern. The magnitude of arterial base deficit (BD) has been shown to be a useful index of the severity of hemorrhagic shock. A BD >= 6 mEq/L is indicative of severe shock.5 Serial BD determinations are important in determining the effectiveness of interventions and lack of response is indicative of a poor prognosis. Other less well studied markers of the severity of shock include venous blood lactate, bicarbonate concentrations and end-tidal CO2 to Paco2 differences. Volume Loading With Isotonic Crystalloid Fluid The key step in resuscitation of the injured patient is the control of active hemorrhage. The actively bleeding patient cannot be adequately resuscitated without hemorrhage control. Resuscitation with isotonic crystalloid fluids has been the standard of care in the United States since the late l960s. The laboratory work of Shires and Moyer demonstrated the best survival was achieved with large volume isotonic crystalloid solution. The basic concept is that interstitial fluid moves into both the intravascular and intracellular spaces in response to shock and that adequate resuscitation requires replenishment of both the intravascular and interstitial spaces. Their studies demonstrated that the optimal ratio of isotonic crystalloid infusion to shed blood infusion was 3 to 1. Subsequent studies demonstrated that the optimal ratio for survival after severe shock increases and can be as high as 8 to 1.6,7 Clinical trials were performed in the l970s and 1980s that compared isotonic resuscitation and colloid resuscitation. Individually, these trials were underpowered and reported conflicting results. When subjected to meta-analysis, they have yielded no consistent differences in overall outcome. When the same data were subjected to subgroup analysis, however, the use of isotonic crystalloids in trauma patients was associated with improved survival. A large clinical trial published in 2004 found no differences in outcome between crystalloid and colloid resuscitation in ICU patients, but again, subgroup analysis demonstrated improved outcomes in trauma patients receiving crystalloid.8 Although these subgroup analyses are not definitive, they are consistent with the early laboratory studies, which indicated that survival in hemorrhagic shock is improved with large volume crystalloid resuscitation. However, in recent years, “damage control” surgery combined with prompt ICU resuscitation appears to be salvaging more patients who are arriving with exsanguinating hemorrhage. Unfortunately, over zealous crystalloid infusion appears to have adverse consequences, e.g. cerebral edema (increased ICP), acute lung injury (worsened pulmonary edema), and the abdominal compartment syndrome (primary and secondary).9 Lactated Ringer's is the Preferred Isotonic Crystalloid Although newer formulations (e.g. Ringer's ethyl pyruvate) are being tested clinically, normal saline (NS) and lactated Ringer's (LR) remain the most commonly used isotonic fluids. In theory, LR is preferable to NS because it provides a better buffer for metabolic acidosis, but to date, investigators have not documented any important differences in outcome. Moreover, the D isomer of lactate may have adverse immunoinflammatory properties. One laboratory study found that NS and LR were equivalent in the setting of moderate hemorrhagic shock but that in the setting of massive hemorrhage, NS was associated with greater physiologic derangement (e.g. hyperchloremic acidosis) and a higher mortality.10 Clinical experience confirms the adverse effects of iatrogenic hyperchloremic acidosis. In addition, the potential benefits of using hypertonic saline (HTS) – rapid blood pressure response, decrease in ICP and improved immunologic status – for resuscitation are unproven but currently in clinical trials. Blood Transfusion to Maintain Hemoglobin Concentration at 10 g/dL The optimal [Hb] continues to be a subject of intense debate. Early laboratory studies of shock resuscitation suggested that survival was improved when [Hb] was maintained in the range of 12 to 13 g/dL. Subsequent studies using isovolemic hemodilution models indicated that the optimal [Hb] for maintaining oxygen delivery was 10 g/dL, and, until relatively recently, this value was the recommended level for critically ill patients. Currently, there is a growing recognition that administration of stored packed red blood cells (PRBC) can adversely affect outcome by modulating the inflammatory response (by both amplifying early proinflammation and aggravating late immunosuppression) and by impairing tissue perfusion (limiting access to or obstructing the microcirculation as a consequence of decreased RBC deformability). A 1999 randomized trial found that patients who received transfusions according to a restrictive policy (i.e. transfusion when the [Hb] fell below 7 g/dL) did as well as, and possibly better than, patients who received transfusions on a more liberal basis (i.e. transfusion when [Hb] fell below 10 g/dL).11 However, this study was done in a select group of euvolemic patients in which those with active hemorrhage were excluded; thus, it is not applicable to severely injured trauma patients requiring active shock resuscitation, but is cogent as their clinical course progresses. (See SOP for blood transfusions.) In addition, if blood transfusions are to be restricted during active resuscitation, it is not clear which alternative fluids should be used. Colloid solutions have been associated with complications and indiscriminant use of crystalloid fluid is detrimental.9 Hypertonic saline and hemoglobin based oxygen carriers are attractive alternatives, but additional clinical trials are needed before these could become standard of care. Additionally, maintaining higher [Hb] during active bleeding may facilitate coagulation. Many patients who are resuscitated by this process will also require a massive transfusion (i.e. >10 units PRBC in 24 hour), and are at risk for developing a coagulopathy. This subset of patients may benefit from early fresh frozen plasma (FFP) administration and this should be factored into their volume loading regimen. Early Central Venous Pressure Monitoring The most likely etiology of shock following major trauma is hypovolemia secondary to acute blood loss. Therefore, initial volume loading with isotonic crystalloids (1 L boluses in adults and 20 cc/kg in children) is recommended. The response to this empiric volume loading assists in early triage decisions. Prompt correction of abnormal vital signs indicates that a lesser volume deficit (10–20% blood volume) was present and that an expedited trauma evaluation can be safely performed to rule out occult bleeding. Patients who do not respond to empiric volume loading may have severe hypovolemia (30–40% blood volume), cardiogenic shock or neurogenic shock. Given that neurogenic shock is usually well tolerated and typically responds to initial volume loading, the key issue is to quickly distinguish hypovolemic shock from cardiogenic shock. Placement of a catheter that permits reliable measurement of central venous pressure (CVP) following the initial boluses can help differentiate these states. A high CVP (>15 mm Hg) suggests cardiogenic shock (likely etiologies include tension pneumothorax, pericardial tamponade or myocardial contusion/infarction). A low CVP (<5 mm Hg) may indicate acute ongoing blood loss, and mandates focus on identifying occult sources of blood loss. In many instances control of hemorrhage requires operating room (OR) or interventional radiologic (IR) interventions. Patients who initially respond to volume loading, but require ongoing crystalloid volume and/or blood transfusion during expedited trauma evaluation, or who have evidence of severe shock by ABG (i.e. BD >= 6 mEq/L), should have a central venous line placed and have continuous CVP measurements displayed to assist with ongoing resuscitation until the patients arrives in the intensive care unit (ICU). In the ICU, with more intensive monitoring available, the decision needs to be made if escalation to pulmonary artery (PA) catheterization is warranted. Pulmonary Artery Catheterization in the ICU The primary goal of shock resuscitation is the early establishment of “adequate” oxygen delivery (DO2) to vital organs. The yet to be resolved controversy is what is “adequate.” The calculated variable DO2 is the product of cardiac output (CO) and arterial oxygen content (Cao2). By convention, CO is indexed to body surface area and expressed as cardiac index (CI), and when multiplied by Cao2 yields an oxygen delivery index (DO2I). Normal DO2I is roughly 450 mL/min/m2. Cao2 and DO2I are calculated as follows: Cao2 (mL O2/dL) = [Hb] (g/dL) × 1.38 mL O2/g Hb × Sao2 (%) + [Pao2 (mmHg) ×: 0.003 mL O2/mmHg] DO2I (mL/min/m2) = CI (L/min/m2) ×: Cao2 (mL/dL) × 10 dL/L, where [Hb] is hemoglobin concentration, Sao2 is hemoglobin O2 saturation, Pao2 is arterial oxygen tension, and 0.003 is solubility of O2 in blood. Thus, there are four variables (i.e. Pao2, Sao2, [Hb], and CI) that determine DO2I. Of the four variables CI is the most difficult to monitor and manipulate. This is the rationale for liberal use of the PA catheter in severely injured patients. Myocardial dysfunction during traumatic shock resuscitation is common, but usually responds to volume loading. However, once a patient has been volume loaded (CVP >15 mm Hg) and has evidence of ongoing shock (e.g. decreased MAP, increased BD or lactate levels), a PA catheter is warranted to better monitor cardiovascular function, especially filling pressures and CI. Once the PA catheter is placed, the key question is what CI is acceptable. Early work from Shoemaker et al. demonstrated that the “survivor” response to traumatic stress is to become hyperdynamic (CI > 4.5 L/min/m2) and consequently have supranormal DO2I (>600 mL/min/m2).12 Supranormal DO2I was, therefore, proposed to be the resuscitation goal. Subsequent prospective randomized controlled trials (RCTs), however, failed to demonstrate improved outcome with goal orientated resuscitation to supranormal DO2I. In fact, several recent studies indicate that this strategy is harmful.13 Recent studies in which a normal DO2I goal of 500 mL/min/m2 was used demonstrated that patients achieve similar hyperdynamic responses to standardized interventions, require less volume loading, and have better outcomes than patients resuscitated to a supranormal DO2I goal.14,15 We recommend using a CI >= 3.8 L/min/m2 as the resuscitation goal for this resuscitation process guideline. During active resuscitation, most severely injured patients will have Sao2 > 92% and [Hb] > 10 g/dL and, therefore, DO2I will approach 500 mL/min/m2. PA catheters capable of continuous monitoring of CO and mixed venous hemoglobin oxygen saturation (SmvO2) are now commonly available and should be utilized. These continuously monitored variables provide rapid feedback that is often necessary to guide effective, timely resuscitation interventions. This approach is based on expert opinion as there are no data to suggest that a PA catheter is either harmful or beneficial in severely injured patients undergoing shock resuscitation. Assessment of Pre-Load by PCWP and the use of the “Starling Curve” Intervention The traditional variable used to assess volume status is the pulmonary capillary wedge pressure (PCWP). It is important to recognize that significant hypovolemia can exist despite reasonable PCWP. Peripheral vasoconstriction of less acutely essential organs (e.g. kidney, gut, muscle, and skin) results in blood volume shifts to maintain the central circulation and perfusion of more essential organs (e.g. heart and brain). With a low CI and a low PCWP (i.e. <10 mm Hg), volume loading should be undertaken. After the PCWP increases to >=15 mm Hg, the benefits of increasing CI by the Frank Starling mechanism should be considered. If additional CI is needed then a stepwise incremental volume loading intervention is used to identify the optimal CI-PCWP “operating point.” Because the shape and position of the Frank Starling curve is dependent on left ventricular contractility, compliance and afterload, it is difficult to identify optimal or plateau PCWP during volume loading without frequent sequential measurements.16 In a recent study, one-third of high risk patients had persistently low CO, high systemic vascular resistance (SVR) and high BD despite volume loading to a PCWP >= 15 mm Hg. However, these patients did respond well to the “Starling curve” intervention, by increasing CO, decreasing SVR and decreasing BD. This observation is consistent with a recent RCT in which patients who did not respond to initial volume loading (to presumed euvolemia) were randomized to additional volume loading or to a vasodilating inotropic agent.17 Patients who received further volume loading were found to have a better resuscitation response than those treated with inotropic agents. This favorable response to additional pre-load must, however, be weighed against the risks of increasing hydrostatic pressure leading to increase pulmonary edema, especially in patients with leaky endothelium (e.g. pulmonary contusion). Increasing PCWP >25 mm Hg in attempts to create a “Starling curve” should not be done because of the potential of causing or worsening pulmonary edema.16 Use of Vasoactive Agents in Non-Responders The primary early problem in shock resuscitation is decreased preload with resulting decreased CO. In this setting, the normal “survivor” response is to become hyperdynamic with volume loading. However, as time and severity of shock increases, a complex pathophysiologic interaction evolves that limits CO. Important factors include relative hypovolemia, primary or secondary myocardial dysfunction and excessive peripheral vasoconstriction. With ineffective intervention, shock will ultimately progress into pathologic vasodilation which heralds irreversible shock. Unfortunately, in the later phases of shock, patients who do not respond to volume loading also do not consistently respond to vasoactive agents. Therefore, a PA catheter should be placed to more accurately characterize their hemodynamic profile and monitor their response to vasoactive agent administration. A specific agent with known physiologic actions should then be administered and titrated to a desired effect. (See Table 1.) -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 1 Vasoactive Agents Commonly Used in Shock Resuscitation -------------------------------------------------------------------------------- For the typical non responding patient (i.e. low CI, adequate PCWP and high SVR), a vasodilating inotrope such as dobutamine (beware of hypotension) or dopamine (beware of tachycardia) is recommended. Patients with a particularly high SVR may respond better to simple afterload reduction with nitroprusside. However, additional volume loading may be needed to maintain an adequate PCWP and oxygenation may worsen due to loss of hypoxic pulmonary vasoconstriction (i.e. worsened V/Q mismatch). For patients with low CO and normal SVR, dopamine or lower dose norepinephrine are reasonable choices. For patients who have low SVR and are thus unable to maintain an adequate MAP (>= 60 mm Hg), higher doses of norepinephrine should be used. It is also important to rule out relative adrenal insufficiency in patients requiring higher doses of norepinephrine.18 Additionally, low dose vasopressin (as replacement therapy) may reduce the need for norepinephrine in patients exhibiting impending irreversible shock.19 Of note, there are no data that demonstrate that use of a specific vasoactive agent in non-responding patients improves outcome. Several studies have demonstrated improved hemodynamic responses to specific agents, and extrapolate this response to an improved outcome.20–22 Protocol Summary Initial Resuscitation Figure 1 depicts initial ED resuscitation and the following text includes explanatory annotations lettered A through F. Variables that drive decision making include SBP, HR, BD, [Hb], CVP and clinical judgment (ever present). Additionally, stopping ongoing active hemorrhage is paramount to the survival of these patients. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 1. Initial resuscitation. -------------------------------------------------------------------------------- A. Major trauma patients arriving in shock (SPB <90 mm Hg and/or HR >130 bpm) are initially managed by using Advanced Trauma Life Support (ATLS).22 Routine monitoring includes frequent vital signs (minimum q 15 minutes), continuous ECG and pulse oximetry (SpO2) and core body temperature. A data flow sheet is necessary to trend physiologic indices, laboratory test results and fluid volume/blood transfusion administration. During the initial ED evaluation an ABG analysis should be obtained in all patients presenting in traumatic shock. B. Major torso trauma patients who have evidence of shock (documented by early SBP <90 mm Hg and/or a BD >=6 mEq/L), and who require ongoing resuscitation, should have a central venous line (via subclavian or internal jugular vein) placed in ED. CVP measurements should be used to differentiate the type of shock and to assist with subsequent monitoring of shock resuscitation. C. Early CVP >15 cm mmHg (before extensive volume loading) suggests cardiogenic shock. D. Differential diagnosis of cardiogenic shock following blunt trauma includes: 1) tension pneumothorax, 2) myocardial contusion/infarction, 3) pericardial tamponade (uncommon) and 4) air embolus (rare). Specific diagnosis and treatment is beyond the scope of this protocol. ATLS guidelines should be followed.23 E. CVP <10 mm Hg despite volume loading indicates persistent hypovolemia and this most likely reflects ongoing bleeding. The endpoint of initial resuscitation is controversial and the algorithm statement “resuscitate until stable” is intentionally vague (i.e. requires clinical judgment). The crux of the issue is whether it is preferable to administer fluids to restore DO2 to the vital organs (risking hemodilution and disruption of early hemostatic clots) or to withhold fluid resuscitation until control of hemorrhage (risking prolonged cellular shock to the extent that it becomes irreversible by the time hemorrhage control is accomplished). At present, the rationale compromise is hypotensive resuscitation (SBP >90 mm Hg and HR <130 bpm) with moderate volume loading until hemorrhage control is accomplished. This approach is becoming the standard of care for penetrating trauma victims. It is most likely safe for blunt torso trauma patients who do not have significant concomitant brain injuries that could be worsened by permissive hypotension. F. LR boluses should continue and, when LR infusion exceeds 30 mL/kg, blood should be administered. Earlier empiric blood transfusion is indicated in patients (especially the elderly) who arrive in severe shock or who have injuries associated with significant bleeding (e.g. vertical shear pelvic fracture or bilateral femur fracture.) Protocols for massive transfusion should be established with the blood bank to ensure prompt availability of blood products for patients arriving with ongoing life-threatening hemorrhage. Among the most devastating complications of massive blood and fluid administration is a coagulopathy. Stored blood is deficient in factors V and VIII and platelets. Timely administration of FFP and platelets will minimize risk of coagulopathy after massive transfusion. Presumptive factor replacement is usually not indicated in the early phase of resuscitation, but may be appropriate in patients with massive hemorrhage caused by significant intracavitary bleeding or an unstable pelvic fracture.24,25 ICU Resuscitation Hemorrhage control is of paramount importance in the initial management of major torso trauma patients arriving in shock. It is assumed that this issue will have been addressed in the vast majority of patients by the time the patient is admitted to the ICU. The priorities in early ICU care are to: a) optimize resuscitation, correct hypothermia, coagulopathy and acidosis and c) monitor for ongoing bleeding requiring OR or IR intervention. Figure 2 depicts ICU resuscitation and the following text includes explanatory annotations lettered A through H. An important early decision is whether to escalate monitoring interventions (i.e. placement of arterial and PA catheters). Variables that drive decisions in the PA catheter algorithm include CI, [Hb], PCWP, BD and clinical judgment. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 2. ICU resuscitation. -------------------------------------------------------------------------------- A. When the patient arrives in the ICU, the physician needs to decide whether to continue resuscitation using serial vital signs, CVP, [Hb] and BD determinations (i.e. CVP Algorithm.) Most patients can be managed using this process, but close observation by a physician at bedside is required because CVP is a very indirect monitor of hemodynamic function. B. For patients who are not responding to ongoing volume loading/blood transfusion (i.e. low MAP or persistently high BD) and/or are demonstrating secondary organ dysfunctions (i.e. worsening oxygenation or decreased urine output), pulmonary artery catheterization is warranted. The possibility of an impending abdominal compartment syndrome needs to be considered if crystalloid fluid volume loading exceeds 10 L or PRBC transfusion exceeds 10 units. Periodic urinary bladder pressure measurements should be obtained to monitor for onset of abdominal compartment syndrome. Urinary bladder pressure >=25 mm Hg indicates significant abdominal hypertension and need for bedside assessment for possible surgical intervention.9,14 C. It is assumed that most patients being treated by this algorithm will be intubated. If not intubated and requiring ongoing volume loading, intubation needs to be considered, because worsening pulmonary function is likely. If intubated and PEEP >=12 cm H2O, the effects of high mean airway pressures on cardiac function needs to be considered, as does use of PA catheter. D. If the patient meets the CI goal of 3.8 L/min/m2, then the patient should be monitored as depicted in this arm of algorithm. Hemodynamic variables should be assessed hourly, and possibly more frequently. Laboratory variables including [Hb] and ABG (BD) should be determined every 4 hours, and possibly more frequently until the patient is fully resuscitated and stable. Coagulation variables and urinary bladder pressure measurements should be monitored as deemed necessary. E. Most young patients easily exceed the CI goal of 3.8 L/min/m2 with modest crystalloid volume loading and blood transfusion. There is no need to increase PCWP to high levels in responding patients, but [Hb] should be maintained >=10 g/dL during acute resuscitation to assure a safety margin in the event of occult or recurring bleeding. However, once the BD has been normalized and the need for ongoing volume loading has resolved, a lower [Hb] is acceptable. (See SOP for transfusion.) F. PCWP may not accurately reflect left ventricular end diastolic volume and increasing PCWP to >=15 mm Hg may enhance cardiac performance. The optimal relationship between PCWP and CI can be determined by incrementally increasing left ventricular preload (PCWP) and then measuring cardiac output (CI) in response, i.e. by generating a “Starling curve” to determine the optimal CI-PCWP operating point.10 This should only be done in patients who are not meeting the CI goal and who have evidence of ongoing shock (i.e. persistently elevated BD.) G. After obtaining optimal PCWP, if CI <3.8 L/min/m2, then infusion of a vasodilating inotropic agent should be started. Dobutamine is recommended as the preferred inotropic agent. Dobutamine infusion should be started at a dose rate of 5.0 µg/kg/min and increased in increments of 2.5 µg/kg/min to a maximum of 20 µg/kg/min to increase CI. If the patient does not tolerate the vasodilation, dopamine should be considered with progression from low to mid- to high dose, while monitoring for excessive tachycardia. H. Occasionally, an inotropic agent with vasoconstrictive effects may be needed to maintain MAP >=60 mm Hg, enhance myocardial contractility and maintain coronary perfusion pressure. These agents decrease peripheral perfusion at the microcirculatory level by [alpha]1 vasoconstriction of metarterioles thereby prolonging or exacerbating the effects of shock, and are therefore an intervention of last resort. Norepinephrine is recommended as the preferred agent. Norepinephrine infusion should be started at 0.05 µg/kg/min and increased in increments of 0.05 µg/kg/min as needed to obtain CI >=3.8 L/min/m2, and maintain MAP >=60 mm Hg. The maximum recommended norepinephrine dose rate is 0.2 µg/kg/min. Adrenal insufficiency in patients requiring norepinephrine to maintain MAP needs to be ruled out. Low dose vasopressin may decrease the required dose of norepinephrine. REFERENCES 1. Moore FA, McKinley BA, Moore EE. The next generation in shock resuscitation. Lancet. 2004;363:1989–96. [Context Link] 2. Moore FA, Moore EE. Ch 1 Initial Management of Life-Threatening Trauma. Ch 6 Trauma and Thermal Injury. ACS Surgery: Principles and Practice. Souba WW, Fink MP, Jurkovich GJ, et al, eds. Web MD Inc, New York, 2005. [Context Link] 3. Davis JW, Davis IC, Bennick LD, et al. Are automated blood pressure measurements accurate in trauma patients? J Trauma. 2003;55:860–863. Ovid Full Text Bibliographic Links [Context Link] 4. Victorino GP, Battistella D, Wisner DH. Does tachycardia correlate with hypotension after trauma? J Am Coll Surg. 2003;196:679–684. Bibliographic Links [Context Link] 5. Rutherford EJ, Morris JA, Reed GW, Hall KS. Base deficit stratifies mortality and determine therapy. J Trauma. 1992;33:417–423. Bibliographic Links [Context Link] 6. Cervera AL, Moss G. Progressive hypovolemia leading to shock after continuous hemorrhage and 3:1 crystalloid replacement. Am J Surg. 1975;129:670–674. Bibliographic Links [Context Link] 7. Healey MA, Samphire J, Hoyt DB, et al. Irreversible shock is not irreversible: A new model of massive hemorrhage and Resuscitation. J Trauma. 2001;50:826–834. Ovid Full Text Bibliographic Links [Context Link] 8. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–2254. [Context Link] 9. Balogh Z McKinley BA, Holcomb JB, et al. Both primary and secondary abdominal compartment syndrome can be predicted early and are harbingers of multiple organ failure. J Trauma. 2003;54:848–859. Ovid Full Text Bibliographic Links [Context Link] 10. Healey MA, Davis RE, Liu FC, et al. Lactated Ringer's is superior to normal saline in a model of massive hemorrhage and resuscitation. J Trauma. 1998;45:894–899. Ovid Full Text Bibliographic Links [Context Link] 11. Herbert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340:409–417. [Context Link] 12. Shoemaker WC, Appel PL, Kram HB, et al. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest. 1988;94:1176–1186. Bibliographic Links [Context Link] 13. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-orientated hemodynamic therapy in critically ill patients. N Engl J Med. 1995;333:1025–1032. [Context Link] 14. Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal trauma resuscitation causes more cases of abdominal compartment syndrome. Arch Surg. 2003;138:637–642. Ovid Full Text Bibliographic Links [Context Link] 15. Velmahos GC, Demetriades D, Shoemaker WC, et al. Endpoints of resuscitation of critically injured patients: normal or supranormal? A prospective randomized trial. Ann Surg. 2000;232:409–418. Ovid Full Text Bibliographic Links [Context Link] 16. Marr AB, Moore FA, Sailors RM, et al. Preload optimization using “Starling Curve” generation during shock resuscitation: can it be done? Shock. 2004;21:300–305. Ovid Full Text Bibliographic Links [Context Link] 17. Miller PR, Meredith JW, Chang MC. Randomized, prospective comparison of increased preload versus inotropes in the resuscitation of trauma patients: effects on cardiopulmonary function and visceral perfusion. J Trauma. 1998;44:107–113. Ovid Full Text Bibliographic Links [Context Link] 18. Cooper MS, Stewart PM. Corticosteroid nsufficiency in acutely ill patients. N Engl J Med. 2003;348:727–734. [Context Link] 19. Landry DW, Oliver JA. Mechanisms of disease: the pathogenesis of Vasodilatory Shock. N Engl J Med. 2001;345:588–595. Ovid Full Text Bibliographic Links [Context Link] 20. Abou-Khalil B, Scalea TM, Trooskin SZ, et al. Hemodynamic responses to shock in young trauma patients: need for invasive monitoring. Crit Care Med. 1994;22:633–639. Bibliographic Links [Context Link] 21. Chang MC, Martin RS, Scherer LA, et al. Improving ventricular-arterial coupling during resuscitation from shock: effects on cardiovascular function and systemic perfusion. J Trauma. 2002;53:679–685. Ovid Full Text Bibliographic Links [Context Link] 22. McKinley BA, Marvin RG, Cocanour CS, et al. Nitroprusside in resuscitation of major torso trauma. J Trauma. 2000;49:1089–1095. Ovid Full Text Bibliographic Links [Context Link] 23. Shock. Advanced Trauma Life Support Manual. Chicago:American College of Surgeons; 2004. [Context Link] 24. Hirshberg A, Dugas M, Banez EI, et al. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: A computer simulation. J Trauma. 2003;54:454–463. Ovid Full Text Bibliographic Links [Context Link] 25. Biffl WL, Smith WR, Moore EE, et al. Evolution of a multidisciplinary clinical pathway for the management of unstable patients with pelvic fractures. Ann Surg. 2001;233:843–850. Ovid Full Text Bibliographic Links [Context Link]

Here's the Full text stucy on this topic... (A Single Bolus of 3% Hypertonic Saline with 6% Dextran Provides Optimal Initial Resuscitation After Uncontrolled Hemorrhagic Shock [Original Articles) Watters, Jennifer M. MD; Tieu, Brandon H. MD; Differding, Jerome A. BS; Muller, Patrick J. BS; Schreiber, Martin A. MD From the Oregon Health & Science University, Portland, Oregon. Submitted for publication January 25, 2006. Accepted for publication March 29, 2006. This work was supported in its entirety by the US Army Medical Research Acquisition Activity Award W81XWH-04-1-0104. Presented at the Northwest Regional Committee on Trauma Resident Paper Competition, December 11, 2004, Centralia, Washington, and the 35th Annual Meeting of the Western Trauma Association, February 27–March 5, 2005, Jackson Hole Wyoming. Address for reprints: Jennifer M. Watters, MD, 3181 SW Sam Jackson Park Road, Mail Code L223A, Portland, OR 97239; email: wattersj@ohsu.edu.] Abstract Background: The optimal fluid for early resuscitation of hemorrhagic shock would restore perfusion without increasing blood loss, hypothermia, acidosis, or coagulopathy. This study examined effects of a single bolus of hypertonic saline (HTS) with or without (±) dextran (D) after uncontrolled hemorrhage (UH) and determined optimal fluid composition. Methods: Fifty swine were anesthetized and underwent invasive line placement, celiotomy, splenectomy, suprapubic catheterization, and grade V liver injury. After 30 minutes of UH, blinded fluid resuscitation was initiated with a 250-mL bolus. Animals were randomized to five groups: normal saline (NS), 3% HTS (3%), 3% HTS/6% D (3% D), 7.5% HTS (7.5%), or 7.5% HTS/6% D (7.5% D). Mean arterial pressure (MAP) and tissue oxygen saturation (StO2) were recorded. Laboratory and thrombelastography (TEG) data were collected every 30 minutes. Animals were sacrificed 120 minutes after injury. Analysis of variance was used to compare groups. Significance was defined as p < 0.05. Results: Baseline characteristics and laboratory values were similar in all groups. All groups achieved a similar degree of shock. Two NS and two 3% animals did not survive to 120 minutes. Fluids containing dextran produced a significantly greater increase in MAP (p < 0.02). Animals receiving 3% D maintained a higher MAP 90 minutes after fluid bolus. Also, 7.5% ± D produced a significantly greater initial increase in StO2 (p < 0.05). This effect declined after fluid bolus while 3% D continued to improve tissue oxygenation. Significant differences developed between groups in TEG values, hematocrit, fibrinogen, urine sodium, serum sodium, serum chloride, and urine output. Conclusions: A single bolus of 3% D after uncontrolled hemorrhagic shock produces an adequate and sustained rise in MAP and StO2 and attenuates hypercoagulability. Resuscitation with 7.5% ± D produces significantly increased urine output accompanied by a decline in MAP and StO2 over time. A single bolus of 7.5% D results in significant dilutional anemia and relative hypofibrinogenemia. -------------------------------------------------------------------------------- Although traumatic injury accounts for the largest number of deaths for persons aged 1 to 44 years,1 many questions remain unanswered about initial, field, or prehospital management of trauma victims. Although therapeutic intervention for the treatment of hemorrhagic shock invariably includes the administration of fluids, the optimal timing, fluid composition, and quantity to infuse are not known. Fluid resuscitation is often the first and only treatment for hypotensive patients available to early responders in the field. However, the mortality benefit of aggressive early fluid resuscitation has been questioned in the presence of uncontrolled hemorrhage in both animal models and human trials.2,3 Although overly aggressive fluid resuscitation may be harmful, adequate resuscitation decreases organ damage and improves survival.4 In addition, many victims of trauma suffer multiple injuries including traumatic brain injuries. It may be difficult or impossible for first responders to rule out a traumatic brain injury, which can be worsened by even a single episode of hypotension,5 but large volume fluid resuscitation is associated with increased intracranial hypertension.6 To further complicate early resuscitation, determinants of adequate initial resuscitation are still debated. Numerous studies have been conducted examining the efficacy of hypertonic saline in initial trauma resuscitation. The ideal initial resuscitation fluid would restore and maintain tissue perfusion while not increasing intracranial pressure, blood loss, hypothermia, or acidosis and mitigating late complications attributed to hypercoagulability. The most widely studied has been 7.5% saline with and without dextran. Hypertonic saline has been shown to rapidly restore blood pressure, improve cardiac performance,7 reduce intracranial pressure and improve cerebral perfusion pressure,8 and may attenuate the proinflammatory response.9 This study sought to examine the effects of a single bolus of hypertonic saline (HTS) after uncontrolled hemorrhagic shock (UHS) from solid organ injury in a clinically relevant model, and to determine the optimal fluid composition by using solutions of varying tonicity with and without (±) the addition of dextran (D). Although dextran has been associated with anaphylaxis and coagulopathy,10,11 a study examining the effects of a single prehospital bolus of 7.5% HTS with 6% dextran-70 did not report any cases of dextran-related anaphylaxis or coagulopathy.6 Our hypotheses were that a single bolus of HTS after UHS in a prehospital model would provide adequate restoration of blood pressure and tissue perfusion and that these effects would increase with increasing tonicity and the addition of dextran to the solutions. MATERIALS AND METHODS The study design was a randomized, blinded, controlled trial conducted in a large animal model. The Institutional Animal Care and Use Committee at Oregon Health & Science University approved the protocol. This facility adheres to the National Institutes of Health guidelines for the care and use of laboratory animals. Uncontrolled Hemorrhagic Shock Model Fifty female Yorkshire crossbred swine with a mean weight of 33 kg were obtained from a commercial breeder. Animals underwent a 16-hour preoperative fast except for water ad libitum. Animals were preanesthetized with 8 mg/kg intramuscular Telazol (Fort Dodge Animal Health, Fort Dodge, IA), oral-endotracheally intubated with a 6.5- to 7.5-mm tube, and mechanically ventilated. Volume control ventilation was used with tidal volumes set at 12 ± 2 cc/kg. Respiratory rate was adjusted to maintain end-tidal CO2 and Pco2 of 40 ± 4 mm Hg. Anesthesia was maintained with isoflurane (Abbott Laboratories, North Chicago, IL) and an independent animal technician assessed adequacy by monitoring jaw laxity and painful stimuli to the nasal septum and forefoot. Euthermia (38.0 ± 1.5°C) was preserved using warmed fluids and external warming devices. Monitoring devices were placed including a left common carotid arterial catheter, left external jugular catheter, esophageal thermometer, and a cutaneous InSpectra Tissue Spectrometer (Hutchinson Technology, Hutchinson, MN) on the left hind limb. The arterial catheter was used for continuous mean arterial blood pressure (MAP) recording and blood sampling. The venous catheter was used for administration of resuscitation fluids. Continuous tissue oxygen saturation (StO2) data were obtained and recorded using the tissue spectrometer. After placement of monitoring devices, animals underwent midline celiotomy, splenectomy, and suprapubic catheterization. Splenectomies are performed in swine hemorrhage models because of the variability of the spleen's distensibility and the resultant variable amounts of sequestered blood. Splenic blood volume was replaced with normal saline (NS) 3 mL/g spleen weight. After a 15-minute stabilization period, preweighed sponges were placed in the pelvis and inferior left and right pericolic gutters to facilitate blood collection and blood loss measurement. Sponges were not in contact with the liver and should not have affected blood loss. Standardized grade V liver injuries were created using a specially designed clamp. The clamp, closed over the central portion of the liver, creates a reproducible injury with extensive parenchymal damage as well as laceration of one or more central hepatic veins, consistent with the AAST Injury Scaling and Scoring System for a grade V hepatic injury.12 Autopsies were performed after animal sacrifice to ensure comparable injuries by determining the number of central hepatic veins injured. Figure 1 is a representative injury demonstrating a large laceration of the left hepatic vein. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 1. Grade V liver injury. This photograph demonstrates a representative grade V liver injury. Use of a specially designed clamp results in extensive parenchymal damage and injury to one or more central hepatic vein. The clamp is passing through a large laceration of the left hepatic vein. -------------------------------------------------------------------------------- Animals were allowed to hemorrhage for 30 minutes. During the hemorrhage period, blood loss was collected by suction as well as with the preweighed sponges and was reported as a mean for each group. Visible hemorrhage ceased in all animals without intervention after reaching similar nadir MAPs. At 30 minutes postinjury, sponges were removed and reweighed and the abdomen was closed. Animals were randomized to one of five fluid groups and blinded resuscitation was initiated. A single 250-mL bolus (7.2 ± 0.8 mL/kg to 7.6 ± 0.7 mL/kg) of study fluid was infused over 10 minutes. Fluids administered were: normal saline (NS), 3% saline (3%), 3% saline with 6% dextran-70 (3% D), 7.5% saline (7.5%), and 7.5% saline with 6% dextran-70 (7.5% D). NS and 3% were commercially prepared (Baxter, Deerfield, IL: NS, pH 4.5–7.0, 154 mEq/L sodium, 154 mEq/L chloride; 3%, pH 5.0, 513 mEq/L sodium, 513 mEq/L chloride) and the remaining fluids (3% D, 513 mEq/L sodium, 513 mEq/L chloride, 60 gm/L dextran-70; 7.5%, 1283 mEq/L sodium, 1283 mEq/L chloride; 7.5% D, 1283 mEq/L sodium, 1283 mEq/L chloride, 60 gm/L dextran-70) were compounded in our laboratory using sodium chloride (Fisher Chemicals, Fairlawn, NJ) and dextran-70 from Leuconostoc mesenteroides (Sigma-Aldrich, Inc., St. Louis, MO) and passed through a 0.22-µm filter to eliminate any bacterial or viral contaminants. MAP and StO2 monitoring continued for a total of 120 minutes before animal sacrifice. Laboratory and thrombelastography (TEG) data were collected at baseline and every 30 minutes. Secondary blood loss was measured at 120 minutes by reopening the abdomen and collecting all blood with suction and a new set of preweighed laparotomy sponges and was reported as a mean for each group. Statistical Analysis Anaylsis of variance (ANOVA) and repeated measures ANOVA were used to compare groups using a statistical software package for personal computers (SPSS, Windows Version 13.0, SPSS, Inc., Chicago, IL). Paired t tests were used to make comparisons within groups. Significance was defined as p < 0.05. RESULTS Two NS and two 3% animals did not survive to 120 minutes. Nonsurvivors' data were included in the analysis until the time of their deaths. All animals had similar injuries (2.1 ± 0.9 vessels) determined by autopsy. Baseline characteristics and end of study data including weight and temperature were similar for all groups (p > 0.2). Hemodynamic and urine output data are presented in Table 1. Despite equal blood loss and resuscitation volumes, animals receiving 7.5% ± D produced considerably more urine than animals receiving 3% ± D or NS, p < 0.03. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 1 Baseline and End-of-Study Data -------------------------------------------------------------------------------- Continuous MAP data are presented in Figure 2. Injuries were created at time zero (T0). All animals experienced a precipitous drop in MAP to similar nadirs followed by a period of autoresuscitation to a significantly higher MAP compared with nadir MAP (p = 0.001). The single fluid bolus was administered over 10 minutes beginning 30 minutes after injury. 7.5% saline solutions initially caused a brief drop in the MAP, which was more pronounced with the fluid containing dextran. The 3% D group produced a significantly greater overall increase in MAP compared with all other fluids except 7.5% D (p < 0.02). However, the overall increase in MAP in the 7.5% D group was not significantly higher than the MAP increase with NS (p = 0.06). Twelve of 50 animals (24%) returned to their baseline MAP after fluid administration. Animals reaching baseline MAP by group: NS, 0/10; 3%, 1/10; 3% D, 5/10; 7.5%, 2/10; 7.5% D, 4/10. Of animals receiving dextran, 9/20 (45%) returned to baseline MAP. There was no significant difference in rate of return to baseline blood pressure between the two groups receiving dextran (p = 1). Compared with NS, 3% D animals returned to their baseline MAP at a significantly higher rate (p = 0.03). With larger cohorts, statistically important differences may have developed compared with other fluids. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 2. Continuous mean arterial pressure. Data presented are the average mean arterial pressures for each group. Injuries were created at time zero (T0). All animals reached similar MAP nadirs followed by significant autoresuscitation (p= 0.001). Fluid bolus administration began 30 minutes after injury. 3% D produced a significantly greater overall increase in MAP compared with all fluids except 7.5% D (p< 0.02). -------------------------------------------------------------------------------- Continuous StO2 data are presented in Figure 3. After injury, tissue oxygen saturation dropped precipitously, mirroring MAP. Likewise, all animals reached similar StO2 nadirs followed by a period of autoresuscitation. The four groups receiving HTS began improving StO2 immediately with fluid administration. 7.5% ± D solutions produced a greater initial increase in StO2. However, this effect began declining within 5 minutes of completing the fluid bolus. The decline was more rapid in the 7.5% group. On the contrary, 3% D continued to improve StO2 during the 90-minute resuscitation period. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 3. Continuous tissue oxygen saturation. Average mean StO2 for each group is presented. The StO2 for each group declined after injury mirroring the drop in MAP. All animals reach similar nadirs followed by a period of autoresuscitation. StO2 improved with fluid administration in all groups. 7.5% ± D solutions produced a greater initial increase in StO2. Upon completing the fluid bolus, StO2 declined in all groups except the 3% D group. -------------------------------------------------------------------------------- Baseline laboratory results were similar for all groups. At 120 minutes, platelet count (299 ± 117), partial thromboplastin time (PTT; 15.5 ± 2.2), prothrombin time (PT; 14.2 ± 1.3), pH (7.39 ± 0.05), pCO2 (48 ± 4), pO2 (481 ± 99), serum lactate (2.4 ± 1.8), and base excess (5.1 ± 3.8) remained similar for all groups. Baseline laboratory data and data at 120 minutes showing significant differences between groups and from baseline are listed in Table 2. Groups receiving HTS developed hypernatremia with Na levels peaking 30 minutes after fluid infusion. Serum Na levels remained significantly different at T120. HTS groups also developed significant hyperchloremia. The degree of hypernatremia and hyperchloremia correlated with the infused fluid's NaCl concentration. Significant anemia and relative hypofibrinogenemia developed in HTS groups, and was exacerbated by the addition of dextran. HTS groups developed elevated urine Na levels corresponding to serum Na. Table 3 displays additional laboratory data comparing end of study with baseline for each group. Although no differences were seen in these data between groups at T120, within each group several of these results differed significantly from baseline data. A significant drop in pH occurred in the NS, 3%, and 7.5% groups. However, a significant increase in lactate was only seen in the 3% group. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 2 Baseline (T0) and End-of-Study (T120) Laboratory Data -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 3 Baseline (T0) versus End-of-Study (T120) Laboratory Data -------------------------------------------------------------------------------- TEG data are shown in Figure 4. Reaction ® time represents the time to onset of clot formation. A significant decrease in R time occurred in all groups except 3% D. The alpha angle represents the rapidity of fibrin buildup and cross-linking. The alpha angle did not increase in animals receiving dextran. Maximum amplitude (MA) is a measurement of clot strength and is affected by platelet number and function as well as by fibrinogen level. The MA decreased significantly in animals receiving dextran. Clotting index (CI) is a calculated measurement of overall coagulation function derived from all measured values. CI increased significantly in all animals except those receiving 3% D. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 4. Thrombelastography data. Comparisons are made between baseline and end of study data. (A) A significant decrease in reaction time occurred in all groups except 3% D. ( Alpha angle did not increase in animals receiving dextran. © Maximum amplitude decreased significantly in animals receiving dextran. (D) Clotting index increased significantly in all animals except those receiving 3% D. p < 0.05, *v. preinjury and **v. 3% D and 7.5% D. -------------------------------------------------------------------------------- DISCUSSION Historically, large-volume resuscitation has been advocated for the hypotensive trauma victim. This approach may increase mortality in the setting of uncontrolled hemorrhage and may lead to increased acidosis, hypothermia, coagulopathy, abdominal compartment syndrome, elevated intracranial pressure, and a host of poorly understood immunologic consequences. The ideal fluid for early resuscitation would restore tissue perfusion and avoid this myriad of ill effects. Hypertonic saline has been shown to rapidly restore blood pressure and improve cardiac performance.7 Studies report a reduction in intracranial pressure and an improvement in cerebral perfusion pressure after resuscitation with hypertonic saline.8 In addition to excellent physiologic performance, hypertonic saline may attenuate the pro-inflammatory response.9 Decreasing dysfunctional inflammation after traumatic injury could profoundly effect the development of late sequelae such as acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). Prior work in our lab demonstrated that up-regulation of pro-inflammatory cytokines in the lung after grade V liver injury and uncontrolled hemorrhage does not occur if fluid resuscitation is withheld.13 Our results suggest that fluid resuscitation of any kind may be responsible for the dysfunctional inflammatory response to traumatic injury. However, the risks of prolonged hypotension and shock are well known. Our study was limited to a short time course and additional work needs to be completed to determine whether this dysfunctional response persists and whether the timing of fluid resuscitation affects the inflammatory response. In addition, our findings motivated the current study to determine whether adequate initial field resuscitation could be achieved and maintained with a single bolus of fluid, avoiding large volume resuscitation during initial intervention. Because we were not performing goal directed resuscitation, such as to a predetermined mean arterial pressure (MAP), we used a near-infrared tissue spectrometer (NIRS) to assess regional tissue oxygenation in hind limb muscle as a marker of resuscitation adequacy. NIRS is noninvasive, provides continuous data, and several previous studies have shown that NIRS is capable of determining local tissue oxygenation under a variety of clinical scenarios.14–16 In swine, hind limb muscle tissue oxygenation reflects both the severity of shock and the adequacy of resuscitation 17 and may be used as a surrogate marker of splanchnic perfusion.18 Our data indicate that a 250-mL bolus of 3% D restores both MAP and StO2 and maintains adequate perfusion for 90 minutes after infusion. The addition of dextran is important for both achieving and maintaining adequate resuscitation. In previous animal studies, it has been shown that the addition of a 6% dextran to 7.5% NaCl resulted in a significantly higher and more sustained cardiac output, mean arterial pressure, lower arterial peripheral resistance,19 and increased survival 20 compared with hypertonic saline and dextran alone. The increase in MAP and StO2 achieved with 3% D is not associated with increased secondary bleeding. Ideally, within 90 minutes, a patient would reach the trauma surgeon who could initiate definitive care including operative intervention and ongoing resuscitation. The greatly increased urine output in animals receiving 7.5% saline solution is likely secondary to hypernatremic natriuresis. Concomitant with these animals' increase in serum sodium was an increase in urine sodium and urine output. Excessive urine output may account for the subsequent decline in MAP and StO2 seen in these animals over time. 3% D resuscitation does not result in the same increase in urine output despite moderate increases in both serum and urine Na. This may explain the superior maintenance of MAP and StO2 in the 3% D group. The data clearly demonstrate that all animals become relatively hypercoagulable after injury and fluid resuscitation as evidenced by decreased R time and increased clotting index. Dextran and specifically 3% saline with dextran attenuates this hypercoagulability. This attenuation is likely multifactorial but dilutional effects may be paramount. The decrease in maximum amplitude may be caused by relative hypofibrinogenemia. However, profound dilutional anemia may adversely affect platelet function by decreasing nitric oxide scavenging.21 Attenuation of the hypercoagulable response to traumatic injury may reduce the number of late thrombotic complications seen in this patient population. Without prophylaxis 58% of trauma patients will develop deep venous thrombosis.22 A hypercoagulable state is associated with the later development of ARDS and MODS.23 Of the fluids tested, 3%D produced the best physiologic and coagulation profile. This study has several limitations. It was performed in anesthetized swine rather than awake human subjects. As such, the effects of general anesthesia on the physiologic parameters measured must be considered. However, performing this type of randomized blinded, controlled trial in humans would be a huge undertaking, both logistically and in cost, needing prior justification such as provided by this study. The study is limited to early intervention and is not extended to include survival data. The limited time course of the study precludes the identification of any late sequelae of limited initial resuscitation. Subsequent work should certainly be extended to capture that data. Animals did not have intracranial abnormality and intracranial pressures were not monitored, limiting the conclusions to be made about the fluid's use in patients with traumatic brain injuries. Adding a traumatic brain injury to the model and placing intracranial monitoring devices would be informative. Although pH decreased in three of five groups, none of our animals became severely acidotic, even in the NS group. The hepatic injury is extensive and animals lose 30 to 40% of their blood volume with nadir MAPs of 30 to 35 mm Hg. The lack of profound acidosis despite significant injury and blood loss is consistent with a moderate shock model representative of patients admitted to and resuscitated at trauma centers. However, our findings may be different if animals achieved a greater degree of shock or if fluid administration were delayed for up to 60 or 90 minutes. CONCLUSIONS After uncontrolled hemorrhagic shock, a single 250-mL bolus of 3% saline with 6% dextran-70 produces an adequate and sustained rise in both mean arterial pressure and tissue oxygen saturation while attenuating posttraumatic hypercoagulability. The sustained use of these fluids for resuscitation may be limited by the development of hypernatremia, hyperchloremic acidosis, increased bleeding as a result of vasodilatation, interference with platelet function, or the exacerbation of pulmonary edema or congestive heart failure caused by circulatory overload. REFERENCES 1. Committee on Injury Prevention and Control, Institute of Medicine. Reducing the Burden of Injury: Advancing Prevention and Treatment. Bonne RJ, Fulco CE, Liverman CT, Eds. Washington, DC: National Academy Press; 1999;42–43. [Context Link] 2. Bickell WH, Bruttig S, Millnamow G, et al. The detrimental effects of intravenous crystalloid after aortotomy in swine. Surgery. 1991;110:529–536. Bibliographic Links [Context Link] 3. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Eng J Med. 1994;331:1105–1109. [Context Link] 4. Wiggers CJ. Physiology of Shock. Cambridge: Harvard University Press; 1950;121–146. [Context Link] 5. Schreiber MA, Aoki N, Scott BG, et al. Determinants of mortality in patients with severe blunt head injury. Arch Surg. 2002;137(3):285–290. Ovid Full Text Bibliographic Links [Context Link] 6. Mattox KL, Manigas PA, Moore EE. Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. The USA Multicenter Trial. Ann Surg. 1991;213:482–491. Bibliographic Links [Context Link] 7. Kramer GC, Perron PR, Lindsey DC, et al. Small volume resuscitation with hypertonic saline dextran solution. Surg. 1986;100:239–246. [Context Link] 8. Valet R, Albanese J, Thomachot L, et al. Isovolemic hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med. 2003;31:1683–1687. Ovid Full Text Bibliographic Links [Context Link] 9. Ciesla DJ, Moore EE, Biffl WL, Gonzalez RJ, Silliman CG. Hypertonic saline attenuation of the neutrophil cytotoxic response is reversed upon restoration of normotonicity and reestablished by repeated hypertonic challenge. Surgery. 2001;129:567–575. Bibliographic Links [Context Link] 10. Barron ME, Wilkes MM, Navickis RJ. A systematic review of the comparative safety of colloids. Arch Surg. 2004;139:552–563. Ovid Full Text Bibliographic Links [Context Link] 11. Roberts JS, Bratton SL. Colloid volume expanders: problems, pitfalls and possibilities. Drugs. 1998;55(5):621–630. Buy Now Bibliographic Links [Context Link] 12. Moore EE, Cogbill TH, Jurkovich GJ, et al. Organ injury scaling: spleen and liver (1994 revision). J Trauma. 1995;38:323–324. Ovid Full Text Bibliographic Links [Context Link] 13. Watters JM, Jackson T, Muller PJ, et al. Fluid Resuscitation Increases Inflammatory Response to Traumatic Injury. J Trauma. 2004;57:1378. Ovid Full Text [Context Link] 14. Cohn SM, Crookes BA, Proctor KG. Near-infrared spectroscopy in resuscitation. J Trauma. 2003;54:S199–S202. Ovid Full Text Bibliographic Links [Context Link] 15. Crookes BA, Cohn SM, Bloch S, et al. Can near-infrared spectroscopy identify the severity of shock in trauma patients? J Trauma. 2005;58:806–816. Ovid Full Text Bibliographic Links [Context Link] 16. Chaisson NF, Kirschner RA, Deyo DJ, et al. Near-infrared spectroscopy-guided closed-loop resuscitation of hemorrhage. J Trauma. 2003;54:S183–S192. Ovid Full Text Bibliographic Links [Context Link] 17. Crookes BA, Cohn SM, Burton EA, et al. Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic shock. Surgery 2004;135:662–670. Bibliographic Links [Context Link] 18. Knudson MM, Lee S, Erickson V, et al. Tissue oxygen monitoring during hemorrhagic shock and resuscitation: A comparison of lactated Ringer's solution, hypertonic saline dextran, and HBOC-201. J Trauma. 2003;54:242–252. Ovid Full Text Bibliographic Links [Context Link] 19. Smith GJ. A comparison of several hypertonic solutions for resuscitation of bled sheep. J Surg Res. 1985;9:529–543. [Context Link] 20. Manigas PA, et al. Small volume infusion of 7.5% NaCl in 6% dextran 70 for the treatment of severe hemorrhagic shock in swine. Ann Emerg Med. 1986;15:1131–1137. Bibliographic Links [Context Link] 21. Valeri CR, Crowley JP, Loscalzo J. The red cell transfusion trigger: Has a sin of commission now become a sin of omission? Transfusion. 1998;38:602–608. Bibliographic Links [Context Link] 22. Geerts WH, Code KI, Jay RM, et al. A prospective study of venous thromboembolism after major trauma. N Eng J Med. 1994;331:1601–1606. [Context Link] 23. Gando S, Kameue T, Matsuda N, et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromd Haemost. 2002;88:943–949. [Context Link]

(Resuscitation With Normal Saline (NS) vs. Lactated Ringers (LR) Modulates Hypercoagulability and Leads to Increased Blood Loss in an Uncontrolled Hemorrhagic Shock Swine Model [Original Articles) Kiraly, Laszlo N. MD; Differding, Jerome A. MS; Enomoto, T Miko MD; Sawai, Rebecca S. MD; Muller, Patrick J. MS; Diggs, Brian PhD; Tieu, Brandon H. MD; Englehart, Michael S. MD; Underwood, Samantha MS; Wiesberg, Tracy T. MD; Schreiber, Martin A. MD From the Oregon Health & Science University, Portland, Oregon. Submitted for publication December 20, 2005. Accepted for publication March 14, 2006. This work was supported in its entirety by US Army Medical Research Acquisition Activity Award# W81XWH-04-1-0104. Presented at the 19th Annual Meeting of the Eastern Association for the Surgery of Trauma, January 10–14, 2006, Orlando, Florida. Corresponding Author: Martin A. Schreiber, MD, FACS, Associate Professor of Surgery, Director of Surgical Critical Care, Trauma/Critical Care Section, Oregon Health & Science University, 3181 SW Sam Jackson Road L223A, Portland, OR 97239; email: schreibm@ohsu.edu.] Abstract Background: Lactated ringers (LR) and normal saline (NS) are used interchangeably in many trauma centers. The purpose of this study was to compare the effects of LR and NS on coagulation in an uncontrolled hemorrhagic swine model. We hypothesized resuscitation with LR would produce hypercoagulability. Methods: There were 20 anesthetized swine (35 ± 3 kg) that underwent central venous and arterial catheterization, celiotomy, and splenectomy. After splenectomy blinded study fluid equal to 3 mL per gram of splenic weight was administered. A grade V liver injury was made and animals bled without resuscitation for 30 minutes. Animals were resuscitated with the respective study fluid to, and maintained, at the preinjury MAP until study end. Prothrombin Time (PT), Partial Thromboplastin Time (PTT), and fibrinogen were collected at baseline (0') and study end (120'). Thrombelastography was performed at 0'and postinjury at 30', 60', 90', and 120'. Results: There were no significant baseline group differences in R value, PT, PTT, and fibrinogen. There was no significant difference between baseline and 30 minutes R value with NS (p = 0.17). There was a significant R value reduction from baseline to 30 minutes with LR (p = 0.02). At 60 minutes, R value (p = 0.002) was shorter while alpha angle, maximum amplitude, and clotting index were higher (p < 0.05) in the LR versus the NS group. R value, PT, and PTT were significantly decreased at study end in the LR group compared with the NS group (p < 0.05). Overall blood loss was significantly higher in the NS versus LR group (p = 0.009). Conclusions: This data indicates that resuscitation with LR leads to greater hypercoagulability and less blood loss than resuscitation with NS in uncontrolled hemorrhagic shock. -------------------------------------------------------------------------------- The choice of intravenous fluid for the resuscitation of hemorrhagic shock has been a source of ongoing controversy for over a century. Normal saline (NS) and lactated Ringers (LR) are treated as equivalent resuscitation fluids in many trauma systems. Numerous studies have examined differences in outcomes and parameters in patients receiving a saline solution versus a balanced salt solution. In vitro and in vivo experiments suggest that crystalloid resuscitation may lead to a hypercoagulable state.1–4 The majority of these trials have associated LR with a hypercoagulable state. A recent trial compared Hetastarch in a balanced salt solution, LR, and hetastarch in normal saline in terms of coagulation during surgery.4 The normal saline based hetastarch treated patients were hypocoagulable compared with baseline while the LR treated patients were hypercoagulable. The in vivo experiments have mainly focused on elective surgery patients.1,3–5 In vitro studies usually use blood from healthy volunteers diluted with a set amount of fluid. A study in an intact large animal trauma model has not been previously performed. Given the significant morbidity and mortality of both coagulopathic hemorrhage and thromboembolic disease in trauma patients, further investigation is warranted to assess the impact of resuscitation fluids on the coagulation system. Beyond the hypercoagulable state seen in the setting of LR resuscitation, the use of NS has been associated with a hyperchloremic acidosis that has the potential to affect coagulation. Waters et al. found that in patients undergoing abdominal aortic aneurysm repair, NS resuscitation resulted in the use of significantly more blood products.5 This suggests that NS may have a harmful effect on the coagulation system. The purpose of this study was to compare coagulation parameters after uncontrolled hemorrhage and resuscitation in an animal model and to determine the etiology of the differences seen between LR and NS. This model is intended to represent the prehospital or battlefield scenario. In this setting, surgical control has not been established and the treatment choices are limited to fluid resuscitation. We hypothesized that, in a swine grade V liver injury model, animals resuscitated with LR would become hypercoagulable compared with animals resuscitated with NS. This model offers an excellent reproduction of the massive resuscitation efforts commonly seen in the modern trauma setting. Given the complex interplay of fluid shifts, inflammatory mediators, and coagulation factors this model may offer a more realistic scenario as compared with previous in vivo and in vitro dilution studies. MATERIALS AND METHODS This was a randomized controlled trial using twenty female Yorkshire crossbred pigs. The pigs underwent a 16-hour preoperative fast except for water ad libitum and were preanesthetized with an intramuscular injection of 8 mg/kg Telazol (Fort Dodge Animal Health, Fort Dodge, Ind.). They then underwent oro-tracheal intubation with a 7.0 mm or 7.5 mm endotracheal tube and were placed on mechanical ventilation. Respiratory rate was adjusted to keep pCO2 values between 40 to 50 mm Hg. Anesthesia was maintained using 2% isoflurane in 100% oxygen. An esophageal thermometer was inserted. Animal temperature was controlled utilizing external warming devices. Once the swine were anesthetized, left cervical cut downs were performed and polyethylene catheters were inserted into the common carotid artery and external jugular vein. The arterial catheter was used for continuous blood pressure monitoring and blood sampling. Mean arterial pressure (MAP) and heart rate (HR) were continuously recorded and averaged every 10 seconds using a digital data collection system with a blood pressure analyzer (DigiMed, Louisville, Ky.). The venous line was used for administration of the resuscitation fluids. The animals underwent a midline celiotomy, suprapubic Foley catheter placement, and splenectomy. Splenectomies are performed in swine hemorrhage models because of the spleen's distensibility and the resultant variation in amounts of sequestered blood. The spleen was weighed and, based on randomization, either LR or NS solution was infused to replace three times the spleen weight. The abdomen was than closed with towel clamps. Following a 15-minute stabilization period, the abdomen was opened and residual peritoneal fluid was removed. Preweighed laparotomy pads were placed in both paracolic gutters and the pelvis to facilitate blood collection. A standardized grade V liver injury (injury to a central hepatic vein) was created with a specially designed clamp. The clamp was positioned in the middle of the liver, placing the right hepatic vein, the left hepatic vein, and the portal vein at risk for injury. This protocol is based upon our experience in previous studies of uncontrolled hemorrhagic shock using the grade V liver injury model.6 The time of injury was considered the start time of the two-hour study period. Following 30 minutes of uncontrolled hemorrhage, the initial blood loss, measured by wall suction and the preweighed laparotomy pads, was determined. The abdomen was then closed. We blindly randomized (using a random numbers table) the swine to receive either NS or LR resuscitation at 165 mL/min. This rate is approximately one half the rate delivered by the Level I rapid infuser as the animals were approximately one half the weight of an average human. Resuscitation fluid was administered to achieve and maintain the baseline MAP for 90 minutes postinjury. Upon completion of the 2-hour study period, the abdomen was reopened and the secondary blood loss was determined by adding the volume of intra-abdominal blood to the weight of the intra-abdominal blood clots. After the completion of the study the animals were sacrificed by exsanguination. To ensure comparable injuries between the study groups, we removed the liver and identified the number of hepatic vessels injured. Blood specimens were collected at baseline and every 30 minutes until completion of the 2-hour study. Blood assays included lactate level, arterial blood gases, chemistry panel and hematocrit. Coagulation studies included partial thromboplastin time (PTT), prothrombin time (PT), and fibrinogen. A TEG analyzer (TEG) (Hemoscope Corporation, Niles, Ill.) was used as a test for overall coagulation. This test was performed immediately after blood was removed from the animal and kaolin activation was utilized. The TEG values were measured every 30 minutes. Thrombelastography has been documented to be a more sensitive measure of coagulation disorders as compared with standard coagulation measures.7 Previous studies have documented hypercoagulability in trauma patients using thrombelastography.8,9 Individual parameters of the thrombelastograms (Fig. 1) can detail the cause of coagulopathy. The R value or reaction time represents the time to onset of clot formation. Elongation of the R value signifies a deficiency in coagulation factors. The [alpha] angle represents the rapidity of fibrin buildup and cross-linking. This value is affected by fibrinogen function and to a lesser extent, platelets. The K time is a measure of the speed to reach a certain level of clot strength. K is shortened by increased fibrinogen function and, to a lesser extent, by platelet function, and is prolonged by anticoagulants that affect both. The maximum amplitude (MA) measures the strength of the clot and is affected primarily by platelets but also by fibrinogen. The Clotting Index (CI) is a composite score of coagulation taking into account all of the above values. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 1. Example of TEG tracing. R value or reaction time represents the time to onset of clot formation. The [alpha] value represents the rapidity of fibrin buildup and cross-linking. The K time is a measure of the speed to reach a certain level of clot strength. The MA value is maximum amplitude and measures the strength of the clot. -------------------------------------------------------------------------------- This protocol was approved by the Institutional Animal Care and Use Committee at Oregon Health & Science University. This facility adheres to the National Institutes of Health guidelines for the use of laboratory animals. An independent samples t test was used to compare the means of continuous variables between the two groups. Statistical significance was defined as a p value <0.05. Values within a group were compared using a post hoc analysis of the variance (ANOVA). These values were calculated using SPSS version 13.0 software (SPSS Inc., Chicago, Ill.) and graphs were produced using Microsoft Excel 2003 (Microsoft Inc., Redmond, Wash.). RESULTS Ten animals were randomized to each group. One animal in the NS group died just before completion of the 2 hour study period. All other animals survived. Table 1 shows the mean initial weight, blood pressure, temperature, vessels injured, blood loss and fluid replacement compared between groups. Despite the fact that the number of vessels injured and initial blood loss were similar between groups, the NS group had greater blood loss after resuscitation and required more than twice the volume of resuscitation fluid to achieve and maintain the baseline blood pressure during the 90 minute resuscitation study period. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 1 Baseline and Postinjury Values. Comparison Between NS and LR Groups of Physiologic Parameters -------------------------------------------------------------------------------- The NS group was significantly more acidotic compared with the LR pigs after resuscitation. Figures 2 through 4 detail the trend of laboratory parameters. pH was significantly lower in the NS group 30 minutes after injury until the end of study. Interestingly, at this point of the study, the only difference in treatment between the two groups was the equivalent volumes of splenic replacement fluids. The bicarbonate value and base excess were significantly lower 60 minutes after injury and beyond. The LR group did show an elevation of lactate level compared with the NS group. The elevation of lactate in the LR group was not accompanied by acidosis and it probably reflects the load of Na lactate from the rapid infusion. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 2. pH values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 3. HCO3- and Base Excess values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 4. Lactate values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. -------------------------------------------------------------------------------- Selected laboratory values are displayed in Table 2. The two groups had equivalent hematocrit values at the start of the study. By the end of the study, the NS group had a lower hematocrit. The partial thromboplastin time (PTT) and prothrombin time (PT) were both significantly greater in the NS group compared with the LR group. Fibrinogen was decreased in both groups compared with baseline. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 2 Baseline and End Study Laboratories. Comparison Between NS and LR Groups of Hematologic Laboratory Parameters Drawn at Discrete Time Points -------------------------------------------------------------------------------- Figures 5 through 8 show the R value, alpha angle, MA, and CI of the two groups. All the parameters showed significant changes during the course of the study. At 60 minutes after injury and beyond, the R value and the alpha angle were significantly different in the LR group as compared with the NS group. At 30 minutes after injury and beyond the MA and CI were significantly higher in the LR group. By the end of the study all of the values in the groups were significantly different from baseline with the exception of the alpha angle in the NS group. These results indicate relative hypercoagulability in both groups but significantly more so in the LR group. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 5. TEG R values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value (p< 0.05). The shaded area indicates normal ranges. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 6. TEG Alpha Angle values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value. (p< 0.05) The shaded area indicates normal ranges. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 7. TEG MA values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value. (p< 0.05) The shaded area indicates normal ranges. -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 8. TEG CI values at discrete time intervals after injury in NS and LR groups. * Indicates a significant difference (p< 0.05) between groups at that time interval. # Indicates a significant difference from the baseline value. (p< 0.05) The shaded area indicates normal ranges. -------------------------------------------------------------------------------- DISCUSSION This study evaluated multiple measures of coagulation in a swine model of uncontrolled hemorrhage. There were significant differences between animals that received LR and NS in nearly every marker of coagulation measured. It is important to note that the saline group did not develop a significant hypocoagulable state in terms of the measured parameters. The more significant changes reflected a hypercoagulable state in the LR animals. There were multiple physiologic and chemical differences between the two groups. The NS group received a mean of 10.9 L of fluid compared with 5.2 L in the LR group. This indicates that the saline group may have had a relative coagulation disorder secondary to a dilutional coagulopathy. Theoretically, this should have the most notable effect on the R value as it involves contact activation and fibrin formation. However, a previous in vitro study measured the coagulation effects of LR and hetastarch solutions by simple dilution. In vitro dilution of blood with LR up to 75% resulted in no significant effect on R time.10 There was a significant difference in several TEG parameters at the 30 minute interval. At this point in the study, the only difference between the two groups was the type of splenic replacement fluid. The actual volume of fluids was equivalent. This suggests that the coagulation changes are at least partially explained by the chemical composition of LR versus NS. The acid base status of the groups was another area of significant difference. At 30 minutes, the mean pH of the NS group was significantly lower than the LR group. This difference progressively increased throughout the course of the study. Our laboratory has previously shown that, in this model, resuscitation with NS results in a profound hyperchloremic acidosis.11 Chloride levels were not measured in this experiment. However, as described in Figure 4, lactate levels were not elevated in the NS group. The resultant acidosis likely accounts for the physiologic differences between groups. Acidosis decreases cardiac contractility, and decreases the effectiveness of circulating catecholamines. Subsequent trials in our laboratory that are not yet published have documented a profound vasodilation in NS resuscitated swine. It is likely that increased blood loss during resuscitation combined with systemic vasodilatation resulted in the high fluid requirements seen with the NS animals. Acidosis has been implicated as a contributor to ongoing bleeding in trauma patients.12 The overall mechanism has not been completely elucidated. An in vitro study documented a decrease in FVIIa and FVIIa tissue factor complex.13 Acidosis has been associated with coagulation changes in vivo as well.14 A recent in vivo model examined the independent contribution of acidosis to coagulopathy. The findings suggested that the acidosis caused a decrease in thrombin generation rates reflected as a decrease in the alpha angle of the TEG. The LR group did have a significantly higher alpha value compared with the NS group at 60 minutes. However, at this time point, the NS value was not significantly different from its baseline value. Given the large blood loss in both groups and the significantly higher volume of fluid given to the NS group, the more pronounced hypercoagulable state in the LR group may be affected by relative hemoconcentration. The difference in hematocrit between the LR and NS groups at 120 minutes was significant (p = 0.028). The difference in actual red blood cell concentration contributes to coagulation. Several studies have detailed red blood cell membrane effects on the coagulation cascade. Activation of factor IX by erythrocyte membranes may cause intrinsic coagulation.15 A third notable difference between the groups was the calcium level. Along with volume dilution, the nontrivial amount of calcium in LR most likely explains this difference. At study end, the LR group had a concentration of 1.34 versus 1.22 for the NS group. Calcium is an important cofactor in the coagulation cascade. Though this difference reached statistical significance, the actual clinical relevance of this decrease is unclear. A recent study investigated coagulopathy and hypocalcemia in humans.16 Using citrated blood from healthy volunteers, various concentrations of calcium were added and TEGs were performed. Coagulopathy was only notable at concentrations less than 0.56 mmol/L. Given the small absolute difference, calcium likely does not account for the coagulation changes seen. The total measured blood loss was significantly higher in the NS group suggesting that the differences in coagulation seen were clinically relevant. There is limitation in this measurement as the total intra-abdominal fluid represents both blood and ascites. The NS group presumably had more ascites secondary to higher volumes of crystalloid administered. The relative hypercoagulability seen in both animal groups is likely the result of significant tissue trauma. Following injury tissue factor is exposed, de-encrypted and released into the bloodstream. It then complexes with activated factor VII resulting in activation of factors IX and X.17 Additional mechanisms relate to an imbalance of procoagulant and anticoagulant factors. A study measuring extensive coagulation profiles in critically injured patients found a negative correlation of functional protein C with severity of injury.18 Further studies show a decrease in plasma antithrombin III in the setting of trauma.18,19 These mechanisms combined with post-traumatic inflammation lead to a hypercoagulable state that has been documented in trauma patients early after admission.8,9 We have previously shown, using TEG, that Grade V liver injury without resuscitation results in a hypercoagulable state that is not affected by resuscitation with LR.20 This suggests that the use of LR for resuscitation has minimal effects on the coagulation changes after trauma. Alternatively, NS appears to modulate the post-trauma hypercoagulability by a series of physiologic derangements including acidosis and increased volume requirements. Our study did have limitations in that the volume of fluid given was variable. However, the fluid was given with set resuscitation endpoints. In this way the physiology guided the resuscitation. This algorithm helped recreate the setting of a clinical trauma resuscitation. Therefore, the difference in volume reflects a more realistic scenario. CONCLUSION In a swine model of uncontrolled hemorrhage, resuscitation with NS resulted in modulation of the hypercoagulable state seen after injury and LR resuscitation. This effect most likely relates to acidosis and may be contributed to by the increased volume of fluid given to NS animals. This study suggests that the choice of crystalloid resuscitation has significant effects on coagulation. Administration of LR during resuscitation appears to have no effect on the hypercoagulable state induced by trauma. This hypercoagulable state may reduce bleeding and be protective initially, but may lead to thromboembolic complications later in the course of trauma admission. Resuscitation with NS modulates hypercoagulability after trauma and results in increased fluid requirements. These changes are associated with increased blood loss after injury and uncontrolled hemorrhage. REFERENCES 1. Bergmann H, Blauhut B, Brucke P, Necek S, Vinazzer H. Early influence of acute preoperative haemodilution with human albumin and ringer's lactate on coagulation. Anaesthesist. 1976;25:175–180. Bibliographic Links [Context Link] 2. Dailey SE, Dysart CB, et al. An in vitro study comparing the effects of Hextend, Hespan, normal saline, and lactated ringer's solution on thrombelastography and the activated partial thromboplastin time. J Cardiothorac Vasc Anesth. 2005;19:358–336. Bibliographic Links [Context Link] 3. Ruttmann TG, James MF, Viljoen JF. Haemodilution induces a hypercoagulable state. Br J Anaesth. 1996;76:412–414. Bibliographic Links [Context Link] 4. Martin G, Bennett-Guerrero E, Wakeling H, et al. A prospective, randomized comparison of thromboelastographic coagulation profile in patients receiving lactated Ringer's solution, 6% hetastarch in a balanced-saline vehicle, or 6% hetastarch in saline during major surgery. J Cardiothorac Vasc Anesth. 2002;16:441–446. Bibliographic Links [Context Link] 5. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer's solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 2001;93:817–822. Ovid Full Text Bibliographic Links [Context Link] 6. Schreiber MA, Holcomb JB, et al. The effect of recombinant factor VIIa on noncoagulopathic pigs with grade V liver injuries. J Am Coll Surg. 2003;196:691–697. Bibliographic Links [Context Link] 7. Zuckerman L, Cohen E, Vagher JP, Woodward E, Caprini JA. Comparison of thrombelastography with common coagulation tests. Thromb Haemst. 1981;46:752–756. [Context Link] 8. Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma. 1997;42:716–720. Ovid Full Text Bibliographic Links [Context Link] 9. Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma. 2005;58:475–480. Ovid Full Text Bibliographic Links [Context Link] 10. Roche AM, James MF, Grocott MP, Mythen MG. Coagulation effects of in vitro serial haemodilution with a balanced electrolyte hetastarch solution compared with a saline-based hetastarch solution and lactated Ringer's solution. Anaesthesia. 2002;57:950–955. Buy Now Bibliographic Links [Context Link] 11. Todd SR, Malinoski D, Schreiber MA. Lactated Ringer's is Superior to Normal Saline in Uncontrolled Hemorrhagic Shock. Shock. 2003;19(suppl):169. [Context Link] 12. Moore EE. Staged laparotomy for the hypothermia, acidosis, and coagulopathy syndrome. Am J Surg. 1996;172:405–10. Bibliographic Links [Context Link] 13. Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. J Trauma. 2003;55:886–891. Ovid Full Text Bibliographic Links [Context Link] 14. Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, Holcomb JB. Independent contributions of hypothermia and acidosis to coagulopathy in swine. J Trauma. 2005;58:1002–1009. Ovid Full Text Bibliographic Links [Context Link] 15. Iwata H, Kaibara M. Activation of factor IX by erythrocyte membranes causes intrinsic coagulation. Blood Coagulation and Fibrinolysis. 2002;13:489–496. [Context Link] 16. James MF, Roche AM. Dose-response relationship between plasma ionized calcium concentration and thrombelastography. J Cardiothorac Vasc Anesth. 2004;18:581–586. Bibliographic Links [Context Link] 17. Eilertsen KE, Osterud B. Tissue factor (patho)physiology and cellular biology. Blood Coagul Fibrinolysis. 2004;15:521–538. Ovid Full Text Bibliographic Links [Context Link] 18. Engelman DT, Gabram SG, Allen L, Ens GE, Jacobs LM. Hypercoagulability following multiple trauma. World J Surg. 1996;20:5–10. Bibliographic Links [Context Link] 19. Owings JT, Bagley M, Gosselin R, Romac D, Disbrow E. Effect of critical injury on plasma antithrombin activity: low antithrombin levels are associated with thromboembolic complications. J Trauma. 1996;41:396–405. Ovid Full Text Bibliographic Links [Context Link] 20. Todd SR, Malinoski D, Schreiber MA. Hextend attenuates the hypercoagulability following severe liver injury in swine. J Trauma. 2004;56:226. [Context Link] DISCUSSION Dr. Stephen M. Cohn (San Antonio, Texas): In this investigation, the authors have expanded their work focusing on the effects of various resuscitation fluids upon changes in coagulation following trauma. In this experiment, pigs were resuscitated to baseline blood pressure with either lactated ringer's or normal saline following 30 minutes of uncontrolled hemorrhage from a severe liver injury. The animals receiving lactated ringer's developed a hypercoagulable state, noted by a reduction in PT, PTT, and TEG values. Swine infused with normal saline required much greater fluid volumes to achieve baseline vital signs and did not become hypercoagulable. I have a few questions for the authors. Why did the authors choose to resuscitate animals to baseline parameters, rather than, say, a mean pressure of 60? Resuscitation to lower target blood pressure would more closely replicate the typical clinical scenario and might have impacted on outcome measures, such as the volume of fluid required, the degree of blood loss and the subsequent coagulopathy noted. What is the impact of the type of anesthesia administered on this animal hemorrhage model? Have the authors tried other methods of anesthesia with similar results? Who ran the TEG analysis? And how did hypothermia impact on the results? This is a very user-dependent test. In fact, that's, I think, one of the major reasons why we have not applied it clinically in the trauma scenario. Why did the normal saline group receive twice the volume of resuscitative fluid? Were these animals actually more severely injured or more ill at baseline? The volume of resuscitative fluid may have diluted out the effects of various coagulation factors as well as impacted on platelet aggregation. How can we be assured that the impact of fluid volume was not the primary factor causing differences in coagulation between lactated ringer's and normal saline rather than the type of fluid itself? Another interesting question for the authors is what changes in coagulation would you expect to see over time in a hemorrhage model like this one? It would appear that becoming hypercoagulable after injury would lead to a survival advantage. Do you have survival data? We currently routinely use normal saline for the resuscitation of trauma patients in the setting of head injury. Do the authors think that normal saline is dangerous? Should we avoid this in clinical care? Dr. L. N. Kiraly (Portland, Oregon): In response to your first question, why we resuscitated to a MAP of 60, our previous models have resuscitated to a baseline blood pressure. We were varying one element of this model. However, the mean pressures of these animals were a MAP of 70, so we were not going to the point of extreme resuscitation. The pigs do have a variable baseline blood pressure. And we were trying to keep things consistent from that point. Next, in terms of anesthesia, we actually have developed a model, which was completed this summer, of a total IV anesthesia regimen and compared it to the isoflurane regimen. Preliminary results indicate that the isoflurane Does have a vaso dilatory response and results in a lower blood pressure. Next, who ran the TEGs? We had an overwhelming majority of the TEGs run by a skilled technician that has done hundreds of these TEGs. In terms of hypothermia, these animals were actively externally re-warmed to keep their temperature within a range of 36 to 38 degrees, so hypothermia was not an issue in these patients. The TEG machine can account for that by setting a different temperature if so desired. Next, why they required different volumes of fluid? We have done some subsequent analysis and found that the normal saline group does have a profound vasodilatory response, making it more difficult for them to be resuscitated to their baseline MAPs. In terms of the question of why is this alone responsible for the coagulation differences, as I mentioned, previous in vitro studies haven't shown this from just a simple dilution of blood products with crystalloid fluid in terms of the TEG values that we found. Furthermore, another point is just with acidosis alone, a previous swine model by another group showed TEG changes similar to ours. That leads me to believe that acidosis is more responsible rather than just simple volume. The next question is, is this clinically relevant? Do we have survival data? We plan to expand our animal model to a survival model to really investigate how these animals will do in the days following a trauma like this. But the clinically relevant point to take from this study is the blood loss, which does seem to be increased in the normal saline group. Finally, in terms of head injury, based on this study, we see the normal saline animals required much more resuscitation fluid. They had increased bleeding and were more acidotic and made it difficult to maintain blood pressure. I think all these argue against using normal saline in the setting of head injuries based on this study. We have alternatives such as the judicious use of hypertonic saline or diuretics. But I have not seen evidence saying that the LR would be harmful in the setting of a head trauma. Dr. Michael F. Rotondo (Greenville, North Carolina): I have one question from the podium. Your acid base status, you sort of suggested that animals develop an acidosis, yet they were getting a lot of normal saline. Is this a hyperchloremic acidosis, or do you have any lactate levels to suggest what ideology this acidosis is? Dr. L. N. Kiraly: From this study, we didn't gather the chloride levels. We had a previous model that used normal saline and showed a similar acidosis, and it was clearly a hyperchloremic acidosis. Dr. Ken Proctor (Miami, Florida): Did you control Pco2? Dr. L. N. Kiraly: Pco2 was controlled within a range of 40 to 50, and we did that based on the ABGs we did every half hour. Dr. Ken Proctor: So why, then, as the Ph was falling in the normal saline group, didn't you hyperventilate? Dr. L. N. Kiraly: The method we used, we based our ventilatory maneuvers based on the Pco2, not the pH.

(Prehospital HBOC-201 After Traumatic Brain Injury and Hemorrhagic Shock in Swine [Original Articles) Patel, Mayur B. MD; Feinstein, Ara J. MD, MPH; Saenz, Alvaro D. MD; Majetschak, Matthias MD, PhD; Proctor, Kenneth G. PhD From the Divisions of Trauma and Surgical Critical Care (M.B.P., A.J.F., M.M., K.G.P.), DeWitt Daughtry Family Department of Surgery; Department of Pathology (A.D.S.), University of Miami Miller School of Medicine, Miami, Florida. Submitted for publication December 18, 2005. Accepted for publication March 1, 2006. Supported by Grants: #N000140210339, #N000140210035 from the Office of Naval Research, and #T32 GM08749-01 from the NIH-GMS. Presented at the 19th Annual Meeting of the Eastern Association for the Surgery of Trauma, January 10–14, 2006, Orlando, Florida, and Winner of the Raymond H. Alexander Award. Address for reprints: Kenneth G. Proctor, PhD, Divisions of Trauma and Surgical Critical Care, Daughtry Family Department of Surgery, University of Miami School of Medicine, Ryder Trauma Center, 1800 NW 10th Ave. Miami, FL 33136; email: kproctor@miami.edu.] Abstract Background: Data are limited on the actions of hemoglobin based oxygen carriers (HBOCs) after traumatic brain injury (TBI). This study evaluates neurotoxicity, vasoactivity, cardiac toxicity, and inflammatory activity of HBOC-201 (Biopure, Cambridge, Mass.) resuscitation in a TBI model. Methods: Swine received TBI and hemorrhage. After 30 minutes, resuscitation was initiated with 10 mL/kg normal saline (NS), followed by either HBOC-201 (6 mL/kg, n = 10) or NS control (n = 10). Supplemental NS was administered to both groups to maintain mean arterial pressure (MAP) >60 mm Hg until 60 minutes, and to maintain cerebral perfusion pressure (CPP) >70 mm Hg from 60 to 300 minutes. The control group received mannitol (1 g/kg) and blood (10 mL/kg) at 90 minutes and half (n = 5) received CPP directed phenylephrine (PE) therapy after 120 minutes. Serum cytokines were measured with ELISA and coagulation was evaluated with thromboelastography. Brains were harvested for neuropathology. Results: With HBOC administration, MAP, CPP, and brain tissue Po2 were restored within 30 minutes and maintained until 300 minutes. Clot strength and fibrin formation were maintained and 9/10 successfully extubated. In contrast, with control, MAP and brain tissue Po2 did not correct until 120 minutes, after mannitol, transfusion and 40% more crystalloid. Furthermore, without PE, CPP did not reach target and 0/5 could be extubated. Lactate, heart rate, cardiac output, mixed venous oxygenation, muscle oxygenation, serum cytokines, and histology did not differ between groups. Conclusions: After TBI, a single HBOC-201 bolus with minimal supplements provided rapid resuscitation, while maintaining CPP and improving brain oxygenation, without causing cardiac dysfunction, coagulopathy, cytokine release, or brain structural changes. -------------------------------------------------------------------------------- Hemoglobin based oxygen carriers (HBOCs) are currently being tested in US Food and Drug Administration (FDA) approved phase III clinical trials in several patient populations, including urban trauma patients with major blood loss.1–5 Efficacy endpoints, such as mortality, transfusion avoidance, or organ perfusion, are key issues in the design and interpretation of all of these trials.6 However, safety remains the major obstacle to FDA approval, with specific concerns related to neurotoxicity, vasoactivity, cardiac toxicity, and proinflammatory activity.7 Current HBOC trials exclude patients sustaining severe TBI, likely because of limited preclinical and animal data. Interestingly, this is the population that stands to substantially benefit with HBOC prehospital resuscitation, as rapid reversal of hypotension and cerebral ischemia represents the cornerstone of therapy against secondary brain injury.8 After fluid percussion TBI and hemorrhagic shock in swine, our group showed that DCLHb (Baxter Healthcare Corp., Round Lake, Ill.) improved cerebral perfusion pressure (CPP) and cerebral oxygen delivery, but had undesired vasoactivity.9,10 We also showed that HBOC-301 (Oxyglobin, Biopure Inc., Cambridge, Mass.) improved cerebrovascular and neurologic function.11 Others have shown Hemolink (Hemosol, Toronto, Ontario) maintains cerebral oxygenation in a model of severe isovolemic hemodilution.12,13 However, DCLHb and Hemolink are no longer available and Oxyglobin has not been developed for use in humans. HBOC-201 or Hemopure (Biopure Inc., Cambridge, Mass.) is in advanced stages of development and it rapidly corrects brain tissue oxygenation (PbtO2) in a non-TBI hemorrhagic swine model.14,15 However, neither HBOC-201 nor any current generation HBOC in phase III clinical trials has been thoroughly characterized after TBI. To fill this gap, we evaluated the neurotoxicity, vasoactivity, cardiac toxicity, and pro-inflammatory actions after resuscitation with HBOC-201 in a simulated “prehospital setting” relative to a control group, which incorporated standard neurotrauma care, including mean arterial pressure (MAP) and CPP management, blood transfusion, mannitol, and ± phenylephrine (PE) pressor therapy. Utilizing a well characterized and clinically relevant swine model of TBI and controlled hemorrhagic shock, the hypothesis was that the safety of prehospital HBOC resuscitation was equivalent, or superior, to standard neurotrauma care. MATERIALS AND METHODS Animal Preparation and Physiologic Endpoints This protocol was approved by the University of Miami Animal Care and Use Committee. All animals in this study were handled according to the Guide of the Care and Use of Laboratory Animals. Twenty-six farm-raised cross-bred swine of both genders (25–32 kg) were fasted overnight. Anesthesia was induced with 10 mg/kg intramuscular ketamine and 1 mg/kg intramuscular xylazine. After orotracheal intubation, anesthesia was maintained with 10 mg/kg/hr, 0.25 mg/kg/hr, and 50 µg/kg/hr of intravenous ketamine, xylazine, and fentanyl, respectively. Mechanical ventilation (Portable Adult Ventilator Model 754; Impact Systems, West Caldwell, N.J.) consisted of tidal volumes of 10 mL/kg, rates adjusted to maintain Paco2 of 40 mm Hg, fraction of inspired oxygen (FiO2) at 0.4, unless otherwise specified, and positive end expiratory pressure of 3 cm H2O. All surgical sites were cleansed with betadine, and subsequently closed with a continuous stitch. Bilateral external jugular veins were accessed with 8-Fr introducer catheters for fluid administration and pulmonary artery catheter placement, respectively. An 8-Fr introducer catheter was placed in the right femoral artery for continuous arterial pressure monitoring and blood sampling. Cardiorespiratory status, pulse oximetry, capnography, MAP, and pulmonary artery pressure (PAP) were continuously monitored (Zoll M-Series Defibrillator Monitor Pacemaker, Chelmsford, Mass.). Cardiac output and mixed venous oxygen saturation (SVO2) were continuously monitored (Baxter CCO Swan-Ganz catheter/Vigilance Monitor; Edwards Lifesciences, Irvine, Calif.). Muscle tissue oxygen saturation was measured using a near infrared spectroscopy probe (InSpectra Tissue Spectrometer; Hutchinson Technologies, Inc., Hutchinson, Minn.) placed on the surface of the left hind limb, as previously described.16 A suprapubic cystostomy was made for Foley catheter placement and monitoring urine output. A heating blanket was used intermittently to maintain core temperature between 36°C and 39°C throughout the experiments. A 1-cm craniotomy was made 1 cm left lateral of the bregma on the coronal suture. A hollow bolt was attached flush with the unbroken surface of the dura for subsequent fluid percussion delivery. Two cm anterior to the hollow bolt, on the contralateral side, another small craniotomy was made to introduce a Camino bolt for introduction of a fiberoptic intracranial pressure (ICP) transducer, a temperature electrode, and an intraparenchymal PbtO2 electrode (all products; Integra Neurosciences, Kiel-Mielkendorf, Germany). Experimental Design After a 60 minutes postsurgery stabilization period, baseline data were collected for 30 minutes before injury. FiO2 was reduced to 0.21 for 15 minutes before injury and remained at this level until 30 minutes after injury. At time zero, the injury was delivered by standardized fluid percussion TBI (~10 msec pulse at 6–8 atm) followed immediately by an arterial hemorrhage to a MAP of 20 mm Hg. The shed blood was stored in sterile plastic bags (CPDA-1 whole blood collection bag; Baxter Healthcare Corp.). After 30 minutes, FiO2 was increased to 0.40 and 10 mL/kg bolus of normal saline (NS) was administered to simulate initial prehospital care. All groups then underwent several sequential resuscitation phases: “prehospital” (t = 30–40 minutes), “emergency room” (ER, t = 40–60 minutes), and “intensive care unit” (ICU, t = 60–300 minutes). The experimental design is outlined in Figure 1. In the prehospital and ER periods, the goal MAP was >60 mm Hg. In the ICU period, the goal CPP was >70 mm Hg. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 1. Resuscitation scheme after TBI and hemorrhage (shock) in swine. NS, normal saline; PE, phenylephrine; HBOC, HBOC-201; ICP, intracranial pressure; CPP, cerebral perfusion pressure. Resuscitation phases are prehospital, emergency room (ER), and intensive care unit (ICU). -------------------------------------------------------------------------------- At 300 minutes, if ICP <20, there was a 60 minutes extubation trial. During the extubation period, anesthesia and mechanical ventilation were discontinued sequentially, if tolerated. Those animals maintaining arterial oxygen saturation >90% were extubated. After the initial bolus of 10 mL/kg NS, the test group (n = 10) received a prehospital bolus HBOC-201 (6 mL/kg) followed by supplemental NS to maintain MAP >60 mm Hg until 90 minutes and CPP >70 mm Hg thereafter. This HBOC-201 dose was shown to be effective in other prehospital models of resuscitation.14,15 After the initial bolus of 10 mL/kg NS, the control group (n = 10) received NS during prehospital care, ER, and ICU periods to the same MAP and CPP targets. Within the ICU phase (t = 90 minutes), this group received a 10 mL/kg transfusion of autologous shed blood, as well as 1 g/kg intravenous bolus of mannitol. After 120 minutes, half of this group (n = 5), received phenylephrine (PE, 0.1 mg/mL) therapy titrated to maintain CPP >70 mm Hg. Supplemental NS was withheld, unless central venous pressure <10 mm Hg. The HBOC group did not receive autologous shed blood, mannitol, or PE. Cerebrovascular reactivity to CO2 was evaluated at baseline, 125, 185, and 245 minutes post TBI. This technique has been previously described in detail.17–19 During the CO2 challenges, inhaled CO2 was maintained at 10% for 10 minutes, while FiO2 was maintained at 0.40. The magnitude of the CO2-evoked ICP and PbtO2 changes varies with cerebral compliance and vascular reactivity in animals 9,11,17–19 and patients.20 Other Outcome Variables In addition to the physiologic data described above, arterial blood gases and electrolytes (Nova Stat Ultra; Nova Biomedical Corp., Waltham, Mass.) and complete leukocyte counts (Abbott Cell Dyne; Abbott Laboratories, Abbott Park, Ill.) were serially measured. Cytokine assays were performed by collecting serum at baseline, 30, 90, 150, 240, and 300 minutes. Serum TNF-[alpha] and IL-6 were quantified using porcine ELISA kits (R&D systems, Minneapolis, Minn.). Blood coagulation parameters were evaluated by thrombelastography (TEG Analyzer and TEG Analytical Software, Hemoscope Corp., Skokie, Ill.), as we previously described using native whole blood samples.19 Briefly, the R time is the period of time from initiation of the test to initial fibrin formation. The K time is measured from the beginning of clot formation until the amplitude of the TEG reaches 20 mm, and represents the dynamics of clot formation. The alpha angle represents the kinetics of fibrin build up and cross-linking. The maximum amplitude (MA) reflects clot strength. Finally, at the end of observation, brains were fixed in situ with 10% formalin via retrograde perfusion through bilateral internal jugular veins, and subsequently stored in 10% formalin. Gross pathology was noted before sectioning and staining with hemotoxylin and eosin with luxol fast blue. The sections of the brain specimens of each animal were screened by an experienced pathologist unaware of the identity and fate of each animal. A qualitative analysis of ischemic changes in uninjured and injured frontal-parietal region was completed. Statistics Data are expressed as mean ± SEM. Between-group comparisons were conducted with ANOVA and post hoc protected least significant difference analyses calculated with SPSS for Windows release 13.0 (Chicago, Ill.). All findings were considered statistically significant at the 95% confidence interval (p < 0.05, two-tailed). Categorical variables were analyzed using the [chi]2 test. RESULTS In baseline preinjury conditions, all physiologic variables were similar between the groups. Before resuscitation group assignment, there were six deaths during the 30 minutes shock period (Fig. 1). The hemorrhage volume to maintain a MAP of 20 mm Hg for 30 minutes (858 ± 39 and 895 ± 36 mm Hg) and the resultant lactate levels (9.4 ± 0.8 and 8.8 ± 0.8 mmol/L) were similar for the control and HBOC groups, respectively. There were no between group differences for any measured variable until the time of resuscitation. Neurotoxicity Upon resuscitation with HBOC, CPP was maintained at target levels throughout the observation period, except during the CO2 challenges. In contrast, in the control group, it was impossible to meet the CPP target with NS (max. flow rate [almost equal to]4 L/h), mannitol (1 g/kg), and autologous blood transfusion (10 mL/kg), because of significantly increased ICP. After 120 minutes, in those that received PE, NS requirements ceased and ICP decreased to HBOC group levels, while CPP was maintained (Fig. 2, top and middle). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 2. Intracranial pressure (ICP, top); cerebral perfusion pressure (CPP, middle); brain tissue oxygenation (PbtO2, bottom). CONTROL, normal saline + mannitol + blood group; CONTROL + PE, normal saline + mannitol + blood + phenylephrine group; HBOC, HBOC-201 group; CO2 represent 10% carbon dioxide challenges assessing cerebrovascular reactivity. In HBOC animals, CPP and brain tissue oxygenation corrected within 30 minutes. ICP, CPP, and brain tissue oxygenation were similar between HBOC and CONTROL + PE at 300 minutes. Cerebrovascular reactivity was higher in CONTROL + PE during all challenges. * p < 0.05 HBOC versus CONTROL, [psi] p < 0.05 CONTROL versus CONTROL + PE, [zeta] p < 0.05 CONTROL + PE versus HBOC. -------------------------------------------------------------------------------- With HBOC, PbtO2 was increased to baseline levels within 30 minutes after TBI. In contrast, control group PbtO2 did not approach baseline levels until 120 minutes after TBI, with restoration to baseline only after PE administration. At 300 minutes, PbtO2 remained significantly higher with HBOC than with NS alone. During the CO2 challenges, PE increased cerebrovascular reactivity compared with the other groups (Fig. 2, bottom). At 330 minutes, 0/5 control animals met criteria to extubate, while 9/10 HBOC and 5/5 control + PE animals had ICP <20 mm Hg. These animals breathed spontaneously on room air, maintained oxygen saturation >90%, and maintained their airway postextubation (p < 0.001, [chi]2). Gross pathologic changes included subarachnoid hemorrhage. Histopathological changes included focal bilateral cortical ischemic changes, but there were no obvious treatment related differences at the site of injury or in the cortex (Fig. 3). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 3. Neuropathology of brain cortex near site of fluid percussion injury (200× magnification). Normal porcine brain (upper left), HBOC animal (upper right), control (lower left), and control + phenylephrine (lower right). Compared with normal porcine brain, all groups had focal areas of acute ischemic changes including neurons with eosinophilic cytoplasm and nuclear pyknosis (arrows). No differences were noted between groups. -------------------------------------------------------------------------------- Vasoactivity With HBOC administration, MAP corrected to baseline levels within 30 minutes of resuscitation (60 minutes post-TBI). During this time, MAP was significantly higher with HBOC than in the control group (Fig. 4, top). Furthermore, less total fluid was required to reach this goal (Fig. 4, bottom). In contrast, baseline MAP was not achieved in the control group until 120 minutes post-TBI, even though more NS and a blood transfusion were administered. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 4. MAP, top. Cumulative intravenous fluid (IVF) requirements, bottom. CONTROL, normal saline + mannitol + blood group; CONTROL + PE, normal saline + mannitol + blood + phenylephrine group; HBOC, HBOC-201 group. MAP was rapidly restored in HBOC group by 60 minutes, while cumulative IVF requirements were lowest. After 120 minutes, all groups maintained MAP >60 mm Hg (except during CO2 challenges). * p < 0.05 HBOC versus CONTROL, [psi] p < 0.05 CONTROL versus CONTROL + PE, [zeta] p < 0.05 CONTROL + PE versus HBOC. -------------------------------------------------------------------------------- Cardiopulmonary Toxicity By the end of the observation period, there were no differences in arterial blood gases or electrolytes (data not shown), however pH decreased in the control group (Table 1). Other physiologic variables, such as heart rate, cardiac output, calculated stroke volume, and SVO2 did not differ significantly between groups. But, central venous pressure was lower in the HBOC and control + PE group. All animals maintained urine output, but there was an osmotic diuresis in the two control groups secondary to the bolus of mannitol at 90 minutes. End organ perfusion as assessed muscle tissue oxygenation and lactate clearance was similar between groups (Table 1). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 1 Physiological Variables at 300 minutes -------------------------------------------------------------------------------- By 180 minutes, peak inspiratory pressure was significantly increased in the control group, compared with the control + PE and HBOC groups. Lung function continued to deteriorate in the control group and by 300 minutes, there was a corresponding decrease in arterial Po2 (Fig. 5). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 5. Peak inspiratory pressure, top, and pulmonary artery pressure, bottom. CONTROL, normal saline + mannitol + blood group; CONTROL + PE, normal saline + mannitol + blood + phenylephrine group; HBOC, HBOC-201 group. The CONTROL group experienced high PIP and PAP by 300 minutes, while HBOC and CONTROL + PE group PIPs and PAPs were similar at the experiment's conclusion. * p < 0.05 HBOC versus CONTROL, [psi] p < 0.05 CONTROL versus CONTROL + PE, [zeta] p < 0.05 CONTROL + PE versus HBOC. -------------------------------------------------------------------------------- Proinflammatory Toxicities In baseline conditions, TEG ranges were as follows: R time, 11.6 to 28.1 minute; K, 2.3 to 18.8 minutes; alpha angle, 14.3 to 54.4 degrees; MA, 41.3 to 73.3 mm. There were no significant differences between groups. Figure 6 shows these coagulation parameters, expressed as % baseline. By 60 minutes post-TBI, time to fibrin formation, as reflected by R time, declined >20% in all groups. At 300 minutes, this R time decrease was sustained and significant with HBOC, compared with control, though not with control + PE. Clot strength, as reflected by MA, was significantly depressed 60 minutes post TBI in the two control groups, and remained depressed at 300 minutes post-TBI without pressor. Control + PE restored MA toward baseline levels. With HBOC, there was no change in MA at any time-point. In all groups, K decreased by 25% postinjury and remained depressed, while [alpha]-angle increased. -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 6. Coagulation parameters measured by thromboelastography at baseline and 60 and 300 minutes post-TBI. R time is the period from initiation of the test to the initial fibrin formation; K time is the period that represents the dynamics of clot formation; [alpha]-angle represents the kinetics of fibrin buildup and cross-linking; maximum amplitude (MA) reflects clot strength; CONTROL, normal saline + mannitol + blood group; CONTROL + PE, normal saline + mannitol + blood + phenylephrine group; HBOC, HBOC-201 group. Fibrin formation was quicker in all groups immediately after injury; however, HBOC-201 treated animals maintained this heightened activity postinjury. Clot strength was maintained in HBOC animals. * p < 0.05 HBOC versus CONTROL, [psi] p < 0.05 CONTROL versus CONTROL + PE, [zeta] p < 0.05 CONTROL + PE versus HBOC. -------------------------------------------------------------------------------- In baseline conditions serum TNF-[alpha] ranged from 0 to 978 pg/mL and IL-6 ranged from 0 to 173 pg/mL. TNF-[alpha] and IL-6 (expressed as % baseline) showed no differences between groups over time (Fig. 7). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Fig. 7. Serum TNF-[alpha] and IL-6 levels, expressed as percent baseline. CONTROL, normal saline + mannitol + blood group; CONTROL + PE, normal saline + mannitol + blood + phenylephrine group; HBOC, HBOC-201 group. There were no differences between groups. -------------------------------------------------------------------------------- White blood cell counts and platelet levels did not differ between groups at any time point before or after injury (Table 2). -------------------------------------------------------------------------------- [Help with image viewing] [Email Jumpstart To Image] Table 2 White Blood Cell and Platelet Counts -------------------------------------------------------------------------------- DISCUSSION No previous studies have compared the neurotoxicity, vasoactivity, cardiac toxicity, and proinflammatory actions of HBOC-201 versus a control group, which incorporated standard neurotrauma care, including MAP and CPP management, blood transfusion, mannitol, and ± pressor therapy. There are several new findings from this study. First, there was no evidence of HBOC-associated neurotoxicity. This is based on the observations that an initial bolus of HBOC-201 in simulated prehospital conditions provided early rapid correction of CPP and PbtO2 while limiting ICP rise (Fig 2). Early extubation was possible without any obvious gross or histologic evidence of pathology, relative to control (Fig. 3). Second, there was no evidence of HBOC-associated vasotoxicity or functional cardiac toxicity. MAP corrected more rapidly with HBOC, but there was no evidence that this early pressor action was harmful. Cardiac output and heart rate were similar between groups (Table 1), which suggests there was no cardiac toxicity associated with HBOC, per se. It should be emphasized that in the control group, without pressor, there were progressive rises in preload and right ventricular afterload, without any increases in stroke volume; this indicates that cardiac performance was compromised within that group (Table 1 and Fig. 5). This is noteworthy because the same pattern was not observed with HBOC or after pressor use in the control animals. Third, there was no evidence for an HBOC-evoked proinflammatory condition. As reflected by changes in coagulation parameters, platelet levels, serum cytokine levels, or leukocyte counts. Fibrin formation was quicker in all groups immediately after injury, indicating a trauma-induced hypercoagulable state. With HBOC-201 and pressor use in controls, this heightened activity was maintained postinjury. Clot strength was maintained in HBOC animals (Fig. 6), and returned to baseline levels in pressor treated animals. No significant changes in serum cytokine levels, platelet levels or leukocyte counts were noted between groups (Fig. 7 and Table 2). Overall, these data suggest that HBOC was both safe and effective when used for the early resuscitation after TBI, at least in these unique model conditions. It provided equivalent outcome compared with a standard of care group that included maximal crystalloid, mannitol, transfusion, and pressor therapy. Obviously in field situations and during transport, a single bolus of HBOC would offer a major logistic advantage, because these unlimited resources would not be available. Even with unlimited resources, HBOC use after TBI could decrease manpower and/or intensive care requirements. Critique There are at least five elements of the experimental design that might limit the practical application of these observations to the clinical situation. First, a single dose of HBOC was administered at a fixed time after a well-defined injury in an anesthetized, mechanically ventilated animal. The outcomes might have differed with various model manipulations, such as providing an HBOC only resuscitation, changing HBOC dose, using uncontrolled hemorrhage with TBI, using a different multisystem trauma model, and/or altering anesthesia (ketamine contraindicated in head injury). Furthermore, in these model conditions, the physiologic changes in the control group may have been somewhat fluid dependent. Immediately upon resuscitation, the control group entered an inescapable cycle where hypotension prompted a flood of fluid administration that resulted in increased third spacing and increases in peak inspiratory pressure and ICP.17–19 By 120 minutes, when MAP was finally restored to baseline levels in this group, ICP had been elevated so much that the CPP goal could never be achieved with fluid alone, plus an autologous blood transfusion, plus mannitol. So, to add a level of clinical relevance, we added pressor management after 120 minutes, which resulted in meeting the CPP goal and in decreasing ICP by limiting fluid requirements.17 The bottom line is that the treatment differences observed in this present study could be model specific. Second, the observation period was relatively short and the neurologic endpoints were primitive. One criterion was extubation at 6 hour, as a surrogate for neurologic outcome. More than likely, this reflected a difference in fluid shifts between pulmonary, neurologic, and other compartments, allowing early extubation. An extended observation period would allow more definitive conclusions regarding the neurologic benefit of any one therapy. Another neurologic criteria was brain oxygenation, which was higher during the immediate postinjury period with HBOC-201, however, it is recognized that a single point measurement of PbtO2 reflects local, but not regional or global oxygenation. Long term studies addressing neurologic outcome, as well as injured, penumbral, and global cerebral blood flow, are necessary to make more definitive statements about the potential benefits of HBOC after TBI. Third, this study provides no new information on the mechanism of action of HBOC after trauma. The rapid increase in MAP after HBOC was probably partly because of its vasoactivity,21 which is likely NO mediated,22 though other mechanisms may exist.23 No adverse vasoactivity and/or functional cardiac toxicity related to HBOC-201 was observed in this model, but this may be a dose- or species-related phenomenon. In this study, preload, afterload, stroke volume, and heart rate, were measured to assess myocardial performance. Echocardiography would have provided more functional data on cardiac toxicity. Fourth, a proinflammatory condition was assessed with changes in coagulation, cytokine levels, and complete leukocyte counts. None of these measurements are specific. Furthermore, TEG is not routinely clinically used, as are standard tests of coagulation, such as prothrombin time, partial thromboplastin time, fibrinogen, and d-dimer. The cytokine levels were highly variable, so there is a possibility that a proinflammatory condition was present, but was not detected with these measurements. Fifth, the large volume of NS, especially, in the control and control + PE groups, likely caused a hyperchloremic metabolic acidosis, although we did not measure chloride ions. This difference in pH could have altered every parameter we measured, including all neurologic, cardiopulmonary, inflammatory, and coagulation measurements. However, this lower pH in the control groups would have left-shifted the oxyhemoglobin dissociation curve, possibly artificially elevating PbtO2 in the controls. Despite these major limitations in the experimental design, the basic observations are consistent with the idea that HBOCs are not inert oxygen carriers, but rather pharmacologic agents with systemic effects that can ameliorate certain patho-physiologic conditions. Comparison to Previous Studies HBOCs have variable results in models of neurologic injury, such as cerebral ischemia,24 subarachnoid hemorrhage,25,26 and TBI.9–11,27 In general local PbtO2 is improved in non-TBI models, as mentioned previously.13–15 Also, Ortegon demonstrated HBOC-201 to be nontoxic to neuronal cells in culture.28 Our model indicates that HBOC-201 rapidly increases and sustains PbtO2 at supraphysiologic levels without histopathologic alterations. Despite the contraindication of pressors during resuscitation after hemorrhagic shock, there is recent data suggesting pressor utility in this scenario.29,30 Furthermore, vasoactive HBOCs may be particularly useful after TBI, where continued episodes of hypotension and hypoxia could lead to secondary brain injury. Our group has demonstrated pressor utility for resuscitation after TBI and hemorrhagic shock in swine, especially if combined with moderate fluid therapy.19,31 After resuscitation from chest trauma, we evaluated the actions of four different HBOCs, all of which reduced fluid requirements and increased right and left ventricular afterload against saline. These actions compromised an already marginal cardiac performance. All of these compounds were eventually removed from commercial development.32 The unacceptable pressor action of early, first generation HBOCs probably depended in part on the dose and route of delivery, as well as toxic effects of the 64 kDa fraction of hemoglobin, and/or various antioxidants that were added to the HBOC solution. Based on these early lessons, the 64 kDa fraction is filtered and the antioxidants are not used in the current generation of HBOCs. Most importantly, HBOCs are no longer considered pharmacologically inert, so the dose and route of administration are key factors in profiling HBOC side effects. In this present study, a bolus of 10 mL/kg NS was first administered over 5 minutes, followed by 6 mL/kg HBOC-201 over 5 minutes. In these conditions, the relatively mild pressor action of HBOC-201 allowed rapid resuscitation postinjury, and there was no delay in lactate clearance, as seen by other investigators,23,33 or any other toxic effect on several other measured variables. Uptake of free hemoglobin or iron based debris by macrophages may increase cytokine release, such as IL-8 and/or TNF-[alpha].34,35 HBOC-201 activates human neutrophils, as measured by CD11b and oxidative burst activity in vitro, and IgG specific anti-HBOC-201 antibodies confirm prior exposure in canines.36 However, in a recent study, resuscitation with HBOC-201 had no significant adverse or beneficial effect on immune function, as measured by lymphocyte counts, differentials, T-lymphocyte subset analysis, or cytokine (TNF-[alpha], IL-6) release.37 Also, polymerized human hemoglobin (Polyheme, Northfield Laboratories, Evanston, Ill.) does not prime neutrophils,38 avoids increases in IL-8 gene expression in neutrophils or total leukocytes,39 and reduces levels of circulating IL-6, IL-8, and IL-10.40 In this study, HBOC-201 did not cause alterations of TNF-[alpha] and IL-6 compared with other groups. However, it is known that a multitude of inflammatory and noninflammatory mediators exist not only in the serum, but also the CSF,41–44 and these intertwined systems may be altered. Coagulation analyzers for standard tests, such as PT, PTT, and fibrinogen may be affected by HBOCs,45 whereas mechanical detection methods may be less affected.46 HBOC-201 prolongs bleeding times and decreases arterial thrombus formation in a rabbit model of carotid arterial thrombosis.47 HBOC-201 and lactated Ringers have similar effects on TEG values in vitro at clinically relevant concentrations.48 Recently, Arnaud showed in a controlled model of hemorrhage that R time increased in HBOC-201 treated animals early and late after resuscitation.49 On the other hand, there are coagulation changes specific to TBI.18 Early after TBI, R time is depressed indicating a hypercoagulable state, and is independent of treatment. However, R time depression was maintained in the HBOC group at 300 minutes post-TBI. Clot strength (MA) was normal throughout the experiment. Perspective At the time of this writing, HBOC-201 is approved in South Africa for treating adult surgical patients who are acutely anemic and for eliminating, reducing or delaying the need for allogenic red blood cell transfusion in these patients; however no peer reviewed publications exist on this experience. The United States Navy's RESUS (Restore Effective Survival in Shock) trial involving HBOC-201 in trauma patients is currently on hold by the FDA, primarily because of the agency's concerns about the risk-benefit profile in this patient population. Concurrently, a pivotal FDA approved phase III study is ongoing and designed to evaluate the safety and efficacy of prehospital PolyHeme for treatment of patients in traumatic hemorrhagic shock. Conclusions After TBI and controlled hemorrhage, a single HBOC-201 bolus provided swift and adequate resuscitation, while maintaining CPP, limiting ICP rise, limiting intravenous fluid requirements, causing no functional coagulopathy or cytokine release, in the absence of a blood transfusion, mannitol, or pressor therapy. Thus, HBOC-201 may provide a safe and effective low volume resuscitation bridge until definitive neurotrauma care is available. ACKNOWLEDGMENTS We appreciate the technical assistance of Jennifer E. Zuccarelli. In addition, we would like to thank Virginia Rentko, DVM, of Biopure, Corp. (Cambridge, Mass.) for providing the Hemopure; Eli Cohen, PhD Hemoscope, Inc. (Niles, Ill.) for providing the thromboelastograph coagulation analyzer; Victor Castro of Zoll Medical (Chelmsford, Mass.) for the hemodynamic monitors; Dave Glover (Hutchinson Technology, Hutchinson, Minn.) for providing the NIR system; George Beck of Impact Instrumentation (West Caldwell, N.J.) for providing the ventilators; Concetta Gorski, RN, BS, CCRA, Integra LifeSciences Corporation, (Plainsboro, N.J.) for providing the camino monitors and LiCOX probes; and Terry Shirey, PhD, of Nova Biomedical (Waltham, Mass.) for providing the Stat Ultra Blood Gas and Electrolyte Analyzer. REFERENCES 1. Moore EE, Johnson JL, Cheng AM, Masuno T, Banerjee A. Insights from studies of blood substitutes in trauma. Shock. 2005;24:197–205. Ovid Full Text Bibliographic Links [Context Link] 2. Greenburg AG, Kim HW. Hemoglobin-based oxygen carriers. Crit Care. 2004;8:S61–S64. Bibliographic Links [Context Link] 3. Wahr JA. 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(Influence of negative expiratory pressure ventilation on hemodynamic variables during severe hemorrhagic shock Anette C. Krismer @ MD; Volker Wenzel, MD; Karl H. Lindner, MD; Achim von Goedecke, MD; Martin Junger, BS; Karl H. Stadlbauer, MD; Alfred Königsrainer, MD; Hans-U. Strohmenger, MD; Martin Sawires, MD; Beate Jahn, MSc; Christoph Hörmann, MD) This project was approved by the Austrian Federal Animal Investigational Committee, and the animals were managed in accordance with the American Physiologic Society, institutional guidelines, and the position of the American Heart Association on Research From the Department of Anesthesiology and Critical Care Medicine (ACK, VW, KHL, AG, MJ, KHS, HUS, MS, CH), the Department of Surgery (AK), and the Department of Medical Statistics, Informatics and Health Economics (BJ), Innsbruck Medical University, Innsbruck, Austria. Supported, in part, by the Austrian National Bank grants 9513 and 11448, Vienna, Austria, and the Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Austria. The authors have not disclosed any potential conflicts of interest. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000229886.98002.2B Objective: Outcome after trauma with severe hemorrhagic shock is still dismal. Since the majority of blood is present in the venous vessels, it might be beneficial to perform venous recruiting via the airway during severe hemorrhagic shock. Therefore, the purpose of our study was to evaluate the effects of negative expiratory pressure ventilation on mean arterial blood pressure, cardiac output, and short-term survival during severe hemorrhagic shock. Design: Prospective study in 21 laboratory animals. Setting: University hospital research laboratory. Subjects: Tyrolean domestic pigs. Interventions: After induction of controlled hemorrhagic shock (blood loss _45 mL/kg), 21 pigs were randomly ventilated with either zero end-expiratory pressure (0 PEEP; n _ 7), 5 cm H2O positive end-expiratory pressure (5 PEEP; n _ 7), or negative expiratory pressure ventilation (up to _30 cm H2O at the endotracheal tube during expiration; n _ 7). Measurements and Main Results: Mean (_SD) arterial blood pressure was significantly higher in the negative expiratory pressure ventilation swine when compared with the 0 PEEP (38 _ 5 vs. 27 _3 mm Hg; p _ .001) and the 5 PEEP animals (38 _ 5 vs. 20 _ 6 mm Hg; p < .001) after 5 mins of the experiment. Cardiac output was significantly higher in the negative expiratory pressure ventilation swine when compared with the 0 PEEP (3.1 _ .4 vs. 1.9 _ .9 L/min;p _ .001) and 5 PEEP animals (3.1 _ .4 vs. 1.2 _ .8 L/min; p < .001) after 5 mins of the experiment. All seven negative expiratory pressure ventilation animals, but only three of seven 0 PEEP animals (p _.022), survived the 120-min study period, whereas all seven of seven 5 PEEP animals were dead within 35 mins (p < .001). Limitations include that blood loss was controlled and that the small sample size limits the evaluation of survival outcome. Conclusions: When compared with pigs ventilated with either 0 PEEP or 5 PEEP, negative expiratory pressure ventilation during severe hemorrhagic shock improved mean arterial blood pressure and cardiac output. (Crit Care Med 2006; 34:2175–2181) Crit Care Med 2006 Vol. 34, No. 8 2175 Management of trauma patients in severe hemorrhagic shock is a challenging aspect of trauma care. Although there is an ongoing discussion regarding beneficial vs. adverse effects of fluid resuscitation during uncontrolled hemorrhagic shock, new approaches such as vasopressin to manage severe bleeding are entering the debate as well (1–4). However, both drugs and fluid resuscitation need to be administered intravenously to be effective. Unfortunately, especially in those patients who need therapy the most since blood pressure is collapsing, obtaining rapid intravenous access may be very difficult. A strategy to improve cardiocirculatory function even before an intravenous access can be obtained could be extremely beneficial in these patients. Since the majority of blood is present in the venous vessel system, it may be helpful to perform venous recruiting when managing a patient in severe hemorrhagic shock, until a venous access can be obtained. Previous studies described positive effects of an inspiratory impedance threshold valve during cardiopulmonary resuscitation and hemorrhagic shock (5– 8) in regard to optimizing right and left atrial filling and, therefore, cardiac output and mean arterial blood pressure. Although the venous recruiting concept of the inspiratory threshold valve is intriguing, it can only be used during cardiopulmonary resuscitation or spontaneous ventilation; however, extrapolating this concept to mechanical ventilation would be desirable. In that case, endotracheal intubation could be used to achieve a secured airway, oxygenation, and additionally venous recruiting with negative expiratory pressure. The purpose of this study was therefore to assess the effects of negative expiratory pressure ventilation with positive pressure ventilation with zero cm H2O PEEP (0 PEEP) and with positive pressure ventilation with 5 cm H2O PEEP (5 PEEP), respectively. The tested primary study outcome was the improvement of mean arterial blood pressure, and secondary study outcomes were cardiac output and short-term survival. MATERIALS AND METHODS Animal care and use were performed by qualified individuals, supervised by veterinarians, and all facilities and transportation comply with current legal requirements and guidelines. Anesthesia was used in all surgical interventions, all unnecessary suffering was avoided, and research would have been terminated if unnecessary pain or fear resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care. Surgical Preparations and Measurements. This study was performed on 21 healthy, 12- to 16-wk-old swine weighing 35–45 kg. The animals were fasted overnight but had free access to water. The pigs were premedicated with azaperone (4 mg/kg intramuscularly,neuroleptic agent, Janssen, Vienna, Austria)and atropine (0.01 mg/kg intramuscularly) 1hr before surgery. Anesthesia was induced with a single bolus dose of ketamine (20mg/kg intramuscularly), propofol (1–2 mg/kgintravenously), and piritramid (30 mg intravenously, opioid with_4–8 hrs half time, Janssen,Vienna, Austria) given via an ear vein. The animals were placed in a supine position, and their trachea was intubated during spontaneous ventilation. After intubation, pigs were ventilated with a prototype volume-controlled ventilator (CAREvent, O-Two-Systems, Mississauga, ON,Canada) with 35% oxygen at 12 breaths/min and with a tidal volume adjusted to maintain normocapnia;furthermore, a PEEP of 5 cm H2O was applied during preparation and hemorrhage. The ventilator is a pneumatically powered, time-cycled, square-wave generator. The negative pressure was generated using an oxygenpowered Venturi vacuum generator. The Venturi vacuum generator was turned on at the end of the inspiratory phase, remained on for the full duration of the expiratory phase, and was turned off at the commencement of the next inspiratory phase (Fig. 1). Respiratory variables were measured and analyzed using a pulmonary monitor (CP-100, Bicore Monitoring System, Irvine, CA) attached to a variable orifice pneumotachograph (Varflex, Allied Health Products, Riverside, CA) and an esophageal balloon catheter (Smart Cath, Allied Health Products, Riverside, CA). The esophageal balloon catheter was 2 mm (7-Fr) in diameter, 70 cm long, and constructed from medical-grade polyurethane. The inflated balloon was 0.9 cm in diameter and 10 cm long. The frequency response was 30 Hz. The esophageal balloon catheter was connected directly to the catheter port on the Bicore system. The Bicore system automatically performs a vacuum leak test and fills the esophageal balloon with 0.8 mL of air. The pneumotachometer was connected directly to the proximal end of the airway tube. Airway pressure and flow were measured at the pneumotachometer. The CO2 sampling port was sited above the flow transducer. The position of the esophageal balloon catheter was checked and adjusted where necessary by observation of the cardiac artifact on the esophageal waveform, as recommended by the manufacturer. Anesthesia was maintained with propofol (6–8 mg/kg/hr intravenously) and a single injection of piritramid (15 mg intravenously). Lactated Ringer’s solution (10 mL/kg/hr intravenously) was administered in the preparation phase, resulting in _500 mL of fluid replacement in all animals before initiation of the experimental protocol (9). A standard lead II electrocardiogram was used to monitor cardiac rhythm; depth of anesthesia was judged according to arterial blood pressure and heart rate. If cardiovascular variables during the preparation phase indicated a reduced depth of anesthesia, additional propofol and piritramid were given. Body temperature was maintained at 38.5–39.5°C. A 7-Fr saline-filled catheter was advanced via femoral cutdown into the right atrium for measurement of right atrial pressure, and two catheters were advanced via bilateral femoral cutdown into the abdominal aorta for measurement of aortic blood pressure, withdrawal of blood to induce hemorrhagic shock, and arterial blood samples. A 7.5-Fr pulmonary artery catheter was placed in the pulmonary artery via the internal jugular vein to measure cardiac output with the thermodilution technique. The intravascular catheters were attached to pressure transducers (1290A, Hewlett Packard, Boeblingen, Germany) that were aligned at the level of the right atrium. All pressure tracings were recorded with a data acquisition system (Dewetron port 2000, Graz, Austria; and Datalogger, custom-made software, Peter Hamm,departmental technician). Blood gases were measured with a blood gas analyzer (Chiron,Walpole, MA); end-tidal carbon dioxide was measured using an infrared absorption analyzer (Multicap, Datex, Helsinki, Finland). Experimental Protocol. After assessing baseline hemodynamic values and blood gases, propofol infusion was adjusted to 2 mg/kg/hr and infusion of lactated Ringer’s solution was stopped. Muscle paralysis was achieved with 0.2 mg/kg/hr pancuronium to prevent spontaneous or agonal breathing. Animals were ventilated with 100% oxygen and were bled _45 mL/kg (estimated 65% of their calculated blood volume) (10) via an arterial catheter over a period of 30 mins to simulate controlled hemorrhagic shock. Subsequently, 21 animals were randomized into three groups and then ventilated with either up to _30 cm H2O negative expiratory pressure ventilation (n _7), 0 cm H2O PEEP (n _ 7), or 5 cm H2O PEEP (n _ 7; investigators were blinded to the treatment protocol; Fig. 2) Besides the endexpiratory pressure level, no other variable was changed in the ventilator setting. One blinded researcher collected all blood gases and another blinded researcher measured cardiac output. Blood gases and cardiac output were measured every 10 mins during the first 60 mins. No fluids were administered during the first 60 mins of the study period; after this time point, fluid resuscitation (25 mL/kg lactated Ringer’s and 25 mL/kg 3% gelatin solution, a colloid fluid used as a volume expander) was performed in all surviving pigs. After fluid resuscitation was started, blood gases and cardiac output were measured every 15 mins. From this point in time, animals were ventilated with the same ventilator settings before randomization; no recruitment maneuver was performed. Animals were declared dead if mean arterial blood pressure fell below 10 mm Hg. At Figure 1. Venturi powered vacuum generator for negative expiratory pressure ventilation. 2176 Crit Care Med 2006 Vol. 34, No. 8 the end of the 120-min study protocol, the surviving animals were killed with an overdose of fentanyl, propofol, and potassium chloride. Statistical Analysis. Values are expressed as mean _ SD. Shapiro Wilks tests were used to test for normality distribution. Baseline data for hemodynamic variables and arterial blood gases were tested with one-way analysis of variance if Gaussian-distributed and with Kruskal-Wallis test if not Gaussian-distributed. Statistical investigation was performed only for baseline data before and after hemorrhage, cardiac output, mean arterial blood pressure, and short-term survival. We did not statistically analyze other variables in order to avoid overinterpretation of the data. To evaluate differences in mean arterial blood pressure and cardiac output between groups, analysis for repeated measurements was used. Because all animals in the 5 PEEP group died before the end of the intervention, differences between the negative expiratory pressure ventilation group and the 5 PEEP group were only tested until 10 mins after start of the intervention (otherwise until the end of the experimental phase). Survival rates were compared using Kaplan-Meier methods with log rank (Mantel Cox) comparison of cumulative survival by treatment groups. We considered p _ .05 to be statistically significant. No corrections were made for multiple comparisons. All statistical calculations were performed using SPSS, version 11.5, for Windows. RESULTS Before induction of hemorrhagic shock, there were no differences in study end points between groups (Tables 1, 2). After induction of hemorrhagic shock, mean arterial blood pressure, cardiac output, and mean right atrial pressure were considerably decreased when compared with baseline values but were comparable between Figure 2. Flowchart of the experiment. Hearts, measurement of hemodynamic variables; triangles, measurement of airway pressures, tidal volumes, and flow rates with a pneumotachometer; teardrops, sampling of blood gases; PEEP, positive end-expiratory pressure; NEP, negative expiratory pressure. Table 1. Hemodynamic variables during the hemorrhage phase, the experimental phase, and fluid resuscitation Variable Hemorrhage Phase Experimental Phase Fluid Resuscitation BL 1 BL 2 5 Mins 10 Mins 20 Mins 30 Mins 60 Mins 90 Mins 120 Mins End-tidal CO2, mm Hg NEP 36 _1 20_5 37_3 38 _3 39 _2 41_3 41_2 41_1 38_ 4 0 PEEP 37 _1 19_7 25_6 25 _5 24 _8 30_4 29_9 37_4 35_ 1 5 PEEP 36 _2 23_4 20_7 22 _7 21 _6 16_5 — — — Heart rate, beats/min NEP 88 _ 5 184 _ 46 217 _ 20 219 _ 19 227 _ 18 230 _ 20 235 _ 21 183 _ 36 187 _ 57 0 PEEP 82 _ 8 183 _ 26 200 _ 28 204 _ 33 198 _ 43 222 _ 19 187 _ 22 184 _ 65 153 _ 36 5 PEEP 90 _ 4 186 _ 36 181 _ 30 186 _ 25 177 _ 14 163 _4 — — — Mean right atrial blood pressure, mm Hg NEP 90 _ 4 186 _ 36 181 _ 30 186 _ 25 177 _ 14 163 _4 90_ 4 186 _ 36 181 _ 30 0 PEEP 8 _1 2_1 1_1 1_1 1_1 1_1 2_2 8_1 5_ 3 5 PEEP 7 _1 3_4 5_2 3_1 3_1 3_1 — — — Mean pulmonary artery blood pressure, mm Hg NEP 18 _1 10_1 5_5 6_1 7_2 7_1 7_2 18_2 19_ 3 0 PEEP 18 _2 11_2 11_2 11 _2 11 _2 13_1 12_1 20_2 18_ 1 5 PEEP 20 _3 10_2 10_2 12 _1 11 _0 10_2 — — — Pulmonary artery occlusion pressure, mm Hg NEP 8 _2 2_2 0_1 1_1 0_ 1 _1 _3 0_1 8_3 8_ 2 0 PEEP 8 _2 3_3 6_3 4_3 3_3 4_1 5_2 8_2 8_ 2 5 PEEP 9 _2 2_2 4_3 5_1 5_1 7_3 — — — Cardiac output, L/min NEP 3.7 _ 0.4 1.1 _ 0.4 3.1 _ 0.4a,b 3.2 _ 0.3a,b 3.2 _ 0.5b 3.5 _ 0.4b 4.0 _ 0.6b 6.0 _ 1.2 7.5 _ 1.4 0 PEEP 3.8 _ 0.5 1.1 _ 0.4 1.9 _ 0.9 2.0 _ 1.0 1.9 _ 0.7 2.5 _ 0.6 2.3 _ .8 6.2 _ 0.1 6.1 _ 1.2 5 PEEP 4.3 _ 0.9 1.0 _ 0.2 1.2 _ 0.8 0.9 _ 0.9 2.0 _ 0.3 0.4 — — — BL 1, baseline 1, measurements before hemorrhage; BL 2, baseline 2, measurements after controlled hemorrhage (_45 mL/kg blood loss); NEP, negative expiratory pressure ventilation; 0 PEEP, ventilation with 0 cm H2O positive end-expiratory pressure; 5 PEEP, ventilation with 5 cm H2O positive end-expiratory pressure; —, not measured due to death of all animals. Values are given as mean _ SD of the mean. ap _ .001 for negative pressure ventilation vs. 5 PEEP; bp _ .001 for negative pressure ventilation vs. 0 PEEP; since all animals in the 5 PEEP group died before the end of the intervention, differences between the negative expiratory pressure ventilation group and the 5 PEEP group where only tested until 10 mins after start of the intervention. No statistical comparison was performed for all other variables in order to avoid overinterpretation of the data. Crit Care Med 2006 Vol. 34, No. 8 2177 groups. Also, total blood loss was comparable between groups. Main Results. Mean arterial blood pressure was significantly higher in the negative expiratory pressure ventilation swine when compared with the 0 PEEP (p _.001) and 5 PEEP animals (p _ .001). Cardiac output was significantly higher in negative expiratory pressure ventilation swine when compared with the 0 PEEP (p _.001) and 5 PEEP animals (p _ .001; Table 1, Fig. 3), Seven of seven negative expiratory pressure ventilation animals, but only three of seven 0 PEEP swine, survived the 120-min study period, whereas seven of seven 5 PEEP pigs were dead within 35 mins. There was a statistically significant difference in cumulative survival between the negative expiratory pressure ventilation swine vs. the 0 PEEP pigs (p _ .022) and between the negative expiratory pressure ventilation swine vs. the 5 PEEP pigs (p _ .001; Fig. 4). Secondary Results. During the shock phase, ventilation with negative expiratory pressure resulted in decreased mean airway pressure and increased delta esophageal pressure and delta airway pressure when compared with the 0 PEEP and 5 PEEP animals. (Table 3). When compared with the 0 PEEP and 5 PEEP group, end-tidal carbon dioxide was notably higher during the experiment, but arterial oxygen partial pressure was considerably lower in the negative expiratory pressure ventilation animals after 20 mins of the shock protocol. Representative tracings of mean arterial pressure and right atrial pressure tracings are given in Figures 5 and 6. DISCUSSION In this model of severe hemorrhagic shock, negative expiratory pressure ventilation ensured survival of seven of seven pigs for 60 mins without administration of vasopressors or fluid resuscitation and subsequently allowed 60 mins of hemodynamic stabilization with fluid resuscitation. In contrast, only three of seven 0 PEEP animals survived the 120-min Table 2. Arterial blood gases during the hemorrhage phase, the experimental phase, and fluid resuscitation Variable Hemorrhage Phase Experimental Phase Fluid Resuscitation BL 1 BL 2 5 Mins 10 Mins 20 Mins 30 Mins 60 Mins 90 Mins 120 Mins Arterial pH NEP 7.50 _ 0.02 7.50 _ 0.06 7.40 _ 0.09 7.31 _ 0.06 7.31 _ 0.05 7.30 _ 0.02 7.32 _ 0.04 7.37 _ 0.05 7.44 _ 0.06 0 PEEP 7.51 _ 0.02 7.49 _ 0.07 7.41 _ 0.09 7.33 _ 0.08 7.33 _ 0.07 7.28 _ 0.06 7.27 _ 0.15 7.38 _ 0.12 7.45 _ 0.05 5 PEEP 7.50 _ 0.03 7.49 _ 0.05 7.40 _ 0.07 7.34 _ 0.05 7.32 _ 0.06 7.34 _ 0.03 — — — Arterial PCO2, mm Hg NEP 38 _2 34_3 34_5 43_5 43_3 45_2 45_4 41_2 38_ 4 0 PEEP 38 _1 33_4 30_6 34_5 33_8 42_2 43_5 39_5 38_ 1 5 PEEP 38 _2 34_3 32_4 33_3 34_6 29_ 1 — — — Arterial PO2, mm Hg NEP 144 _ 12 443 _ 55 384 _ 58 337 _ 64 283 _ 56 307 _ 32 326 _ 36 397 _ 81 417 _ 62 0 PEEP 151 _ 21 375 _ 57 352 _ 57 355 _ 84 381 _ 50 394 _ 65 353 _ 48 441 _ 50 415 _ 38 5 PEEP 178 _ 93 424 _ 85 393 _ 80 373 _ 62 436 _ 48 390 _ 67 — — — Arterial base excess, mmol/L NEP 6 _2 4_ 4 _4 _ 4 _5 _ 3 _5 _ 3 _4 _ 2 _3 _ 2 _2 _2 1_ 3 0 PEEP 6 _2 2_ 3 _5 _ 4 _7 _ 4 _4 _ 9 _7 _ 4 _7 _ 6 _2 _5 1_ 3 5 PEEP 6 _2 2_ 3 _5 _ 3 _8 _ 3 _8 _ 1 _10 _ 1 — — — Arterial lactate, mmol/L NEP 1.8 _ 0.5 4.7 _ 1.2 8.8 _ 1.8 7.8 _ 1.6 7.6 _ 1.4 7.5 _ 1.6 6.5 _ 1.9 6.1 _ 2.1 4.6 _ 1.9 0 PEEP 1.8 _ 0.4 5.8 _ 1.2 10.0 _ 2.5 9.8 _ 2.0 10.2 _ 2.2 10.1 _ 3.0 9.3 _ 2.6 7.8 _ 2.5 5.7 _ 1.9 5 PEEP 1.8 _ 0.6 5.6 _ 1.6 10.0 _ 2.3 10.4 _ 3.2 11.4 _ 5.0 9.4 _ 4.6 — — — BL 1, baseline 1, measurements before hemorrhage; BL 2, baseline 2, measurements after controlled hemorrhage (_45 mL/kg blood loss); NEP, negative expiratory pressure ventilation; 0 PEEP, ventilation with 0 cm H2O positive end-expiratory pressure; 5 PEEP, ventilation with 5 cm H2O positive end-expiratory pressure; —, not measured due to death of all animals. Values are given as mean _ SD of the mean. No statistical comparison was performed in order to avoid overinterpretation of data. Figure 3. Mean _ SD mean arterial blood pressure during ventilation with negative expiratory pressure ventilation (NEP; triangles), 0 cmH2O positive end-expiratory pressure (0 PEEP; diamonds), and 5 cm H2O PEEP (5 PEEP; squares). BL 1, baseline 1 before blood withdrawal; BL 2, baseline 2 after 45 mL/kg blood loss. Note that the time line between BL 1 and BL 2 is not subject to scale. Fluid resuscitation indicates infusion of 25 mL/kg lactated Ringer’s solution and 25 mL/kg 3% gelatin solution. *p _ .001 between negative expiratory pressure and 0 cm PEEP, respectively. study period, and seven of seven 5 PEEP animals died within 35 mins. We withdrew _65% of the calculated blood volume in order to simulate severe hemorrhagic shock. Our pigs had a mean arterial blood pressure of _20 mm Hg immediately before randomization, indicating a critically decreased brain perfusion. A patient in this condition is most likely unconscious and should be immediately intubated and ventilated at the accident site according to the Advanced Trauma Life Support guidelines (11). Our prototype ventilator producing positive pressure during inspiration, and negative pressure during expiration, thus mimicking a “normal” ventilation cycle with reversed pressure ratios, may thus combine the advantage of ensuring ventilation plus enhancing venous return and perfusion. We deliberately withheld vasopressors and fluid resuscitation for the first 60 mins of the experiment in order to investigate the effects of different ventilation strategies over a prolonged period of time. Fluid resuscitation was then started to simulate further shock management and to determine whether the shock state was reversible or refractory. Since spontaneous inspiration decreases intrathoracic pressure and induces decreases in right atrial blood pressure, venous return increases (12). Mechanical ventilation reverses this effect, since positive airway pressure and PEEP ventilation increase intrathoracic pressure, causing venous return to decrease (12). In contrast to current Advanced Trauma Life Support treatment concepts, this may be of considerable clinical importance during management of severe hemorrhagic shock. For example, in a porcine study simulating severe hemorrhagic shock, positive pressure ventilation with 5 or 10 PEEP significantly decreased cardiac output and mean arterial blood pressure, resulting in death within 5–30 mins (13). In contrast, an inspiratory threshold valve maintains and prolongs a vacuum created within the thorax during inspiration. This results in increased venous return and vital organ blood flow during cardiopulmonary resuscitation with an active compression decompression device and during controlled hemorrhagic shock (14, 15). Unfortunately, the innovative inspiratory threshold valve concept to recruit venous return cannot be applied after mechanical ventilation is initiated; thus, severely injured patients who usually require both airway and blood pressure management may be unable to benefit of this novel technique. By analogy, noninvasive negative pressure ventilation also influences the cardiovascular system. Cuirass negative pressure ventilation significantly improved cardiac output in children after cardiac surgery (16, 17). It has been therefore discussed as adjunctive hemodynamic therapy in patients with a low cardiac output (18). As demonstrated in our animals, negative expiratory pressure ventilation decreased mean airway pressure, and subsequently mean right atrial blood pressure, as well as mean pulmonary artery blood pressure. Accordingly, cardiac output almost tripled in the negative expiratory pressure ventilation animals and was even comparable to prehemorrhage levels. This was accompanied by significantly higher end-tidal carbon Figure 4. Kaplan-Meier survival curves in animals being ventilated with either negative expiratory pressure ventilation (NEP), 0 positive end-expiratory pressure (PEEP), or 5 PEEP. Note that the hemorrhage phase is not presented. Table 3. Secondary results NEP 0 PEEP 5 PEEP Baseline 2 Expiratory tidal volume, mL 603 _ 44 661 _ 81 657 _ 92 Respiratory rate, per min 12 _0 12 _0 12 _ 0 Peak airway pressure, cm H2O 34 _2 33 _3 32 _ 4 Mean airway pressure, cm H2O 15 _0 14 _0 14 _ 1 Peak inspiratory flow rate, mL/sec 572 _ 59 626 _ 96 583 _ 70 _ PES, cm H2O 6 _4 9_2 8_ 3 _ PAW, cm H2O 28 _2 26 _3 25 _ 4 Experimental phase Expiratory tidal volume, mL 617 _ 66 683 _ 65 684 _ 97 Respiratory rate, per min 12 _0 12 _0 12 _ 0 Peak airway pressure, cm H2O 29 _2 29 _3 35 _ 6 Mean airway pressure, cm H2O 0 _0 12 _1 15 _ 1 Peak inspiratory flow rate, mL/sec 581 _ 57 594 _ 83 563 _ 63 _ PES, cm H2O 24 _ 12 10 _2 8_ 2 _ PAW, cm H2O 58 _4 27 _3 26 _ 4 Fluid resuscitation Expiratory tidal volume, mL 644 _ 61 700 _ 57 — Respiratory rate, per min 12 _0 12 _0 — Peak airway pressure, cm H2O 35 _4 31 _5 — Mean airway pressure, cm H2O 16 _1 15 _1 — Peak inspiratory flow rate, L/sec 594 _ 62 645 _ 36 — _ PES, cm H2O 7 _3 9_2 — _ PAW, cm H2O 28 _4 24 _5 — NEP, negative expiratory pressure ventilation; 0 PEEP, ventilation with 0 cm H2O positive end-expiratory pressure; 5 PEEP, ventilation with 5 cm H2O positive end-expiratory pressure; Baseline 2, measurements after controlled hemorrhage (45 mL/kg blood loss); _ PES, pressure change in the esophagus due to ventilation; _ PAW, peak airway pressure minus the minimum airway pressure during each breath; —, not measured due to death of all animals. Values are given as mean _ SD of the mean. No statistical comparison was performed in order to avoid overinterpretation of data. dioxide levels when compared with the 0 and 5 PEEP animals, indicating a stabilization of hemodynamic status. Negative expiratory pressure ventilation resulted in a lower, but not hypoxic, arterial oxygen partial pressure when compared with the 0 and 5 PEEP animals. Although speculative, this may be due to formation of atelectasis and increased pulmonary shunting; however, arterial oxygen partial pressure improved after the ventilator settings were changed to preshock parameters. Furthermore, no recruitment maneuver was necessary. Fluid resuscitation showed that shock was reversible, and pH, lactate, and base excess improved in the 1-hr observation period both in the negative expiratory pressure ventilation and also in the remaining 0 PEEP animals. Taken together, negative expiratory pressure ventilation may be a strategy to immediately improve cardiac output, which may be especially beneficial in trauma patients with collapsing blood pressure (19). Limitations include that we withheld fluid resuscitation. Second, the small sample size limits the evaluation of survival outcome. Blood loss was controlled; and the effect of negative expiratory pressure ventilation in uncontrolled bleeding needs to be determined. Also, intubation with no subsequent fluid resuscitation may be contradictory to the Advanced Trauma Life Support guidelines but was used because of the experimental design of the study. We used young and healthy animals with flexible ribcages; therefore, it may be possible that the observed effects may be less profound in the elderly with a more rigid chest wall. Furthermore, we cannot report about the degree of functional residual capacity reduction or the extent of atelectasis formation. Also, we did not perform a histologic examination of the lungs. Further, negative pressure ventilation is a very stressful intervention for the lung. We do not know what happens with pulmonary mediator function and whether possible changes are fully reversible after return to positive pressure ventilation. Since we do not know if potentially detrimental effects, such as a negative pulmonary pressure edema, could occur during normovolemia, a fourth group of normovolemic animals ventilated with negative pressure might have been interesting. We do not know if this mode of ventilation could trigger an acute respiratory distress syndrome. CONCLUSIONS When compared with pigs ventilated with either 0 PEEP or 5 PEEP, negative expiratory pressure ventilation during severe hemorrhagic shock improved mean arterial blood pressure and cardiac output. ACKNOWLEDGMENTS We are indebted to Kathrin Ebert and Kevin Bowden for technical assistance. REFERENCES 1. 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Another potential use for your defibrillator during CPR??? Interesting article for you all to read. (Thoracic impedance changes measured via defibrillator pads can monitor ventilation in critically ill patients and during cardiopulmonary resuscitation* Heidrun Losert @ MD; Martin Risdal, MSc; Fritz Sterz, MD, PhD; Jon Nysæther, PhD; Klemens Köhler, MD; Trygve Eftestøl, PhD; Cosima Wandaller, MD; Helge Myklebust, BEng; Thomas Uray, MD; Gottfried Sodeck, MD; Anton N. Laggner, MD, PhD) Recent reports (1–4) discussed the suboptimal quality of cardiopulmonary resuscitation (CPR) (5). Aufderheide et al. (4) demonstrated that rescuers consistently tend to hyperventilate out-of-hospital cardiac arrest patients. Karlsson et al. (6) stated that in their pig model, increased tidal volumes and hypocarbia were known to develop and adversely affect cardiac output. Dorph et al. (7) suggested a tidal volume of 10 mL/kg delivered three times per minute during CPR to achieve normocapnia, and Baskett et al. (8) found that the tidal volume perceived to achieve chest rise was on the order of 300– 500 mL. Wik et al. (9) demonstrated that a too short inspiration time was a common problem in a manikin model where emergency medical service personnel delivered mouth-to-mouth ventilations. The possibility for measuring ventilation rate, tidal volume, and inspiration time based on thorax impedance changes has long been known (10, 11). Pellis et al. (12) measured ventilations in pigs by thorax impedance through defibrillator pads. Those authors suggested that the same method can be used to monitor human ventilation activity during resuscitation. The preceding findings highlight the need for continuous ventilation monitoring during CPR, even if debate continues as to whether ventilation is indeed required in addition to uninterrupted chest compression (5). In manikin studies it was found that such monitoring would improve the efficacy of CPR. Wik et al. (9) presented this effective method for CPR training. Handley et al. (13) suggested that if a feedback system is incorporated into an automatic external defibrillator (AED), this could lead to a better performance of CPR. Therefore, the concept of measuring thoracic impedance via defibrillator pads in patients to guide CPR is *See also p. xx. From Department of Emergency Medicine, Medical University of Vienna, Austria (HL, FS, KK, CW, TU, GS, ANL); Department of Electrical and Computer Engineering, University of Stavanger, Norway (MR, TE); and Laerdal Medical, Stavanger, Norway (JN, HM). Helge Myklebust and Jon Nysæther are Laerdal Medical Employees. Klemens Köhler was employed for 12 months at the Department of Emergency Medicine, Medical University Vienna with support of a grant from Laerdal Medical, Stavanger, Norway. Laerdal Medical, Stavanger, Norway provided travel grants for scientific meetings for Heidrun Losert and Klemens Köhler. Heartstart 4000SP with the necessary analysis software was provided by Laerdal Medical. Heidrun Losert received a laptop from Laerdal Medical, Stavanger, Norway. The study was supported in part by a commercial sponsor (Laerdal Medical, Stavanger, Norway). Non-Laerdal employees had unrestricting editing rights, so that the manuscript was as free from corporate bias as possible. The sponsor could not have suppressed publication if the results were negative or detrimental to the product they produce. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000235666.40378.60 Objective: Monitoring of ventilation performance during cardiopulmonary resuscitation would be desirable to improve the quality of cardiopulmonary resuscitation. To investigate the potential for measuring ventilation rate and inspiration time, we calculated the correlation in waveform between transthoracic impedance measured via defibrillator pads and tidal volume given by a ventilator. Design: Clinical study. Setting: Emergency department of a tertiary care university hospital. Patients: A convenience sample of mechanical ventilated patients (n _ 32), cardiac arrest patients (n _ 20), and patients after restoration of spontaneous circulation (n _ 31) older than 18 from an emergency department of a tertiary care university hospital were eligible. In many of the latter patients, cardiac arrest data could not be obtained. Interventions: The Heartstart 4000SP defibrillator (Laerdal Medical Cooperation, Stavanger, Norway) with additional capabilities of recording thoracic impedance changes was used. Measurements and Main Results: The relationship between impedance change and tidal volume (impedance coefficient) was calculated. The mean (SD) correlations between the impedance waveform and the tidal volume waveform in the patient groups studied were .971 (.027), .969 (.032), and .967 (.035), respectively. The mean (SD) impedance coefficient for all patients in the study was .00194 (.0078) _/mL, and the mean (SD) specific (weightcorrected) impedance coefficient was .152 (.048) _/kg/mL. The measured thorax impedance change for different tidal volumes (400–1000 mL) was approximately linear. Conclusions: The impedance sensor of a defibrillator is accurate in identifying tidal volumes, when chest compressions are interrupted. This also allows quantifying ventilation rates and inspiration times. However this technology, at its present state, provides only limited practical means for exact tidal volume estimation. (Crit Care Med 2006; 34:●●●–●●●) KEY WORDS: cardiopulmonary resuscitation; defibrillation; heart arrest; impedance; monitoring; ventilation Crit Care Med 2006 Vol. 34, No. 9 1 practically important in the settings of out-of-hospital cardiac arrest. The aim of our study was to investigate the potential of using impedance measurements for quantifying tidal volume using defibrillator pads in the standard lead II position on a convenience sample of ventilated patients (reference ventilated patients, full cardiac arrest patients, and patients after restoration of spontaneous circulation). Estimates of the impact of alternative electrode pad placement on the accuracy of assessment of respiratory rate, inspiratory time, and tidal volume are also reported. METHODS Study Design This was a prospective, observational case series of a convenience sample of ventilated emergency department patients between December 2003 and March 2005. The study procedures were in accordance with the ethical standards of the Medical University of Vienna and approved by the responsible committee on human experimentation at university. Setting The study was carried out at an emergency department of a tertiary care university hospital with an annual census of 75,000 patients. Participants A convenience sample of endotracheally intubated patients _18 yrs of age in hemodynamically stable, controlled mechanically ventilated conditions (reference group) were eligible for entry into this study. To evaluate our findings, we further tested patients suffering a nontraumatic, normothermic, witnessed cardiopulmonary arrest (cardiac arrest group). The latter were also studied during times of restoration of spontaneous circulation (ROSC group). Patients were not included if they had known terminal conditions, pregnancy, or contraindications for high peak pressure ventilation, such as patients with chronic obstructive pulmonary disease or asthma, cerebral bleeding, or insult (Table 1). Intensive care medicine such as controlled mechanical ventilation and/or advanced cardiac life support was provided according to a standard protocol (14, 15). Admission diagnosis and known medical history were routinely assessed, and the data for cardiac arrest patients encompassed all information required for the international Utstein-style criteria (16). Medications given were evaluated, and chest radiograph was performed immediately before or after the measurements to exclude any lung pathologies. Measurement All patients were ventilated with a ServoI Ventilator system (version 1.2, Siemens Medical Group, Frankfurt, Germany). This was necessary to use the monitoring capabilities of Table 1. Clinically relevant data of patients in hemodynamically stable, controlled, mechanically ventilated conditions (reference group), patients in nontraumatic, normothermic, witnessed cardiopulmonary arrest (cardiac arrest group), and patients during times of restoration of spontaneous circulation (ROSC group) Reference Group Cardiac Arrest Group ROSC Group No 32 20 31 Age, yrs 50 (44–59) 55 (40–70) 54 (37–67) Female, n (%) 9 (28) 6 (30) 7 (23) BMI 25 (23–30) 29 (26–31) 28 (25–29) Body temperature during measurements, °C 36.1 (33.5–36.8) [n _ 30] 35.1 (34.5–36.1) [n _ 11] 35 (34.5–35.7) [n _ 27] Vasporessors used during measurements, n (%) 20 (63) 19 (95) 24 (77) Vasodilatators used during measurements, n (%) 0 0 0 Cardiac rhythm during measurements, n (%) Sinus 32 (100) 0 31 (100) Ventricular fibrillation Not applicable 6 (30) Not applicable Ventricular tachycardia 0 2 (10) 0 (0) Asystole Not applicable 6 (30) Not applicable Pulseless electrical activity Not applicable 13 (65) Not applicable CPR duration, mins Not applicable 30 (2.25–70) Not applicable Adrenaline used during resuscitation before measurements, mg Not applicable 1.5 (0–6) 2 (0–6) Admission diagnosis, n (%) Cardiac arrest cardiac etiology 14 (44) 20 (100) 31 (100) Cerebrovascular disease 9 (28) Not applicable 0 Intoxication 5 (16) Not applicable 0 Cardiogenic shock 2 (6) Not applicable 0 Sepsis (n, %) 1 (3) Not applicable 0 Gastrointestinal bleeding 1 (3) Not applicable 0 Patients history, n (%) Mild pulmonary emphysema 1 (3) 1 (5) 2 (6) Cardiomyopathy 4 (13) 1 (5) 3 (10) Pulmonary artery embolism 1 (3) 3 (15) 3 (10) Chest radiograph, n (%) 32 (100) 11 (55) 22 (71) Pneumonia 4 (13) 0 2 (6) Pneumothorax 1 (3) 0 0 Effusion 8 (25) 0 1 (3) Edema 5 (16) 5 (25) 8 (26) Enlarged cardiac silhouette 7 (22) 3 (15) 5 (16) Atelectasis 3 (9) 1 (5) 1 (3) Pacemaker 3 (9) 2 (10) 2 (6) ROSC, restoration of spontaneous circulation; BMI, body mass index; CPR, cardiopulmonary resuscitation. Data are presented as the n (%) or as median (interquartile range; range from the 25th to the 75th percentile). 2 Crit Care Med 2006 Vol. 34, No. 9 the ServoI, which would not have been possible under ongoing bag-valve-mask ventilation. The ServoI was interfaced to a local server (Vipdas Biosys GesmbH, Wien, Austria) for continuous recording of ventilation data, such as pressure flow and volume. This enabled the recorded ventilator data to act as reference for impedance data. An investigational monitor/defibrillator was used in the study to record thoracic impedance (Heartstart 4000SP, Laerdal Medical Cooperation, Stavanger, Norway). This device was equipped with additional investigational capabilities of recording thoracic impedance changes related to ventilation. Heartstart 4000SP with the necessary analysis software was provided by Laerdal Medical. The thorax impedance measurements were recorded using commercially available self-adhesive electrode defibrillator pads (Heartstart Pads, Philips Medical Systems, Seattle, WA). Male patients’ chest were not shaved, and no additional adherence pressure was applied to the pads. Reference Group The patients in the reference group were ventilated with tidal volumes of 400, 600, 800, and 1000 mL each for 2 mins, and the resulting impedance changes were recorded via defibrillator pads in recommended standard positions with the left apical pad “to the left of the nipple with the center of the electrode in the midaxillary line” and correlated with tidal volumes given by the mechanical ventilation device. To evaluate the impact of alternative pad displacement on the measurement of tidal volume via thoracic impedance change (17–19), the left apical electrode was relocated three times. For pad position B, the left apical pad was placed far down with the lower end at the crista illiaca. For pad position C, the left apical pad was placed beneath the sternal electrode on the left side of the sternum. Pad position D was the same as position A, with the left apical pad rotated 90°. The right sternal electrode remained in standard position. For each position, the patients were ventilated with a tidal volume of 600 mL for 2 mins. Cardiac Arrest and ROSC Groups To investigate whether cardiac arrest caused variations in the impedance response, we elected to record data from patients in and after cardiac arrest. Ventilations were performed in accordance with standard CPR procedures, with the pad in the standard position A. Measurements include periods of cardiac arrest (no pulse or blood flow detected) (cardiac arrest group) and monitoring periods after return of spontaneous circulation (ROSC group). Because of artifacts during ongoing external chest compressions, only ventilation segments without chest compressions were used for analysis. Data Analysis The tidal volume and impedance data were analyzed with Matlab 7.0 (The MathWorks, Figure 1. A, sample volume trace and resulting thorax impedance signal for a patient weighing 120 kg and ventilated with a tidal volume of 600 mL. B, the same traces after noise reduction with filtering. C, the volume measurement in A is then plotted against the impedance trace to show the correlation C. The linearity of the relationship is even more evident in D, which shows the volume measurements in B plotted against the resulting impedance change. Crit Care Med 2006 Vol. 34, No. 9 3 Natick, MA). A change in lung volume, denoted _V, will cause a transthoracic impedance change, denoted _Z. According to Baker et al. (20 –22), the relationship between impedance change and lung volume for an individual is essentially linear (_Z _ aDV). The parameter _ is termed the impedance coefficient. By dividing lung volume by the weight W of the patient, the specific lung volume, expressed in mL/kg, is obtained. The relationship between impedance change _Z and specific lung volume can be expressed as _Z _ _w(_V/W). The parameter _w _ A • W will in this work be termed the specific impedance coefficient. _ and _w are expected to vary from individual to individual. To explore the potential of using thorax impedance for measuring ventilation rate and inspiration time, we investigated the correlation of waveforms between the lung volume _V and the impedance waveform _Z. We also explored the improvement in correlation when removing pulse artifacts (12) and baseline drift in the impedance channel with a finite impulse response equiripple band-pass filter. The filter was used on both the impedance and the volume measurements to impose the same effects on both signals. The correlation between the impedance curve-forms was analyzed in terms of linearity by performing a robust linear regression (23) to each ventilation measurement pair (_V, _Z) to model their relationship. The constant term of the model was forced to zero so that for zero impedance change we estimate a tidal volume of zero. The maximum deviation in volume from the linear model, here termed the maximum prediction error, was then calculated for each ventilation measurement pair and averaged across all ventilations. The correlation coefficient (24) between each measurement pair was also calculated. Average correlation coefficients were calculated for each patient and pad position, before and after filtering. A high similarity in waveform implies good potential for using impedance for quantifying ventilation rate and inspiration time. To investigate whether thorax impedance can also be used for tidal volume estimation, we measured the impedance change _ZT from onset of inspiration to onset of expiration for all compression-less ventilations with a distinct tidal volume _VT (mL). Based on the measurements of _ZT and _VT and the measured weight W of the patient, the average coefficients _ and _w for each patient in all groups were estimated as the average impedance change divided by the (specific) tidal volume given. A specific tidal volume estimate _Vest of an observed _ZT can then be found as _ZT /aw, which can be considered as a tidal volume estimation model. We evaluate the impedance as a source for tidal volume estimation by finding the model estimation error. We first evaluate the patientspecific model for each patient and then use the average of _w over all patients with defibrillator pads in standard position as a general model. The general model is then evaluated over the entire patient material. Finally we calculate the estimation error of the general model when the pads are in different positions (25). RESULTS Characteristics of Study Subjects In the reference group, 32 of 37 patients in hemodynamically stable, controlled, mechanically ventilated conditions could be used for analysis. Due to data transfer problems between the monitor and our computer-based data analysis system, the remaining five patients had to be excluded. For 26 patients, measurements were available for all pad positions A–D. The remaining six patients were only measured in pad position A. Admission diagnosis, known medical history, and other relevant clinical data are shown in Table 1. In the group of patients in or after cardiac arrest, 101 patients were eligible for entry into the study. For further analysis, 41 patients’ data were available, because in 60 patients simultaneous ventilation recordings were not available due to having patients ventilated via a bag valve system and not the ventilator. Under cardiac arrest (pulseless conditions), 20 of these patients could be analyzed (cardiac arrest group). Those patients either were admitted under ongoing chest compressions by the ambulance service (n _ 12) or had a witnessed cardiac arrest in our department (n _ 8); Figure 2. Mean thorax impedance change for each patient at tidal volumes of 400, 600, 800, and 1000 mL, with the tidal volumes expressed in mL (A) and mL/kg (. Each patient is represented with one set of markers for each tidal volume. 4 Crit Care Med 2006 Vol. 34, No. 9 six of the latter patients rearrested after achieving restoration of spontaneous circulation out of hospital. Spontaneous circulation was restored in 31 patients (nine of the former cardiac arrest group) during the resuscitation attempt (ROSC group). Patient characteristics, reasons for admittance, and clinically relevant data for cardiac arrest and ROSC patients are shown in table 1. Main Results Correlation Between Volume and Impedance Waveforms. Figure 1 shows a volume trace from a patient in the reference group and the corresponding thorax impedance signal before and after filtering. In Figure 1C and 1D, the volume trace is plotted against the resulting impedance. The mean (SD) correlation between the tidal volume waveforms and impedance waveforms for all ventilation cycles of all reference group patients in pad position A was calculated to be .971 (.027) before filtering and .9996 (.0008) after filtering. The correlations in the other pad positions were similar. For the ROSC group, the correlation was .969 (.032) and .9996 (.0009) before and after filtering. For the cardiac arrest group, the correlation was .967 (.035) before filtering. Relationship Between Tidal Volume and Impedance Change. Figure 2A shows the measured thorax impedance change for tidal volumes of 400, 600, 800, and 1000 mL for all patients in the reference group for pad position A. Figure 2B shows the same data as a function of specific tidal volume in mL/kg. It is seen that the measurement points for each patient essentially fall on a straight line, confirming a linear relationship across the entire tidal volume range. The mean (SD) of the impedance coefficients _ and _w for all useable patients in the reference group in pad position A were .00195 (.00066) _/mL and .148 (.035) _/kg/mL. It is seen that the percent-wise SD for the specific impedance coefficient _w (24%) is lower than for the impedance coefficient _ (34%), which implies that the impedance is more accurate for estimating the specific tidal volume. For all patients in all groups, the mean (SD) of the impedance coefficients _ and _w was .00194 (.0078) _/mL and .152 (.048) _/kg/mL. Accuracy of Tidal Volume Estimation. Figure 3 shows the estimation error of using the impedance for estimation of tidal volume. In Figure 3A a patientspecific model is used, and in Figure 3B a general model calculated from the entire data material is used. For the patientspecific model, most errors fall within 1 mL/kg of the true tidal volume. The mean (SD) estimation error for each patient is .0 (.108) for the patient-dependent model, with an SD of .0 for the patient means. If assuming that the estimation error is normal distribution, this implies that an estimate of 10 mL/kg will have an estimation error _2 mL/kg 95% of the time. The general model is less accurate, with a Figure 3. Estimation error overview of (A) the patient-fitted model and ( the general model. Each bin represents the percentage of ventilations with a specific estimation error for a specific tidal volume. The size of one bin is 0.5 _ 0.5 mL/kg. Crit Care Med 2006 Vol. 34, No. 9 5 larger spread in the estimation errors. For this model, the mean (SD) estimation error for each patient is .0 (.103), which is similar to the patient-dependent model. The SD of the patient means is, however, .365. If we assume that the patient means are normally distributed, this implies that for _30% of the patients, the mean estimation error will be _36.5% of the true tidal volume. Effect of Pad Position. Figure 4 shows box plots of the mean estimation error for each patient using the general model described previously. We observed that the spread of the estimation error is the same in the different pad positions. In pad positions B and C, the tidal volume is more susceptible to overestimation. DISCUSSION Choosing appropriate impedance thresholds for detecting the start and stop point of each ventilation enables to us estimate inspiration time and ventilation rate with good accuracy as a new concept in a clinical situation of advanced cardiac life support after cardiac arrest. As indicated by Figures 1 and 2, there is a very good correlation between tidal volume and impedance waveform. Although several studies prove the importance of correct pad placement for defibrillation or cardioversion, in daily routine most of the defibrillator pads are not placed according to guidelines (5, 17, 18). We found that the high correlation between impedance and tidal volume waveforms is not affected by alternative placement of the pads. This shows the robustness of the method for ventilation rate and inspiration time monitoring. The spread in _w across the patient group is found to be lowest for pad position A. This is an advantage, since A is the recommended position for the defibrillator pads and the normal position in a cardiac arrest situation. The specific impedance coefficient is generally lower for pad positions B, resulting in an underestimation of the tidal volume for these positions. By means of signal filtering, pulse and chest compression artifacts and noise can be removed and the correlation further improved, thus making monitoring necessary not only during isolated rescue breathing but also during segments of chest compressions. The filter employed in this work is an offline filter, which will introduce a significant signal delay, in the order of seconds. For electrocardiographic signals, chest compression artifacts have been successfully removed by advanced filtering techniques (26). To investigate the use of similar techniques to remove artifacts from impedance signals is, however, beyond the scope of this article. Therefore, no measurements have been carried out during ongoing chest compressions. For quantifying tidal volume, the large variation in the measured impedance coefficients represents a challenge. The physical mechanisms contributing to the interpatient variation in the impedance coefficient _ are not fully understood, but weight is an influencing factor. By dividing tidal volume with patient weight to obtain the specific impedance coefficient _w, the variation is reduced. This is in accordance with results from Valentenuzzi et al. (22), who found that there is an inverse correlation between the impedance coefficient and body weight. Baker and Geddes (21) observed that the impedance coefficient was correlated with the type of body build. However, we found no correlation between _w and the body mass index of the subjects. Trying to group our patient material based on visual appearance did not provide further insight on the inter-patient variation. It therefore seems questionable whether impedance-based feedback on ventilation volume will have any advantage over observing chest rise (7). Limitations of our study are that no measurements were carried out using a bag-valve-mask, which is a more widespread technique than using a ventilator. However, since thoracic impedance is first of all affected by changes in the lung volume, it is reasonable to assume that a high correlation would be found also with the use of a bag-valve-mask. Despite these potential drawbacks, many investigators (11, 27–34) have reported that transthoracic impedance plethysmography correlates well with reference standard clinical measurement of respiratory rate. If clinical measurement of respiratory rate and volume is inaccurate or impractical, an obvious imperative is to seek an alternative. There is a long list of proposed alternatives (35). All of them have been reported to correlate well with “criterion standard” clinical measurement of respiratory rate. We chose to use transthoracic impedance plethysmography in this study because it could easily be used via AED pads and its use has not been described in a life-threatening situation such as advanced cardiac life support after cardiac arrest. The potential for a study bias needs to be addressed as a result of the number of exclusions necessary by the technical potentialities and by the comorbidity of our patients. Our study does not encompass patients with COPD or ventilations during gasping, which may limit the generalizability of our findings. Rescuers who encounter an unconscious patient are trained to follow the chain of survival developed by the American Heart Association (5). Checking for signs of circulation and breathing is fundamental. Optimally, rescuers would be appropriately directed to perform initial defibrillation and chest compression in settings of primary cardiac arrest and to provide initial attention to the airway and ventilation in instances of asphyxial cardiac arrest. However, there is presently no capability on the part of lay rescuers to distinguish between primary cardiac arrest and asphyxial arrest. Impedance is measured Figure 4. Distribution (box plot) of the mean relative estimation error per mL/kg of tidal volume given for the general model at different pad positions. 6 Crit Care Med 2006 Vol. 34, No. 9 through the defibrillator pads in their standard position. If incorporated into an AED, this technique can thus be used to monitor ventilation rate and inspiration time in a cardiac arrest situation, as an aid to give ventilation-related feedback to the rescuer. There is increasing evidence that feedback during CPR is important because of the bad quality of CPR (1–4). CPR quality could be improved by monitoring ventilation activity and giving real-time feedback to avoid hyperventilation or inadequate ventilation (9, 13). This monitoring/feedback technique was designed to be incorporated into conventional AEDs and to work in conjunction with the information derived from rhythm analyses by the AED. The equipment is familiar to medical personnel and is user friendly. Impedance plethysmography was described as early as 1897 by Stewart and proposed for noninvasive measurements of cardiac output (33, 34, 36–38). Further studies have to prove whether the method is valid if only bag-valve-mask ventilation is employed, whether esophageal intubations could be detected, and whether the device could also be used in pediatric patients, after traumatic injuries, during drowning, after obstruction to the airway by food or other particulates, or in settings of sudden infant death. CONCLUSION The present study showed that the impedance measurement system sensor of a defibrillator is likely to provide adequate monitoring of the presence or absence of ventilations, which would also allow quantification of ventilation rates and inspiration times. However, this technology, at its present state, provides only limited practical means for exact tidal volume estimation. REFERENCES 1. Wik L, Kramer-Johansen J, Myklebust H, et al: Quality of cardiopulmonary resuscitation during out-of-hospital cardiac arrest. JAMA 2005; 293:299–304 2. Abella BS, Alvarado JP, Myklebust H, et al: Quality of cardiopulmonary resuscitation during in-hospital cardiac arrest. JAMA 2005; 293:305–310 3. Abella BS, Sandbo N, Vassilatos P, et al: Chest compression rates during cardiopulmonary resuscitation are suboptimal. A prospective study during in-hospital cardiac arrest. Circulation 2005; 111:428–434 4. 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Hello Everyone, Here's a recent study which shows that even in hospital ETI and RSI have many of the same complications we experience.... So as you can see this doesn't just happen to us... Hope This Helps, ACE844 (Clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: A prospective @ multiple-center study* Samir Jaber, MD, PhD; Jibba Amraoui, MD; Jean-Yves Lefrant, MD, PhD; Charles Arich, MD; Robert Cohendy, MD, PhD; Liliane Landreau, MD; Yves Calvet, MD; Xavier Capdevila, MD, PhD; Aba Mahamat, MD; Jean-Jacques Eledjam, MD, PhD) Emergency endotracheal intubation (ETI) in critically ill patients can be fraught with mild to severe life-threatening complications related to hemodynamic alterations and difficulty with oxygenation and ventilation (1–4). In the intensive care unit (ICU), this procedure differs significantly from ETI carried out for routine surgical procedures (5–9). In the operating room, most intubations are performed under elective controlled conditions by anesthesiologists experienced in airway management (8, 10, 11). The rate of complications is relatively low (8, 10, 11). In the ICU, tracheal intubations are frequently done urgently to treat severe respiratory failure and/or as part of cardiorespiratory resuscitation (1–3, 12). Tracheal intubation is sometimes done electively, but diseases that require mechanical ventilation often necessitate rapid endotracheal intubation to avoid arterial desaturation. Emergency ETI performed outside the operating room has been studied more often in prehospital settings (13, 14) and in emergency departments (13, 14). Only two studies have focused on the complications related to ETI performed in the ICU. Schwartz et al. (1) performed a descriptive study in three ICUs of a single institution, investigating the complications of emergency airway management in 297 critically ill patients carried out by the ICU team. Le Tacon et al. (2), in a prospective study on relatively small cohort (n 80), performed a single-center evaluation of the frequency of difficult ETI and listed the related complications. No study has focused on potential conditions that could be considered as risk factors for complications associated with ETI and reported associated hemodynamic complications. Therefore, a multiple-center observational study was performed in seven French ICUs to describe the current practice of physicians, to report complications associated with endotracheal intubation in ICU, and to isolate predictive factors of immediate life-threatening complications. PATIENTS AND METHODS Eligibility Criteria The present observational study was performed in seven southern French ICUs (three *See also p. 00. From the Intensive Care Unit, Department of Anesthesiology B, DAR B CHU de Montpellier, Hôpital Saint Eloi, Université Montpellier 1, Montpellier, cedex 5 France (SJ, JA, JJE); Fédération Anesthésie-Douleur-Urgences- Réanimation, Groupe Hospitalo-Universitaire Caremeau, Centre Hospitalier Universitaire Nîmes, Nîmes cedex 9,France (JA, JYL, CA, RC); Service de réanimation médicale assistance respiratoire, CHU de Montpellier, Hôpital Gui-de-Chauliac, Montpellier cedex 5, France (LL); Réanimation polyvalente, Clinique du Parc, Castelnau-le-Lez, France (YC); Intensive Care Unit, Department of Anesthesiology A, DAR A CHU de Montpellier, Hôpital Lapeyronie, Montpellier, cedex 5 France (XC); and Département d’Information Médicale, Groupe Hospitalo-Universitaire Caremeau, Centre Hospitalier Universitaire Nîmes, Nîmes cedex 9, France (AM). The authors have not disclosed any involvement in any organization with a direct financial interest in the subject of the manuscript. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000233879.58720.87 Objectives: To describe the current practice of physicians, to report complications associated with endotracheal intubation (ETI) performed in THE intensive care unit (ICU), and to isolate predictive factors of immediate life-threatening complications. Design: Multiple-center observational study. Setting: Seven intensive care units of two university hospitals. Patients: We evaluated 253 occurrences of ETI in 220 patients. Interventions: From January 1 to June 30, 2003, data related to all ETI performed in ICU were collected. Information regarding patient descriptors, procedures, and immediate complications were analyzed. Measurements and Main Results: The main indications to intubate the trachea were acute respiratory failure, shock, and coma. Some 148 ETIs (59%) were performed by residents. At least one severe complication occurred in 71 ETIs (28%): severe hypoxemia (26%), hemodynamic collapse (25%), and cardiac arrest (2%). The other complications were difficult intubation (12%), cardiac arrhythmia (10%), esophageal intubation (5%), and aspiration (2%). Presence of acute respiratory failure and the presence of shock as an indication for ETI were identified as independent risk factors for occurrence of complications, and ETI performed by a junior physician supervised by a senior (i.e., two operators) was identified as a protective factor for the occurrence of complications. Conclusions: ETI in ICU patients is associated with a high rate of immediate and severe life-threatening complications. Independent risk factors of complication occurrence were presence of acute respiratory failure and presence of shock as an indication for ETI. Further studies should aim to better define protocols for intubation in critically ill patients to make this procedure safer. (Crit Care Med 2006; 34:●●●–●●●) Crit Care Med 2006 Vol. 34, No. 9 1 medicosurgical, two medical, and two surgical units) that included a total of 85 beds. From January 1 to June 30, 2003, data related to all ETIs performed in these ICUs were collected and analyzed. Intubations performed outside of the ICU (in the operating room, in and outside the hospital) were not studied. The local ethics committee in human research of Montpellier University Hospital approved this observational study and stated that no informed consent of the patient or next of kin was required. No attempt was made to change intubation practices during the course of the study. Definitions and Measurements All data for each ETI were obtained by the intubating physician or the supervisor and verified by the investigators. For each ETI performed in ICU, the following variables were documented: Patient Characteristics. We documented age; gender; reason for admission to ICU; Simplified Acute Physiology Score (SAPS) II (15) on admission; status of the following within the 60 mins before ETI: systolic blood pressure, heart rate, the use of vasopressors, pulse oximetry, the use of nasal oxygen therapy and noninvasive ventilation; route of ETI (nasal or oral); and status of the following in the 60 mins after ETI: systolic blood pressure, heart rate, the use of vasopressor, pulse oximetry. Clinical outcomes measured included the number of days of mechanical ventilation, the length of stay in ICU, and the vital status (dead or alive). Procedure Descriptors. We documented time of the procedure: Daytime procedure was defined as an ETI performed between Monday and Friday from 8 am to 7 pm. Otherwise, time of procedure was defined as on-call procedure. We also documented the mean reason for ETI, defined as acute respiratory failure (dyspnea with arterial desaturation 90% and/or altered mental state), shock (systolic blood pressure 90 mm Hg), cardiac arrest, or neurologic disorder (Glasgow Coma Scale score 8). The emergency characteristic of ETI was categorized as follows: real emergency ETI required without any delay, relative emergency ETI required within 1 hr, and deferred emergency ETI required in 1 hr; whether the patient was informed about the ETI; and the physician involved in the ETI. The medical staff included residents training in anesthesiology (all had experience in ETI in operating room 1 yr) and skilled physicians (anesthesiologists and intensivists with experience in ETI 5 yrs and experience in ICU1 yr). We also recorded the use of anesthesia and the anesthetic drugs used: Hypnotics were separated into short-acting (thiopental, etomidate, propofol) and long-acting groups (hypnotics such as benzodiazepine) and opioids (fentanyl, sufentanil, others). Neuromuscular blocking drugs (NMBDs) were separated into short-acting (succinylcholine) and longacting NMBDs (pancuronium, vecuronium, atracurium, and cis-atracurium). A rapid sequence induction was defined as the administration of a short-acting induction agent and succinylcholine to achieve rapid loss of consciousness and paralysis, the application of cricoid pressure (Sellick maneuver), and securing of the airway without insufflation to avoid regurgitation (16). Immediate Complications Associated With ETI. Immediate complications occurring within 30 mins after ETI were divided into two categories (1, 13, 17, 18): a) severe life-threatening complications: cardiac arrest or death, severe cardiovascular collapse defined as systolic blood pressure 65 mm Hg recorded at least one time and/or 90 mm Hg that lasted 30 mins despite 500–1000 mL of vascular loading (crystalloids/or colloids solutions) and/or necessitating introduction of vasoactive support, or severe hypoxemia (decrease in oxygen saturation by pulse oximetry to 80% during attempts); mild to moderate complications: difficult intubation (three or more attempts at laryngoscopy to place the endotracheal tube into the trachea and/or 10 mins using conventional laryngoscopy and/or the need for another operator) (1, 19), aspiration of gastric contents, esophageal intubation, dental injury, supraventricular and/or ventricular arrhythmia (without loss of pulse), and dangerous agitation. Statistical Analysis Continuous measurements are expressed in mean SD. Patients who had ETI complications were compared with those who did not have complications. Categorical variables were compared using Fisher’s exact test. Ordinal and continuous variables were compared using the Mann-Whitney test. For the observational study, all procedures were included. However, to determine predictors of an adverse outcome, only the first ETI in ICU was considered; patients with ETI due to cardiac arrest were excluded. Univariate regression analysis was used to assess association between the following risk factors and the risk of ETI complications: age, gender, SAPS II score, acute respiratory failure, coma, use of NMBDs, use of etomidate, use of opioids, ETI performed by junior, vascular loading (500, 500–1000, 1000 mL), lowest systolic blood pressure, lowest pulse oxygen saturation, and weaning failure. All prognostic variables that had a p .20 determined by the univariate regression were entered into a multivariate logistic regression model. ETI as the dependent variable and the models were performed by the means of a stepwise backward procedure. Odds ratios are presented with 95% confidence intervals. The Hosmer and Lemeshow test was used to test the goodness-of-fit. All reported p values are twotailed, and a value .05 was considered statistically significant. Statistical analyses were performed using SAS/STAT software version 8.1 (SAS Institute, Cary, NC). RESULTS During the study period, 1,650 patients were admitted in the 85 beds of the seven ICUs. Two hundred and sixty-three ETIs were performed during the study but ten could not be analyzed because data were missing and/or incomplete. Therefore, the present study included 253 ETIs in 220 patients. The mean rate of intubated patients in the seven ICUs was 74% (1,221 of 1,650). In fact, among the 1,221 intubated patients, 263 intubations were performed in the ICU (22%) and the others were performed outside the ICU (operating room, emergency department, prehospital setting). Table 1 shows the comparison between patients with life-threatening complications related to ETI and those with no life-threatening complications. Thirty-one patients were intubated twice, two patients three times, and one patient four times. ETI Procedure Description Among 253 ETIs, the main indications for intubation were acute respiratory failure, shock, and neurologic disorders (Table 1). The main characteristics of the procedure are reported in Table 2. The hypnotic, opioid, and neuromuscular drugs used are shown in Table 3. ETIs were performed by oral or nasal route in 246 and seven patients, respectively. Seventy-five percent of intubations were done on the first attempt, 13% required two attempts, 9% required three attempts, and 3% required at least four attempts. ETI-Related Complications The two categories of ETI complications (severe life-threatening and mild to moderate complications) are shown in Figure 1. At least one severe complication occurred in 71 ETI procedures (28%). Severe hemodynamic collapse was observed in 65 of them, and severe hypoxemia occurred in 66 ETI procedures. Cardiac arrest occurred in four ETI (1.6%) procedures, and there were two deaths at the time of or within 30 mins after intubation; two other patients died at day 2 and day 9. In 30 patients (12%), three or more attempts were needed and/or the intervention of another skilled operator was required. Among these 30 patients with difficult intubation, 12 developed severe hypoxemia and seven had severe cardiovascular collapse. The use of a fiberoptic laryngoscope was required in two of the 30 patients. Among the 22 patients intubated for shock, none had a difficult intubation. 2 Crit Care Med 2006 Vol. 34, No. 9 Cardiac arrhythmias occurred in 25 patients (10%). Esophageal intubations occurred in 12 patients (4.6%) but were always diagnosed with auscultation leading to immediate reintubation without any oxygen desaturation. The mean decreases in the highest and lowest systolic blood pressure values obtained before and during or immediately after the ETI attempt are presented in Figures 2 and 3. The mean decreases in lowest pulse oxygen saturation calculated between the values before and during the procedure for patients with complicated ETI and those with no complication are presented in Figure 4. Risk Factors for Serious ETI-Related Complication The patients with severe ETI complications were significantly older and had a significantly higher SAPS II than those with no ETI complications (Table 1). They also had a significantly more precarious hemodynamic status as evidenced by shock being a more prevalent reason for ICU admission, a lower systolic blood pressure (Fig. 2), increased fluid loading requirement, and vasopressor use. The multivariate analysis (Table 4) showed that the lower the systolic blood pressure was before the intubation, the higher the risk of having an ETI complication. The other independent risk factor for ETI complication was acute respiratory failure as a reason for intubation. An ETI attempt performed by a resident who was always supervised by a senior (i.e., two operators) was found to be the only protective factor for the ETI complication occurrence. The main outcomes of the 220 included ICU patients are shown in Table 5. The patients who had serious complications had a significantly higher mortality rate than the patients who did not have complications, but they also had a significantly higher SAPS II score (Table 1). In fact, the observed mortality rate was in agreement with the predicted mortality rate according to the SAPS II for each group. DISCUSSION The main results of this study are that ETI performed in ICU patients is associated with a high rate of immediate and severe life-threatening complications of about 28% and that independent risk factors of complications were presence of acute respiratory failure and/or presence shock as an indication for ETI. Moreover, ETI performed by a junior physician supervised by a senior (i.e., two operators) was identified as a protective factor for ETI complication occurrence. This is the second prospective study to evaluate the early complications of airway management in critically ill adults, but it is the first study to report the risk factors of ETI complications with hemodynamic profiles and it is the largest series reported including 253 intubations performed in 220 ICU patients. Table 1. Patient characteristics and reasons for intensive care unit (ICU) admission Total (n 253) Complications (n 71) No Complications (n 182) p Value Age, yrs, mean (SD) 63 16 68 12 61 17 .001 Male gender, n (%) 180 (71) 44 (62) 136 (75) .04 SAPS II, mean (SD) 46 19 54 21 43 17 .001 Weight, kg, mean (SD) 73 18 74 19 73 18 NS Height, cm, mean (SD) 169 8 169 8 169 9 NS Type of admission, n (%) Medical 203 (80) 56 (79) 147 (81) NS Surgical 50 (20) 15 (21) 35 (19) NS Reason for ICU admission, n (%) Acute respiratory failure 134 (53) 34 (48) 100 (55) NS Shock 33 (13) 18 (25) 15 (8) .02 Trauma 7 (3) 1 (1) 6 (3) NS Postoperative 20 (8) 5 (7) 15 (8) NS Cardiac arrest 3 (1) 2 (3) 1 (1) NS Neurologic 34 (13) 5 (7) 29 (16) NS Others 22 (9) 6 (9) 16 (9) NS Reason for intubation, n (%) Acute respiratory failure 159 (63) 33 (47) 126 (69) NS Shock 22 (9) 15 (21) 7 (4) .03 Coma 33 (13) 10 (14) 23 (13) NS Cardiac arrest 6 (3) 6 (9) 0 (0) NS Replace the endotracheal tube 7 (3) 1 (1) 6 (3) NS Unplanned extubation 7 (3) 1 (1) 6 (3) NS Others 19 (8) 5 (7) 14 (8) NS SAPS, Simplified Acute Physiology Score (15); NS, not significant. Table 2. Operator status and main variables obtained before intubation Total (n 253) Complications (n 71) No Complications (n 182) p Value Time, n (%) Day 128 (51) 38 (54) 90 (49) NS Night 125 (49) 33 (46) 92 (51) NS Anesthesiology training, n (%) 171 (68) 51 (72) 120 (66) NS Operator, n (%) Senior 107 (42) 38 (54) 69 (38) .04 Junior 146 (58) 33 (46) 113 (62) .04 Informed patient, n (%) 129 (51) 34 (48) 95 (52) NS Fluid loading, n (%) 109 (43) 43 (61) 66 (36) .001 500 mL 51 (20) 18 (25) 33 (18) NS 500–1000 mL 45 (18) 18 (25) 27 (14) 0.05 1000 mL 13 (5) 7 (10) 6 (3) 0.03 Lowest systolic blood pressure, mm Hg, mean (SD) 102 35 80 37 113 28 .001 Emergency characteristic of ETI, n (%) Real emergency 127 (50) 40 (56) 87 (48) NS Relative emergency 97 (38) 25 (35) 72 (39) NS Deferred emergency 29 (12) 6 (9) 23 (13) NS Vasopressor use, n (%) 41 (16) 23 (32) 18 (10) .001 Noninvasive ventilation, n (%) 97 (38) 24 (34) 73 (40) NS Nasogastric tube, n (%) 89 (35) 24 (34) 65 (36) NS Glasgow Coma Scale score 11 4 10 4 11 4 NS NS, not significant. Crit Care Med 2006 Vol. 34, No. 9 3 ETI Practices In this prospective multiple-center descriptive study, 88% of the 253 ETIs were performed in emergency or in relative emergency conditions. Etomidate was the most common hypnotic agent (50%) used, and succinylcholine was the neuromuscular blocker (69%) most used for this cohort of patients (Table 3). Etomidate has become the induction agent of choice in many institutions because of its hemodynamic safety profile (9, 20). The use of neuromuscular blockers, especially nondepolarizing agents, could lead to life-threatening hypoxia when the trachea cannot be intubated; these agents induce prolonged paralysis with no spontaneous respiration. This explains why succinylcholine was the most commonly used neuromuscular blocker, allowing the patient to breathe spontaneously after 2–3 mins. Muscle relaxants were used to facilitate 62% of all intubations in our study, which was lower than the 80% rate reported by Schwartz et al. (1) and higher than the 22% rate reported by Le Tacon et al. (2). The use of succinylcholine in our study (69%) was more frequent than that reported by Schwartz et al. (1) and Le Tacon et al. (2), who reported usage rates of 57% and 41%, respectively. These differences in anesthetic agents use and more particularly neuromuscular blocker use among different studies can be explained in part by the lack of randomized controlled studies comparing different protocols to manage tracheal intubation in the ICU, as well as the lack of exhaustive recommendations for airway management in critically ill patients contrary to patients anesthetized in the operating room for surgery (19). Immediate Complications Associated With ETI and Risk Factors Complications occurred in nearly half of the patients, and serious complications occurred in 28%. The most frequent of them were hypotension leading to a frequent use of vasopressor and severe hypoxemia, which occurred with a similar incidence (Fig. 1). The complications of ETI did not differ by location or time of day of the procedure (Table 2) as reported by Schwartz et al. (1). After a multivariate analysis, hypotension and acute respiratory failure were independent risk factors for complications, whereas an ETI performed by a junior supervised by senior physician was a protective factor. This fact can be surprising, but all the ETI procedures performed by the junior were supervised by a senior, which could mean that for each ETI, the presence of at least two operators improved the conditions of the procedure. In other words, a second pair of hands is often useful in helping to manage a difficult situation. In fact, the two main risk factors for immediate complications after tracheal intubation are precisely the two main indications for tracheal intubation. In other words, if tracheal intubation is justified because of shock or acute respiratory failure, tracheal intubation may result in severe hemodynamic collapse or severe hypoxemia. In these cases, it is difficult to clearly differentiate the cause from the effect. The incidence of difficult intubation in the present study was 12%. This percentage is similar to that reported by Schwartz et al. (8%) (1) but remains lower than those reported in the Le Tacon study of 22% (2). Although 67% of physicians and residents involved in the present study were anesthesiologists, there was no difference in diffi- Table 3. Incidence of use of each anesthetic drug for endotracheal intubation Total (n 253) Complications (n 71) No Complications (n 182) p Value Anesthetic drugs used, n (%) 229 (91) 61 (86) 168 (92) NS Rapid sequence induction, n (%) 92 (36) 26 (37) 66 (36) NS Hypnotic, n (%) Thiopental 23 (9) 5 (7) 18 (10) NS Propofol 36 (14) 5 (7) 31 (17) NS Etomidate 126 (50) 33 (46) 93 (51) NS Others 44 (17) 18 (25) 26 (14) NS Opioids, n (%) 66 (30) 22 (31) 44 (24) NS Fentanyl 27 (41) 7 (32) 20 (45) NS Sufentanyl 12 (18) 6 (27) 6 (14) NS Others 27 (41) 9 (41) 18 (41) NS Neuromuscular blocking drugs, n (%) 156 (62) 35 (49) 121 (67) .04 Succinylcholine 108 (69) 20 (57) 88 (73) NS Others 48 (31) 15 (43) 33 (27) NS 0% 5% 10% 15% 20% 25% 30% Severe hypoxemia Severe collapse Cardiacarrest Death Difficult intubation Cardiacarrhythmia Esophgeal intubation Agitation Aspiration Dental injury Figure 1. Incidence of the two categories of endotracheal intubation complications in the whole group: severe complications (serious hypoxemia, severe collapses, cardiac arrest and death) and mild to moderate complications (difficult intubation, cardiac arrhythmia, esophageal intubation, agitation, aspiration and dental injury). Mortality rate is calculated based on the 247 intubations carried out for patients with an obtainable blood pressure at the time of procedure. 4 Crit Care Med 2006 Vol. 34, No. 9 cult intubations between anesthesiologists and nonanesthesiologists. Therefore, most of the operators could be considered experienced in this procedure. The lack of statistically significant differences in complication rates between anesthesiologists and nonanesthesiologist physicians shows that appropriately trained and experienced nonanesthetist physicians in the ICU have a similar high level of airway management patient safety compared with anesthesiologists. As reported by Schwartz et al. (1), multiple attempts were not associated with adverse outcomes such as seizures or cardiac arrest. Rapid sequence induction with Sellick’s technique was applied in 36% of ETIs and was not significantly different between the complicated and noncomplicated ETI patients, whereas it is recommended in emergency conditions and/or in patients with a full stomach (19). This technique is strongly recommended for emergency anesthesia and is probably unknown among nonanesthesiologists. However, even when this technique was applied, aspiration was not always avoided (5). In our study, we defined cardiac arrest and mortality associated with intubation if they occurred during or within 30 mins of the procedure. During 247 intubations performed in 214 patients for reasons other than cardiac arrest, four patients developed cardiac arrest (1.6%) and two (0.8%) met the definition of intubation-associated mortality. The two other patients died at day 2 and day 9. The rate of death in the Schwartz study (1) was 3% and was higher than in the present study. However, these authors reported all intubations including those performed outside the ICU. One of the most critical determinations during noninvasive ventilation is when intubation is necessary. It is possible that a delay in intubation was a cause for the significant increase in the risk of death in patients treated by noninvasive ventilation reported in clinical trials, through a number of mechanisms such as cardiac ischemia, increased respiratory muscle fatigue, aspiration pneumonitis, and complications of emergency intubation (21–23). The high rates of serious complications obtained in our study for severe collapse (25%) and severe hypoxemia (26%) were surprising, although we used a very strict definition for this complication even if it occurred transiently. However, these rates were reported for the first time, because no previous study documented these complications. Limitations Our study has some limitations. The data were self-reported by the persons who performed the ETI, so the degree of intubation difficulty may have been underestimated or overestimated to be consistent with the results. This study is purely a descriptive report of the ETI practices in ICU. Because patients were not randomly assigned to different methods of intubation, Lowest systolic blood pressure 0 30 60 90 120 150 180 before ETI during ETI mmHg complications no complications Highest systolic blood pressure 0 30 60 90 120 150 180 before ETI during ETI mmHg complications no complications * ** * ** Figure 2. Evolution of lowest and highest systolic blood pressures recorded before and during 253 endotracheal intubation (ETI) procedures obtained for the 71 patients who had severe complications (complications) and the 182 patients who did not have severe complications (no complications). The lowest and highest systolic blood pressures were those recorded within the 10 mins before and after ETI procedure. *p .05; **p .01 (p values pertain to differences between complication group and noncomplication group). -50 -40 -30 -20 -10 0 Decrease in lowest SBP Decrease in Highest SBP % complications no complications ** ** Figure 3. Variation between the lowest and the highest systolic blood pressures (SBP) obtained before and during the endotracheal intubation procedures obtained for the 71 attempts with severe complications (complications) and the 182 attempts with no severe complications (no complications). **p .01. Crit Care Med 2006 Vol. 34, No. 9 5 the success rates and rates of immediate complications for the different methods must be interpreted with caution. Because the observed complications may be due to the severity of illness of the patient, we chose very “extreme” definitions of collapse due to ETI and severe hypoxemia. Indeed, the patients who had hemodynamic instability before ETI developed severe hypoxemia more often and patients who had been intubated for respiratory distress developed a collapse more often after ETI. Another limitation is that we did not record the dose of total administered drugs used for ETI, and we cannot evaluate the correlation with the degree of hypotension occurring after the attempt. However, among the 22 patients intubated for shock, none had a difficult intubation, which implies that in these patients the dose of administered drugs did not influence intubation conditions. CONCLUSION This prospective multiple-center study of 253 endotracheal intubations performed in ICU showed a high frequency of serious life-threatening complications (28%) including severe hypotension (26%), severe hypoxemia (25%), cardiac arrest (1.6%), and death (0.8%). Presence of acute respiratory failure and presence of shock as an indication for ETI were identified as independent risk factors of complication occurrence. Moreover, ETI performed by a junior physician supervised by a senior (i.e., two operators) was identified as a protective effect of ETI complication occurrence. Further studies should aim to better define protocols (drugs, dosage, rapid sequence induction, systematic loading) for endotracheal intubation in critically ill patients to make this procedure safer. ACKNOWLEDGMENTS We thank all the nurses and doctors of all the units who contributed to this effort. We are grateful to Pr. Frédéric Adnet and Pr. Peter Dodek for very useful comments. REFERENCES 1. Schwartz DE, Matthay MA, Cohen NH: Death and other complications of emergency airway management in critically ill adults. Anesthesiology 1995; 82:367–376 2. Le Tacon S, Wolter P, Rusterholtz T, et al: Complications of difficult tracheal intubations in a critical care unit. 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Lowest pulse oxygen saturation (SpO2) obtained before and during attempts for the 233 endotracheal intubation (ETI) procedures for which pulse oximetry can be recorded: 59 attempts with severe complications (complications) and 174 attempts without severe complications (no complications). NS, not significant; *p .05. Table 4. Multivariate logistic regression analysis to assess independent risk factors for development of endotracheal intubation (ETI) complications Predictive Risk Factor Odds Ratio 95% Confidence Interval Acute respiratory failure 3.04 1.08 8.75 Lowest systolic blood pressure 0.98 0.98 0.99 Junior operator 0.42 0.22 0.78 The 247 ETI attempts obtained in 214 patients were included for analysis. The six patients intubated for cardiac arrest were not included for the multivariate logistic regression analysis. For the lowest systolic blood pressure, the odd ratio is expressed per 1 mm Hg. 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I agree with all the above posters. You know I can't decide which factor or factors in this case that is the worst in the following factors. A.) Be it that this individual came here and tried use us all to help themselves feel better for bashing on Nurses and having no real understanding of the events that were unfolding. B.) The fact they came from an 'educated' area-sysstem design and still suffered #1. C.) That this person had no concept that by their own description this patient was at best highly unstable, and more than probably unsafe for transfer. D.) As mentioned previously; that this individual posted more anecdotal 'shtuff' to try to support their case and yet saw nothing wrong with their or their partners actions here. E.) That this they never considered air or other more appropriate asset use or to call their OLMC doc to expalin why they thought this patient may be should not take an hour ride with the standard non-CCT ALS ground ambulance and that this individual had no idea this IS A TRUE EMERGENCY. This is further compounded by the fact that there was no consideration given to thwe fact that 'immediate non-stabilized transfer' in this method may actually increase this patients mortality... :roll: F.) All of the above factors in combination with so many more I don't have the time or deire to expend the effort to point them all out... Why do we allow people like this to practice and continue with this type of performance in EMS?!?!? If we allow this to continue amongst our peers why are we surprised when the Janitors and secretaries make more than we do and achieve a better professional standing?!?!?!!? Out Here, ACE844

"Dust," Just for future reference the 2 cities are about 70-80 miles apart. Although I do agree that your assessment could have been a distinct possibility in many systems..GREAT ADVICE!! Good Hunting, ACE844

"Imagine," As someone who has worked extensively in that I system I can tell you the following. UMASS ER is extremely busy, busy enough to rival BMC or MGH most days. So most probably you got an over worked ER nurse on the C-med radio who in terse language tried to explain THAT YOU SHOULD HAVE DONE THE FOLLOWING FOR FUTURE REFRENCE: A.) UMass pedi and adult ER's are 'joined' but are next to one another with the 'adults' on one side, and pedi on another. They also have 2 c-maed extensions on different 'frequencies' which is the best way to explain it. The 'Adult' radio is located behind the trauma rooms and the 'PEDI' radio is in the glass cubicle where the pedi residents and attendings sit and write their notes etc.. There is also usually always a nurse or secretary in the area to 'hear' the radio. B.) When you began your entry note via Worcester C-med, you should have told the operator that you wanted an ENTRY NOTE TO UMASS PEDI, that would have caused the operator to 'put you through' to the correct radio and thus relieved yourself and the nurse of 'ire' and the need for explanation. C.) So in closing most like this was a breakdown at the c-med dispatcher level, or a result of a person improperly requesting a patch, or any combination there of. Fact of the matter is, the only way to control which radio the patch goes to is at the CMASS EMS c-med dispatcher level. D.) If your partner or the other person involved worked for sleazecare, I mean EAScare, in worc. than they should have known better to begin with. E.) I find it SAD AND DISTURBING THAT NOONE ON YOUR SERVICE KNEW BETTER AS THIS IS COMMON KNOWLEDGE IN THIS SYSTEM!!! Hope this Helps, ACE844

This Seems to be pandemic today

see above

:!: In a manner of speaking yes, one may safely arrive at that conclusion :arrow: :!: :!: :shock: :shock: :shock: you have a PM.... :arrow:

How is a seizing gravid overdue Female PATIENT NOT AN EMERGENCY!?!?!?!?!?!!?

Mr Miyage Karate Kid

Because I have been warned that i must be PC and kind... I will again say this...ALSO ADD THIS PAGE TO THAT LIST [marq=UP:40d37741d3]PLEASE [/marq:40d37741d3]

Excellent points and well written "Paramedicmike,"!!! In addition to "Mike's," last point I'd also recommend you admit you made the mistake, man up and take responsibility. At that point you may find the reception you get is abit more welcoming.... ACE

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[marq=up:952c18eaea]WHAT?!!?!?!?!?!?!?[/marq:952c18eaea]

[marq=left:3600578e43]I ADVISE YOU TO READ THIS THREAD ENTIRELY AND THEN DO A SEARCH AND READ THOSE IN THEIR ENTIRETY AS WELL!!! THEN COME BACK HERE AND RE-READ WHAT YOU POSTED AND THEN YOU'LL SEE WHY YOU GOT THE RESPONSE YOU DID...THANKS...ACE844[/marq:3600578e43] THE BURDEN OF PROOF AND EVIDENCE IS ON YOU!!! Out Here, ACE844

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