Extracorporeal life support (ECLS) encompasses an increasingly broad range of modalities. While life support systems such as mechanical ventilation and renal replacement therapies have become more commonplace, the increasing level of complexity of patients managed in critical care settings has also increased the need for ECLS. This review highlights the most current ECLS therapies for patients with severe traumatic injuries and proposes a total extracorporeal organ support system (TECOS) as the future direction of multi-organ system life support.  
by Dr Maureen McCunn and Dr Amy J Reed

Extracorporeal support systems
Emergency perfusion resuscitation (EPR)
A major cause of cardiac arrest and death following traumatic injury is hemorrhage. Extensive laboratory research has led to the suggestion that there may be a role for extracorporeal “suspended animation” with ECLS/EPR and hypothermia following hemorrhagic cardiac arrest. Rapid induction of hypothermia with delayed resuscitation using cardiopulmonary bypass in laboratory animals provides a
near-bloodless surgical field and often allows a good recovery.

In humans a suggested clinical indication for EPR is in patients suffering traumatic cardiac arrest from hemorrhage, with loss of vital signs on hospital admission. The EPR protocol, designed for those patients who do not immediately respond to emergent thoracotomy, is currently in clinical trials. Following cannulation, patients are cooled with a rapid intra-aortic flush and cardiopulmonary bypass is used during delayed resuscitation and rewarming.

Extracorporeal cardiopulmonary resuscitation (ECPR)
Extracorporeal cardiopulmonary resuscitation (ECPR) following cardiac arrest is the most rapidly increasing indication for ECLS. A recent review from the Extracorporeal Life Support Organization reported that 11% of the use of ECLS for ECPR in adults was with cases of cardiac arrest. In these patients, there was a statistically significant trend towards decreased survival with increased length of treatment. Survival to hospital discharge was 27%, but 33% of patients suffered neurological sequela (seizure, intracranial bleeding, stroke or brain death).

Extracorporeal membrane oxygenation (ECMO)
ECMO is often the only option when mechanical ventilation fails to achieve adequate oxygenation and/or carbon dioxide exchange. The CESAR (Conventional Ventilation or ECMO for Severe Adult Respiratory Failure) trial evaluated ECMO versus conventional ventilation for severe respiratory failure. Of the patients who received ECMO, 57 of 90 met the primary endpoint of survival or absence of severe disability at six months compared with 41 of 87 patients in the conventional ventilation group. This translated to a relative risk in favor of the ECMO group of 0.69, suggesting early ECMO intervention may be beneficial.

Concern over the use of ECMO following trauma is not supported by the literature. A case series from 2004 -2007 reports on nine patients with post-traumatic acute respiratory distress syndrome (ARDS) who had failed conventional therapies. Of these, seven patients (77.8%) were weaned and discharged. Clinicians in Germany have also had recent success with VA ECMO in treating ARDS following severe chest injury in poly-traumatized patients.

Use of a pumpless extracorporeal circuit has been recently reviewed, which has the advantage of being simple and efficient. This allows  for easier intra-hospital, inter-hospital and even international transport. Weaning was successful in 52.2% of patients and overall 33.1% of patients survived to hospital discharge. There are technical hemodynamic limitations imposed by this system due to an arteriovenous shunt intrinsic in the circuit, although a pump can be added into the circuit and VA ECMO, with flow reversal through the cannulas. This system has applications for military field use and as a ‘bridge’ to definitive resuscitation.

Despite the need for specialized equipment and practitioners, a recent study series suggest that even hospitals with limited experience may have good results following ECLS. Usage of this treatment modality is further expanded by data supporting inclusion of patient populations who were previously excluded (e.g.
based on age).

Renal replacement therapy
Acute kidney injury (AKI) or exacerbation of existing renal dysfunction is a common sequela of traumatic injury. Additionally, AKI can lead to lung damage via cellular and soluble mediators. Acute lung injury (ALI) in turn, facilitates and exacerbates kidney dysfunction via metabolic and biomechanical derangements and may also lead to the production of factors that may be renally cytotoxic. In situations where AKI and ALI are combined, mortality exceeds 80%. Therefore the impetus exists to treat AKI, but when to initiate renal replacement therapy (RRT), what ‘dose’ to prescribe, and if these strategies improve survival remain debatable.
The data supporting early RRT in patients following trauma are limited to small studies. In combat settings, the development and use of dialysis decreased mortality from renal failure through the 1970s, but no overall change in mortality has been demonstrated since. An extensive report of dialysis use in recent military conflicts highlights the need for portable, easy-to-use systems. In a small study examining burn patients with AKI, CRRT lowered both 28-day and in-hospital mortality. Furthermore, design improvements such as larger pore sizes filters and antibiotic-coated fibers show encouraging results in preliminary studies, and should further expand the applications for CRRT.

Finally, extensive experience has shown that RRT can be used safely in trauma patients without affecting systemic coagulation parameters. A case report of CRRT initiated for refractory intracranial hypertension following traumatic brain injury (TBI) was recently published. The removal of fluids, solutes and inflammatory cytokines correlated with decreased intracranial pressure in the patient without deleterious
coagulopathic sequela.

Liver dialysis
Conventional hemofiltration and hemodialysis techniques are insufficient to clear albumin-bound toxins present in the setting of liver failure. Direct charcoal hemoperfusion and albumin-dialysis detoxification systems remove albumin-bound (bilirubin and bile acids) and water-soluble toxins. Liver dialysis decreases levels of nitric oxide, cytokines (TNF-alpha, IL-6, IL-8 and interferon gamma) and lowers mortality in acute-on-chronic liver failure. Large randomized trials are currently underway, but each of the commercially available systems (e.g. MARS) has demonstrated benefit in small preliminary trials. However, in trauma patients, this therapy remains at the level of case reports.

Extracorporeal brain support
It is now recognized that non-neurological organ dysfunction is common in patients with severe TBI and is independently associated with worse outcome. Respiratory failure is the most common, followed by cardiovascular failure. Failure of the coagulation and renal systems has also been seen. Therefore, the need to support organ systems following severe neurological injury should be anticipated.

There is currently no brain ‘dialysis’ system in clinical use for neurological injury or failure, but new laboratory findings support the development of such a system. In an animal model study of TBI, dialysis on the brain surface (following a decompressive craniectomy) with a semi-permeable membrane allowed water and small molecules to move from the damaged brain surface across the dialysis membrane into the osmotic chamber, rather than into brain, resulting in significantly lower
CSF pressures.

Traumatic brain injury is often cited as a contraindication for the clinical use of ECLS, despite reports of good neurological outcomes in these patients. Two recent case reports describe the use of ECLS in this patient population and challenge this belief. Acute cardiopulmonary failure associated with increased ICP, resulting from severe TBI, has been successfully treated with ECLS at both a U.S. and a Taiwanese trauma center with full neurological recovery in both cases.

Evolution of extracorporeal support
Indications for ECLS have broadened to include nearly all organ systems. The severity of patient diseases and the imagination of healthcare providers have progressed more rapidly than has the available technology, limiting clinical use of these circuits to more technologically advanced institutions. Fortunately, recent advances that broaden both the treatment base and systems development continue to move the field forward. Systems that were initially crude and used only as terminal treatment efforts, such as dialysis and mechanical ventilation, are now used routinely in operating rooms, ICUs, rehabilitation facilities and even in homes. Extracorporeal systems have matured from the lab to the bedside, from the OR to the ICU, and have the potential to travel across the world. The future of extracorporeal support will likely involve both refinement of existing materials (i.e. biomembranes) and techniques, as well as development of novel ones (i.e. nanotechnology).

 Since our patients present with multiple organ failure, one must consider multiple organ support. We hereby suggest the concept of a single ‘organ support’ machine to be brought to and travel with the patient, initiated as therapy prior to the patient developing multiple-organ failure. Such a total extracorporeal organ support (TECOS) system would derive individual subunits from current ECLS modalities (see figure), thereby supporting multiple organ systems, as necessary, through a single cannulation strategy. There is clear support for the use of ECMO in patients with multiple organ dysfunction. Inasmuch as patients treated with ECPR often develop organ dysfunction, i.e. lungs and/or kidneys, they could potentially benefit from modalities aimed at these organ systems. Treatment of acute liver failure with extracorporeal support has been shown to improve survival, and as such would be an important component of a multi-modal strategy. ECLS, although often initiated for single organ dysfunction, may also support the hematologic, coagulation and
central nervous organ systems, among others.

TECOS could also be used as a nontraditional bridge to transplant. Most donations after cardiac death (DCD) of organs for transplantation are obtained from patients following traumatic injury. Implementation of a DCD protocol using extracorporeal perfusion has been shown to increase both the number of viable organs as well as individual graft function, resulting in an overall shorter duration of hospital stay. TECOS could theoretically provide multi-organ support for this endeavor, maximizing utility of single patient donation.

Extracorporeal modalities can be life-saving interventions in the critically ill and injured. Through their continued evolution as technology advances, the real challenges that persist will be to determine the indications and contraindications for individual patients, and the  appropriate timing for initiation and withdrawal.

Background reading
Anderson HL 3rd, Shapiro MB, Delius RE et al. Extracorporeal life support for respiratory failure after multiple trauma. J Trauma. 1994; 37: 266-272.
Bakhtiary F, Keller H, Dogan S et al. Venoarterial extracorporeal membrane oxygenation for treatment of cardiogenic shock: Clinical experiences in 45 adult patients. Journ Thor and Cardiovas Surg 2008; 135: 382 – 388.
Flörchinger B, Philipp A, Klose A et al. Pumpless extracorporeal lung assist: a 10-year institutional experience. Ann Thorac Surg 2008; 86: 410 – 417.
Stadlbauer V, Krisper P, Aigner R, Haditsch B, Jung A, Lackner Honore PM, Joannes-Bovau O, Merson L et al. The big bang of hemofiltration: the beginning of a new era in the third millennium for extracorporeal blood purification! Int J Artif Organs 2006; 29: 649 – 659.
Huang YK, Liu KS, Lu MS et al. Extracorporeal life support in post-traumatic respiratory distress patients. Resuscitation 2009; 80: 535 – 539.
Liu JP, Gluud LL, Als-Nielsen B et al. Artificial and bioartificial support systems for liver failure. Cochrane Database Syst Rev 2004; 1:CD003628.
Madershahian N, Wittwer T, Strauch J et al. Application of ECMO in multitrauma patients with ARDS as rescue therapy. J Card Surg 2007; 22: 180 – 184.
Marasco SF, Lukas G, McDonald M et al. Review of ECMO (extracorporeal membrane oxygenation) support in critically ill adult patients. Heart, Lung and Circ 2008; 17S: S41-S47.
McCunn M, Reynolds HN, Reuter J et al. Continuous renal replacement therapy in patients following traumatic injury. Int J Artif Organs 2006; 29:
166 - 186.
Michaels AJ, Schriener RJ, Kolla S et al. Extracorporeal life support in pulmonary failure after trauma. J Trauma 1999;46:638-645.
Phua J, Lee KH. Liver support devices. Curr Opin Crit Care 2008; 14: 208 – 215.
Ricci Z, Ronco Cm D’Amico G et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrol Dial Transplant 2006; 21: 690- 696.
Thiagarajan RR, Brogan TV, Scheurer MA. Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in adults. Ann Thorac Surg 2009; 87: 778 – 785.
VA/NIH Acute renal failure network: Intensity of renal support in critically ill patients with acute kidney injury.
Zygun DA, Klortbeek JB, Fick GH et al. Non-neurologic organ dysfunction in severe traumatic brain injury. Crit Care Med 2005; 33: 654 – 660.

The authors
Maureen McCunn, MD, MIPP, FCCM
Amy J Reed, MD, PhD
Department of Anesthesiology and Critical Care Medicine
University of Pennsylvania School of Medicine
USA

Correspondence to:
Maureen McCunn, MD, MIPP, FCCM
Department of Anesthesiology and Critical Care Medicine
University of Pennsylvania School of Medicine
3400 Spruce Street, Dulles 6
Philadelphia, Pennsylvania 19104
215-662-3738
mccunnm@uphs.upenn.edu

Note: The full version of this overview has been previously published:
McCunn M, Reed AJ, Critical care organ support: a focus on extracorporeal systems. Curr Opin Crit Care. 2009; 15: 554-559.

Acknowledgements
HN Reynolds, MD, and Karen A. McQuillan, RN, MS, CCRN, CNRN, for design assistance;
Robert H. Bartlett, MD for manuscript review.

Second study supports use of NGAL test for early identification of acute kidney injury in critically ill patients

According to a recent study published in Intensive Care Medicine [1], a novel bedside blood test carried out in critically ill patients being admitted to the intensive care unit can help to identify which patients are at risk of acute kidney injury (AKI). The study carried out in Vicenza, Italy, involved the testing of blood samples collected during admission to the ICU. The test were carried out using the Triage NGAL Test, a product currently sold by Inverness Medical Innovations, Inc. outside of the United States.

AKI is a common and often devastating complication for up to 25% of critically ill patients admitted to the ICU and can lead to a significant increase in hospital length of stay and associated costs. Also associated with an increased risk of death, AKI is often detected too late into its clinical progression when a substantial portion of kidney function may already have been lost and the window for initiating treatment to prevent further harm has closed.
A small study conducted in early 2009 at the University Hospital of Clermont-Ferrand, France and published in the Journal of Critical Care [2] found that a new bedside blood test for a blood biomarker called neutrophil gelatinase-associated lipocalin (NGAL) offered the promise of rapidly assessing if a critically ill patient is suffering from AKI. Now results from the prestigious Department of Nephrology at San Bortolo Hospital in Vicenza Italy have confirmed these findings in a larger study published in Intensive Care Medicine [1]. In this study of 301 critically ill patients, plasma NGAL measured with the Triage NGAL Test was a statistically significant diagnostic marker of AKI development within the next 48 hours (area-under-ROC 0.78), and for renal replacement therapy use (area-under-ROC 0.82).  Moreover, peak plasma NGAL concentrations increased with worsening AKI severity (R=0.554, p<0.001).

¹. Cruz DN et al. Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med. 2009 Dec 3.
². Constantin JM et al. Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: A prospective study. J Crit Care. 2009 Sep 23.