a b s t r a c t

Non-Traumatic cardiac arrest is a major Public health problem that carries an extremely high mortality rate. If we hope to increase the survivability of this condition, it is imperative that alternative methods of treatment are given due consideration.

Balloon occlusion of the aorta can be used as a method of Circulatory support in the critically ill patient. Intra-aor- tic balloon pumps have been used to temporize patients in cardiogenic shock for decades. More recently, resus- citative Endovascular balloon occlusion of the aorta (REBOA) has been utilized in the patient in hemorrhagic shock or cardiac arrest secondary to trauma.

Aortic occlusion in non-traumatic cardiac arrest has the effect of reducing the vascular volume that the generated cardiac output is distributed across. This augments myocardial and cerebral perfusion, increasing the probability of a return to a good quality of life for the patient. This phenomenon has been the subject of numerous animal studies dating back to the early 1980s; however, the human evidence is limited to several small case series. An- imal research has demonstrated improvements in cerebral and coronary perfusion pressure during ACLS that lead to statistically significant differences in mortality. Several case series in humans have replicated these find- ings, suggesting the efficacy of this procedure.

The objectives of this review are to: 1) introduce the reader to REBOA 2) review the physiology of NTCA and ex-

amine the current limitations of traditional ACLS 3) summarize the literature regarding the efficacy and feasibility of aortic balloon occlusion to support traditional ACLS.

(C) 2017

1. Background
   1. Introduction

Non-traumatic cardiac arrest is a significant burden to the public health that, after decades of research, still carries an extremely high mortality rate. Despite the advent of automated external defibrillators, increases in bystander CPR, Automated CPR devices, and post-arrest Targeted temperature management, the proportion of patients surviv- ing to hospital discharge has only minimally improved. If we hope to in- crease the survivability of this condition, it is imperative that alternative methods of treatment are given due consideration.

Balloon occlusion of the aorta can be used as a method of circulatory support in the critically ill patient. intra-aortic balloon pumps that

* Corresponding author at: Yale New Haven Hospital, Department of Emergency Medicine, 464 Congress Avenue, suite 260, New Haven 06519, United States.

E-mail address: [email protected] (J. Daley).

intermittently occlude the aorta have been used to temporize patients in cardiogenic shock for decades, although evidence for their efficacy re- mains unclear. More recently, resuscitative endovascular balloon occlu- sion of the aorta (REBOA) has been utilized in the patient in hemorrhagic shock or cardiac arrest secondary to trauma. Continuous occlusion of the aorta with REBOA allows for redistribution of cardiac output to the most critical organs, prevents further bleeding from non-compressible sites, and causes immediate and significant increases in blood pressure.

Thoracic aortic occlusion in cardiac arrest from non-Traumatic causes has the effect of reducing the vascular volume that the generated cardiac output is distributed across. This augments myocardial and cere- bral perfusion, increasing the probability of a return to a good quality of life for the patient. This phenomenon has been the subject of numerous large animal studies dating back to the early 1980s; however, the human evidence is limited to case reports [1,2]. Animal research has demonstrated striking improvements cerebral and coronary perfusion pressure during ACLS that lead to statistically significant differences in

http://dx.doi.org/10.1016/j.ajem.2017.01.010

0735-6757/(C) 2017

Contemporary practice“>return of spontaneous circulation and mortality that favor the REBOA groups.

The objectives of this review are to: 1) introduce the reader to REBOA 2) review the physiology of NTCA and examine the current lim- itations of traditional ACLS 3) summarize the literature regarding the ef- ficacy and feasibility of aortic balloon occlusion to support traditional ACLS.

Historical perspective

The use of balloon occlusion of the aorta in critically ill patients dates back to the Korean War in the management of intra-abdominal hemor- rhage [3]. This technology was subsequently applied to the non-trauma patient with the advent of the IABP in 1967 [4]. Pioneered by cardiac surgeons, IABPs were found to improve coronary perfusion during car- diogenic shock and cardiac arrest [4]. Cardiologists began using the technology in 1979, when the first percutaneous IABP made its debut, allowing “any physician familiar with Arterial puncture techniques to insert it” [5].

Despite the widespread use of balloon occlusion of the aorta by car- diologists during the subsequent years, its surgical role was limited to vascular specialists and the repair of aortic aneurysms. In the current decade, trauma surgeons and emergency physicians have increased their use of what has become known as REBOA, in the management of non-compressible torso hemorrhage [6-8]. Occlusion of the aorta and cessation of distal flow limits further internal blood loss and can provide a bridge to definitive operative repair [6-8].

Evidence for contemporary practice

The last decade has seen a proliferation of human data on the subject of REBOA. Martinelli et al. reported one of the first case series from Eu- rope, where REBOA was successfully used in 13 severely shocked pa- tients (mean SBP 41 +- 26 mm Hg) with pelvic fractures (mean ISS 48 +- 16) [9]. Balloon deployment saw the blood pressure rise by an av- erage of 70 mm Hg, with a survival rate of 46% in cohort with a predicted survival of 39%.

Moore et al. reported a retrospective cohort study, from two high volume Level 1 Trauma Centers from the United States [10]. They exam- ined a cohort of trauma patients with extra-thoracic hemorrhage, who either underwent resuscitative thoracotomy with aortic clamping (n = 72) or REBOA (n = 24). It was a non-randomized, before/after study design which demonstrated a lower mortality in the REBOA pa- tients (9.7% vs. 37.5%; p = 0.003).

While such evidence is promising, REBOA remains controversial. The Japanese trauma registry reports a very different experience [11,12]. Retrospective examination of their registry by several investigators has demonstrated inferior survival in patients treated with REBOA. This is concerning; however, case reports from the country have dem- onstrated long times to transfusion, balloon deflation and definitive care, suggesting the existence of confounding variables.

A recent systematic review was unable to demonstrate a Survival benefit with REBOA in hemorrhagic shock, but the improvements in he- modynamic profile were robustly demonstrated. The forthcoming ran- domized UK-REBOA trial should help to answer many of these questions. However, due to complexities of endovascular intervention and uncertainties relating to its efficacy, REBOA has yet to enter main- stream clinical practice [13].

Placement of the REBOA catheter

A REBOA catheter can be placed at the bedside by any physician adept at the use of the seldinger technique. Femoral access is obtained via the insertion of a femoral arterial introducer, varying in size from 7 Fr to 14 Fr, depending on the particular device used. Femoral cannula- tion can be accomplished via surgical cut-down, a blind percutaneous

approach, or most recently, with the use of bedside ultrasound [13].A catheter with a compliant balloon at the tip is advanced into the aorta in one of three zones, dependent on the location of non-compressible hemorrhage.

The majority of catheters currently available are considered “con- ventional” REBOA systems, which are designed to be compatible with complex endovascular maneuvers such as endoluminal stent-grafting. These systems are generally of a large caliber, requiring access sheath sizes of 12 Fr or greater and are inserted over a wire under fluoroscopic imaging. More recently, trauma specific “wireless” REBOA systems have become available, which use smaller access sheaths (7 Fr) and do not re- quire a long wire to be deployed initially. While fluoroscopy is still rec- ommended to guide placement, many clinicians are inserting blindly and checking position with other imaging modalities.

The balloon is inflated with a 50:50 iodinated contrast-saline mix, thereby occluding the aorta and preventing distal blood flow. Placement is traditionally confirmed with fluoroscopy or chest X-ray, however re- cent evidence supports the use balloon inflation with contrast dye that permits the confirmation of placement with bedside ultrasound [13,14]. Definitive Hemorrhage control and balloon deflation should be accom- plished as quickly as possible, due to the theoretical risk of spinal cord ischemia, however no instances of lower extremity paralysis due to REBOA have been reported in the literature [13]. Removal of the device and introducer sheath requires surgical Vascular repair for sheaths larg- er than 8 Fr, while newer devices with smaller introducers typically do not [15].

1. Non-traumatic cardiac arrest: epidemiology and physiology
   1. Epidemiology of non-traumatic cardiac arrest

A common misconception with respect to the epidemiology of cardi- ac arrest is that patients have low theoretical likelihood of survival due to age and the existence of significant comorbidities. However, a large proportion of victims of NTCA are in fact younger, relatively healthy, and could potentially survive their arrest with a meaningful quality of life. The mean age of arrest has been reported to range from 72 to 78 years old [16-18], while 33% of patients in NTCA are of working age (18 to 64 years old) [16]. The Charlson Comorbidity Index (CCI) is a method of classifying comorbidities based on categories, with each cat- egory having an associated weight (from one to six points). In a registry study of 1332 NTCA victims, 46% had a CCI of zero or one; meaning that they had at maximum only one comorbid condition, while 39% had a CCI of two or three, indicating the presence of several less-severe comorbid conditions. Only 15% of patients had a CCI of greater than three, indicat- ing the presence of many comorbidities [18].

A significant number of patients presenting with NTCA have a poten- tially reversible etiology of their arrest, while rates of terminal illness among victims of NTCA have been reported to be as low as 9.4% [17]. For the purposes of this review, reversible etiology is defined as any cause of arrest that if rapidly and effectively treated may allow the pa- tient to recover with significant quality of life. Examples include myo- cardial infarction, pulmonary embolism, hyperkalemia, and toxicological overdose.

Between 65% and 89% of NTCA have been estimated to be of primary Cardiac origin with coronary artery disease as the leading cause of arrest [19]. One study estimated that 43% of arrests were due to acute myocar- dial infarction and 2% from pulmonary embolism [20]. Another found that on post-mortem examination, approximately 50% of patients had an obstructive coronary lesion that was the likely cause of their arrest [19]. Between 6% and 15% of cases are estimated to have a toxicological cause [20,21].

Historical information which can be obtained on patient arrival can be of significant prognostic utility. The best outcomes in NTCA are seen in patients with at least one of the following significant positive predictors: initial rhythm of ventricular fibrillation or tachycardia,

defibrillation attempted prior to arrival, early time to defibrillation, witnessed arrest, and/or received bystander CPR [19].

Physiology of non-traumatic cardiac arrest

In the moments following a ventricular fibrillation arrest, blood flow throughout the body continues after contraction has ceased, until the pressure gradient between the aorta and the right atrium equalizes [22]. A study in swine demonstrated persistent marginal blood flow for up to 5 min after arrest [23]. Carotid flow ceases fully at 4 min after arrest, while coronary flow cessation occurs after only 1 min [23]. A reduction in blood flow results in cerebral and coronary hypo- perfusion, decreasing oxygen delivery to these critical regions.

Coronary perfusion pressure represents the gradient that drives blood flow through myocardial capillary beds, which subsequently drain into the coronary sinus and right atrium. It is calculated by subtracting the right atrial pressure from the diastolic aortic pressure, as the contracting heart prevents coronary perfusion during systole [24]. Coronary perfusion pressure and coronary artery flow are signifi- cant predictors of increased rates of ROSC and survival to hospital dis- charge [22,24-26]. In a landmark study of one hundred cardiac arrest patients, Paradis et al. described a strong association between ROSC and a coronary perfusion pressure greater than 15 mm Hg, or an arterial relaxation pressure greater than 17 mm Hg [24]. Increases in coronary perfusion pressure during ACLS are followed by improvements in cere- bral perfusion pressure and enhanced cerebral oxygenation [27].

Traditional ACLS is often unable to maintain the circulatory support required for ROSC and the preservation of neurologic function. During chest compressions, coronary perfusion pressure rises gradually over minutes and falls abruptly when CPR is interrupted. During NTCA, ACLS generates coronary perfusion pressures between 0% and 30% of normal values, which are associated with a low probability of ROSC and survival [28,29] Inadequate coronary perfusion pressures achieved with ACLS are associated with decreased levels of cerebral flow and ox- ygenation [27,30], impeding Neurologic recovery after ROSC.

While coronary perfusion pressure is critical to restoring cardiac ac- tivity, cerebral perfusion pressure is as important for neurologic preser- vation during an arrest. Cerebral perfusion pressure refers to the gradient between the carotid artery and intra-cranial pressure, which drives cerebral flow and oxygen delivery. Increases in flow through the Carotid arteries serve to bolster the cerebral perfusion pressure, in- creasing cerebral flow. Cerebral perfusion pressure, cerebral flow, and carotid flow are associated with improved neurologic outcomes [22, 25,31,32].

In swine models of cardiac arrest, blood flow in the common carotid plateaus a little more than a minute after CPR is initiated, and even then only at 30% of what is considered requisite [23]. Similar data from dogs demonstrates that when CPR commences immediately after an arrest, coronary perfusion pressures of 25 mm Hg are sufficient to maintain ce- rebral flow and ATP levels at 60% of pre-arrest values. As delays to initi- ation of CPR increase, increasing coronary perfusion pressures are required to maintain the same level of cerebral perfusion. After 6 min of down time without CPR, a coronary perfusion pressure of 35 mm Hg was necessary to maintain cerebral perfusion at that level, and after 12 min of down time without compressions, even 35 mm Hg was insufficient to maintain adequate cerebral flow.

Another more indirect marker of cardiac output and perfusion is end tidal carbon dioxide, a measure of the partial pressure of carbon dioxide at the end of an exhalation. Its three main determinants are pulmonary ventilation, pulmonary perfusion (cardiac output), and cellular metabo- lism. However, during a cardiac arrest, pulmonary perfusion is the pre- dominant factor driving any fluctuations [25]. Levels N 10 mm Hg have been shown to be significantly associated with ROSC and can be trended to monitor CPR quality [25]. However, while end tidal carbon dioxide is of clear clinical utility during cardiac arrest, its sensitivity for ROSC has been reported to be between 70% and 90% and hence should not be

used as the sole determinant of prognostication during resuscitation [25].

1. Evidence for balloon occlusion in non-traumatic cardiac arrest

Significant improvements in hemodynamics during NTCA are seen immediately after the thoracic aorta is subjected to occlusion by a com- pliant balloon. The heart and the brain are subject to relative increases in blood flow, which lead to higher perfusion pressures, improving ox- ygen delivery to cardiac myocytes and neurons. IncreasED flow to these organs is achieved by a relative reduction in the vascular bed over which the cardiac output is now distributed. Selective perfusion of the two organs most critical for ROSC and meaningful neurologic re- covery is thereby maximized.

The following section presents an overview of the published litera- ture on aortic balloon occlusion in NCTA. The EMBASE and SCOPUS da- tabases were searched for relevant articles published from 1946 to July 2016 inclusive. Key words used in the search were composed of combi- nations of “Aortic Balloon Occlusion,” “REBOA,” and “cardiac arrest.” All studies discussed in this section involve continuous (as opposed to in- termittent) balloon occlusion of the aorta and closed (as opposed to open) chest CPR (Fig. 1).

Improved outcomes in NTCA using continuous balloon occlusion of the aorta

Nine studies of continuous balloon occlusion in animal models of NTCA have shown meaningful increases in both coronary artery flow and coronary perfusion pressure [33-41], while none failed to do so. A cross-over study in a swine model of ventricular fibrillation arrest dem- onstrated a near three-fold increase in coronary perfusion pressure upon balloon inflation from 10.9 mm Hg to 29.2 mm Hg [33], while a similar study reported an 86% increase in Coronary blood flow [36].A case report involving two human subjects demonstrated improved cor- onary perfusion pressure after continuous balloon inflation [2].

Fig. 1. Thoracic aortic balloon occlusion during cardiac arrest. Balloon occlusion of the thoracic aorta during cardiac arrest leads to the redistribution of cardiac output into a smaller effective vascular bed, allowing for the selective perfusion of the heart and brain. Resultant increases in cardiac and cerebral oxygen delivery improve the probability of neurologically-intact survival.

Balloon inflation during resuscitation is also associated with im- provements in ETCO2 [2,33]. Similarly, a case report where continuous balloon inflation was used in two human patients in NTCA demonstrat- ed increases in ETCO2 following balloon inflation [2]. Superior cardiac perfusion after aortic occlusion lead to significantly increased rates of ROSC in numerous controlled animal trials [35,37,38,40,49].A study in a swine model of cardiac arrest with a simulated a down-time of 10 min, 67% of animals attained ROSC in the balloon occlusion plus ACLS group, while 23% had ROSC in the ACLS only group (p b 0.05) [36]. Augmentation of ACLS with REBOA allows for better cerebral perfu- sion and is associated with superior rates of neurologic recovery in ani- mal studies. Aortic occlusion during resuscitation lead to clinically relevant increases in carotid artery flow [36,46], cerebral arterial flow [34,35,46,49,50], and cerebral perfusion pressure [34,35,46,51]. An ex- periment in swine described a 200% increase in cerebral perfusion pres- sure [33], while another study in canines demonstrated a 66% increase

in carotid artery flow [36].

The increases in cerebral perfusion seen with REBOA translate to im- provements in neurologic outcomes and 48 hour survival [38,47]. A study in swine resuscitated with REBOA and ACLS described a 48-hour survival rate of 100% with near-normal neurologic function, while the ACLS-only control group had a 10% 48-hour survival rate and worse neurologic outcomes [47]. A case report describes a 74-year old female who underwent cardiac catheterization for a myocardial infarction. She suffered an asystolic cardiac arrest and after 5 min of ACLS, rescuers inserted used an IABP to continuously occlude the aorta. After 30 s of oc- clusion, she began to spontaneously gasp, regained pulses, and was discharged from the hospital without neurological deficit [1].

Selective aortic arch perfusion (SAAP)

Certain aortic balloon catheters are able to infuse oxygen carrying materials and medications directly proximal to the aortic balloon occlu- sion, a technique known as selective aortic arch perfusion (SAAP). A study in canines suffering prolonged cardiac arrest (20 min) who re- ceived an infusion of stroma-free ultra-purified bovine hemoglobin in combination with aortic occlusion demonstrated significant differences in coronary perfusion pressures and survival. Animals that underwent aortic occlusion with a purified hemoglobin infusion had a mean coro- nary perfusion pressure of 62 mm Hg and a 70% survival rate, compared to coronary perfusion pressure of 33 mm Hg and survival rate of only 20% in those that underwent standard ACLS alone [41]. In a similar trial, the same authors demonstrated a dose-response relationship be- tween increasing concentrations of the purified hemoglobin infusion and survival [45]. A separate research group investigated the use of aor- tic occlusion and infusion of oxygen carrying fluorocarbon emulsion and found similar effects on coronary perfusion pressure and survival in the SAAP animals [42,43].

Studies involving the infusion of vasopressors demonstrated posi- tive effects on cardiac output, however no effect on cerebral perfusion. Intra-aortic vasopressin and balloon occlusion was associated with an increase in coronary perfusion pressure during CPR in swine, but had no effect on cerebral cortical blood flow [34]. In a similar study by the same authors, balloon occlusion produced significant improvements in cerebral cortical blood flow. However, administration of intra-aortic epinephrine had no significant effect on cerebral cortical blood flow and possibly an adverse effect [35].

Feasibility of REBOA augmented ACLS during NTCA

Femoral artery cannulation and aortic balloon placement during NTCA in the pre-hospital and hospital environment is technically feasi- ble. In a case series, researchers successfully placed IABPs via percutane- ous femoral artery cannulation in five patients in NTCA and three patients in cardiogenic shock [5]. A similar case report described the placement of IABPs in two patients in NTCA [2]. The surgical literature

contains many examples of REBOA use in patients with impending cir- culatory collapse and traumatic cardiac arrest [10,13] and it is now uti- lized in the pre-hospital environment by the emergency medicine physicians and trauma surgeons of London’s Air ambulance service [52]. Clinicians with technical expertise in the use of REBOA state that the most difficult aspect of the procedure is obtaining femoral artery access [53]. The use of bedside ultrasound improves femoral artery Cannulation success, while allowing real-time confirmation of the location of the aortic catheter tip [13,14]. Manning et al. demonstrated the feasibility of blind femoral arterial cannulation and aortic catheter placement in 22 victims of NTCA in the pre-hospital environment [44]. The success of pre-hospital extra corporeal membranous oxygenation (ECMO) pro- grams further support the practicality of this concept, as these teams routinely place large femoral arterial catheters in patients undergoing

ACLS for cardiac arrest [54,55].

Patient selection: when is ACLS not enough?

Patients who undergo prolonged resuscitation without resumption of sustained Cardiac activity have an extremely poor prognosis and can be considered to have failed traditional ACLS, however these pa- tients may still be neurologically viable [56]. In a study of 1204 cases of NTCA, 90% of those who achieved ROSC had done so by 24 min of CPR, with rates of ROSC declining significantly after that point. Further research has demonstrated that after 16-21 min of conventional ACLS in patients without ROSC, the probability of Neurologically intact surviv- al drops precipitously [16,56,57]. It is highly unlikely that patients with- out ROSC will survive their arrest with good neurologic out outcome once their traditional resuscitation has exceeded 21 min. Based on the compelling animal data and human case series, it is conceivable that these patients may still benefit from REBOA.

Proposed selection criteria

In order to maximize the probability of a patient’s return to a good quality of life, detailed inclusion criteria must be applied before utilizing REBOA during a cardiac arrest. REBOA should only be employed if the physician believes that the patient has a reversible etiology of their ar- rest that may be immediately treated. For example, in a patient with acute myocardial infarction or pulmonary embolism who is otherwise healthy, REBOA may be able to provide enough circulatory support to buy time while they are treated with tPA.

Physicians at the bedside must assess for contraindications, such as presence of an end-stage terminal illness, severe neurologic impairment at baseline, or suspected devastating neurologic injury as the etiology of arrest. Before initiation of REBOA, the patient must have failed therapy with traditional ACLS; a requirement that the authors consider satisfied after 20 min of resuscitation with ACLS and no ROSC. Finally, the ideal patient should show at least some signs of life prior to the initiation of REBOA, which may include findings such as reactive pupils, agonal breathing, end tidal carbon dioxide N 10 mm Hg, arterial relaxation pressure N 17 mm Hg, any cardiac activity on bedside echocardiogram, or any shock-able rhythm. If these strict inclusion criteria are not satis- fied, the resuscitation should continue to follow the ACLS algorithm, as the patient is unlikely to benefit meaningfully from REBOA.

1. Conclusions
   1. Future directions: researcher

There is a plethora of high quality preclinical research in animal models of cardiac arrest that supports balloon occlusion of the aorta during resuscitation. However, significant clinical research must be done before this technology may be broadly applied to patients in the hospital. It is the authors’ opinion that there has been sufficient preclin- ical study of this topic and that the time to begin human investigation

using modern technology has arrived. The authors recommend that the next step should be a case-series using REBOA in NTCA in the ED. Phys- iologic markers associated with favorable clinical outcomes such as ce- rebral oxygenation [58,59], blood pressure, and ETCO2 may be compared pre- and post-balloon inflation. Positive results could pave the way for small randomized trials that would examine physiologic outcomes and subsequent larger trials of sufficient power to assess for benefits in rates of ROSC and mortality.

Future directions: REBOA and ECMO

While it seems possible that this promising new technology can im- prove rates of ROSC and Neurologically intact survival in NTCA, it may also serve as a temporary bridge to other treatments such as ECMO or cardiac catheterization. The evidence that the use of ECMO in combina- tion with ACLS improves outcomes has been mounting over the past de- cade [54,55,60,61]. However, ECMO is extremely resource intensive and requires significant investment and experience, limiting its use by the majority of emergency departments. REBOA is much less resource in- tensive than an ECMO program. If REBOA proves to be of clinical utility in NTCA, smaller emergency departments may place a REBOA catheter in patients who present in cardiac arrest, and then transport them to designated resuscitation centers with ECMO capability. The use of REBOA as a bridge to ECMO is also possible in the pre-hospital setting; specialized pre-hospital ICU teams (similar to the London Air Ambu- lance service) could place REBOA in the field and then transport the pa- tient to a resuscitation center.

The selective perfusion of the heart and brain to augment traditional ACLS during NTCA is supported by decades of scientific research. Cur- rent rates of survival of NTCA using traditional ACLS are dismal at best. Balloon occlusion of the aorta during NTCA has been conclusively dem- onstrated to improve physiologic outcomes and survival in animal models, with similar results from limited, but promising studies in humans. The feasibility of femoral arterial cannulation and aortic bal- loon placement during NTCA has been demonstrated in the literature and has now become even more practical with new technological advancements.

After decades of research, it is apparent that Alternative therapies are required if we intend to significantly advance our ability to provide re- suscitative care. The use of REBOA as an adjunct to ACLS is an innovative new strategy that has the potential to revolutionize the management of cardiac arrest and is deserving of due consideration and rigorous clinical investigation.

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