Objectives: This study explored the limits of good outcome of brain and organism achievable after cardiac arrest (no blood flow) of 60-120 mins, with preservation (suspended animation) induced immediately after the start of exsanguination cardiac arrest.
Design: Prospective experimental comparison of three arrest times, without randomization.
Setting: University research laboratory.
Subjects: Twenty-seven custom-bred hunting dogs (17-25 kg).
Interventions: Dogs were exsanguinated over 5 mins to cardiac arrest no-flow of 60 mins, 90 mins, or 120 mins. At 2 mins of cardiac arrest, the dogs received, via a balloon-tipped catheter, an aortic flush of isotonic saline at 2°C (at a rate of 1 L/min), until tympanic temperature reached 20°C (for 60 mins of cardiac arrest), 15°C (for 60 mins of cardiac arrest), or 10°C (for 60, 90, or 120 mins of cardiac arrest). Resuscitation was by closed-chest cardiopulmonary bypass, postcardiac arrest mild hypothermia (tympanic temperature 34°C) to 12 hrs, controlled ventilation to 20 hrs, and intensive care to 72 hrs.
Measurements and Main Results: We assessed overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), regional and total brain histologic damage scores at 72 hrs (total HDS >0-40, mild; 40-100, moderate; >100, severe damage), and morphologic damage of extracerebral organs. For 60 mins of cardiac arrest (n = 14), tympanic temperature 20°C (n = 6) was achieved after flush of 3 mins and resulted in two dogs with OPC 1 and four dogs with OPC 2: median NDS, 13% (range 0-27%); and median total HDS, 28 (range, 4-36). Tympanic temperature of 15°C (n = 5) was achieved after flush of 7 mins and resulted in all five dogs with OPC 1, NDS 0% (0-3%), and HDS 8 (0-48). Tympanic temperature 10°C (n = 3) was achieved after flush of 11 mins and resulted in all three dogs with OPC 1, NDS 0%, and HDS 16 (2-18). For 90 mins of cardiac arrest (n = 6), tympanic temperature 10°C was achieved after flush of 15 mins and resulted in all six dogs with OPC 1, NDS 0%, and HDS 8 (0-37). For 120 mins of cardiac arrest (n = 7), three dogs had to be excluded. In the four dogs within protocol, tympanic temperature 10°C was achieved after flush of 15 mins. This resulted in one dog with OPC 1, NDS 0%, and total HDS 14; one with OPC 1, NDS 6%, and total HDS 20; one with OPC 2, NDS 13%, and total HDS 10; and one with OPC 3, NDS 39%, and total HDS 22.
Conclusions: In a systematic series of studies in dogs, the rapid induction of profound cerebral hypothermia (tympanic temperature 10°C) by aortic flush of cold saline immediately after the start of exsanguination cardiac arrest-which rarely can be resuscitated effectively with current methods-can achieve survival without functional or histologic brain damage, after cardiac arrest no-flow of 60 or 90 mins and possibly 120 mins. The use of additional preservation strategies should be pursued in the 120-min arrest model.
In considering resuscitation from severe hemorrhage, one must differentiate between hemorrhagic shock, which is low-flow and common, and exsanguination cardiac arrest (CA), which is no-flow and rare. CA is the topic of this study. Civilian trauma patients and military combat casualties with penetrating (often repairable) trunkal injuries exsanguinate rapidly to CA. Conventional resuscitation attempts are futile, and survival rates are near zero (1-4). For such unresuscitable conditions, since 1984, Safar and Bellamy have recommended research into suspended animation for delayed resuscitation. This they have defined as induction of preservation of the organism within the first 5 min of CA (no-flow) for transport and surgical hemostasis during clinical death, to be followed by delayed resuscitation to survival without brain damage (4).
Treatment induced before arrest (protection) and maintained during arrest (preservation) is more likely to mitigate postischemic brain damage than when induced after arrest (resuscitation) (5, 6). Suspended animation is preservation-resuscitation with use of drugs or hypothermia. Using systematic studies of exsanguination CA in a reproducible dog outcome model with induction of preservation by aortic flush at 2 mins CA, of saline at 24°C, via a balloon-tipped catheter (7-10), we obtained disappointing outcome results with a series of mechanism-specific pharmacologic therapies (11-15). The exception was the antioxidant tempol, which improved functional outcome (15). In contrast, lowering the temperature of the flushed saline to 2°C and progressively increasing the flush volume, starting the flush at 2 mins of normothermic exsanguination CA, we could decrease brain (tympanic membrane) temperature (Tty) to around 34°C, which preserved brain viability during CA of 15 mins (7) and 20 mins (8), and to around 28°C, which preserved brain viability for 30 mins (9). The present study is an extension of these systematic efforts to maximize the duration of CA (no-flow) from which resuscitation to survival can be achieved without vital organ system damage (10). Attempting to extend this maximal CA period from 30 to 120 mins is called for by the fact that transport and surgical hemostasis in patients with traumatic exsanguination to CA would require such prolonged preservation, particularly in military combat scenarios.
Protective-preservative hypothermia, induced and reversed with cardiopulmonary bypass (CPB), is clinically used for some elective operations on heart or brain but has not been evaluated yet for emergency scenarios as in this study. Elective therapeutic hypothermia has been shown to protect the brain and whole organism in animals or patients for up to 15 mins of CA at brain temperature of about 35°C (mild hypothermia) (16, 17), for up to 20 mins of CA at about 30°C (moderate hypothermia) (18), for up to 30 mins of CA at about 20°C (deep hypothermia) (19), for up to 60-150 mins of CA at 5-10°C (profound hypothermia) (20-27), and perhaps even for longer CA with ultraprofound hypothermia (28-30). The normal brain is not damaged by temperatures lowered to 5-10°C (31) but can be damaged by temperatures below 5°C (32, 33). In most of the previously mentioned studies of protective-preservative hypothermia for elective prolonged CA (23-30), induction of hypothermia was with CPB, before induction of CA and without total exsanguination; also, evaluation of cerebral function and histology was not quantitative as in our present study.
The experiments reported in this article are the first systematic explorations of emergency measures aimed at maximizing the reversible CA no-flow duration. The method should ultimately be inducible for patients also outside hospitals. Ours is the only group experimenting with this suspended animation approach, which includes early and rapid induction of preservation with aortic flush and intensive care life support for 72 hrs to give the ischemic anoxic encephalopathy time to mature. The objective of this study was to simulate the scenario of rapid exsanguination to death from a laceration in the aorta or vena cava and to determine, for the first time, the longest no-flow period from which resuscitation to complete recovery can be accomplished with the aid of CPB. This study is also the first to use a single aortic saline flush immediately after the start of CA (no-flow), to include preservation and long-term intensive care to outcome evaluation in terms of function and semiquantitative histologic brain damage. We hypothesized (10) that preservation during CA 60, 90, or 120 mins (no-flow) requires Tty 10°C to achieve intact survival without histologic brain damage.