Our data demonstrate that our PCLC ReFit algorithm using a minimally invasive monitoring approach in a porcine model of lethal uncontrolled hemorrhagic shock resulted in rapid and sustained stabilization for up to 3 h when conducted in both a laboratory or remotely during air or ground to air transport. To our knowledge, this is the first time a remote autonomous resuscitation and stabilization system applied during transport of a severely injured animal is reported to be successful. The potential this brings to the practice of care in remote field setting without access to advanced medical expertise is significant.

Furthermore, the ReFit algorithm functions as a precision medicine tool. It uses dynamic parameters to guide fluid administration and wean vasopressors and also infuses fluids proportional to the degree of volume responsiveness. Thus, volume boluses are individualized based on the degree of volume responsiveness and not given if the subject is not perceived to be volume responsive, even if in shock. Similarly, weaning of norepinephrine is done only if MAP remains stable and vasomotor tone, estimated by Eadyn is > 1, thereby minimizing the risk of reactive hypotension. This approach is not only precise, by giving only treatments that are needed, but personalized by giving a dose of treatment proportional to the subject’s volume responsiveness or intrinsic vasomotor levels. This ReFit approach should minimize fluid overload, iatrogenic hypotension, and conserve resources. The desired resuscitation MAP and HR targets can be adjusted, as ongoing bleeding is often resuscitated to lower MAP targets (i.e., hypotensive resuscitation) or when resuscitative products are limited. Once bleeding is controlled, in the setting of traumatic brain injury or additional resources are available, higher MAP targets may be needed for end organ perfusion with comorbid disease such as pre-existing hypertension. The ReFit algorithm can be set to target any defined MAP.

The ReFit algorithm has several advantages over fixed protocolized approaches. First, it does not require advanced care expertise to initiate and run. What is needed is an indwelling arterial catheter, the ReFit infusion pumps, monitoring array module and resuscitation fluids. Second, it is not a “black box” algorithm, but individualizes resuscitative care since every therapeutic intervention is linked to a specific expected physiologic response of the subject being treated. It is sensor specific but device agnostic, any monitoring device that accurately reports MAP, SVV and PPV within a 20–30 s moving window can be used to drive the algorithm and many available monitoring devices fit this requirement [10]. In addition to improving vital signs, the algorithm supports end organ perfusion, as evinced by the improvement in cardiac output and SvO2, demonstrating the robustness of this approach. Future applications include fully autonomous unmanned vehicle-based transport.

Our approach has several limitations. First, we demonstrated this in an anesthetized porcine model of uncontrolled hemorrhagic shock. To the extent that similar effectiveness would be seen in human trauma patients with a myriad of insults needs to be validated. Second, it requires the subject to be on controlled mechanical ventilation. Dynamic measures such as PPV and SVV deteriorate in their predictive power during spontaneous ventilation [11]. However, Eadyn remains accurate at all times [12]. We are actively searching for signatures of volume responsiveness that can be easily applied autonomously during spontaneous breathing. Candidate diagnostics such as a passive leg raising or mini-fluid challenge presently do not translate well to austere environments. Third, the ReFit algorithm treats only shock due to hypovolemia and vasoplegia, not due to obstruction or primary cardiac events. Thus, patient selection will need to be done carefully and other treatments for tension pneumothorax and cardiac injury, for example, will need to be addressed separately. Fourth, measures of PPV and SVV are essential to drive this algorithm. FDA-approved non-invasive devices that report these parameters using finger cuff exist. However, in profound hypotensive shock, peripheral perfusion is often lost as is pulse oximetry measures of SpO2. If field responses presume profound hypotension requires immediate fluid boluses as are also applied to a modified ReFit algorithm, then those devices will resume reporting MAP, pulse rate, PPV and SVV once MAP exceeds 50 mmHg. However, it is not clear if such levels of profound hypotension can be effectively managed for our algorithm beyond the initial fluid boluses. In practice, all animals increased their MAP to > 50 mmHg after the first blood and CaCl2 bolus. Finally, as illustrated in the third transported pig, the ReFit algorithm has no disconnect alarms. This was easily addressed in a recent revision of the ReFit software and also secured with more permanent connection appliances. Also, as a default mode, if no physiologic input is sensed the ReFit algorithm defaults to a fixed mode of constant norepinephrine at the dose it was already on and no new fluid boluses. Clearly, if any of the components of the PCLC system (input data, infusion pumps or resuscitation fluids) are removed the system cannot operate. Still, if unmanned care during transport of critically ill trauma patients is needed, the ReFit algorithm results in better stabilization that that seen by no treatment at all.

In conclusion, our data demonstrated that ReFit, a physiology-based, personalized, closed-loop resuscitation system can effectively stabilize an acutely anesthetized animal subjected to lethal uncontrolled hemorrhagic shock in both laboratory conditions and during real-life ground and air transportation without human intervention. Our results also suggest that this system can be monitored and operated remotely, adding an important feature of ‘human-in-the-loop’ capacity that potentially could be more adaptive if monitoring inputs are limited or pathophysiologic processes are more complex. Overall, this first report of successful application of an autonomous resuscitation during transport opens promising possibilities to extend the concept of the ‘golden hour’ to a realistic three hours, and sustain organ perfusion until definitive treatment is achieved. Finally, it raises the prospect of a system that can expand the capability of delivery of personalized care in situations where resources may be constrained.