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Presently, in spaceflight, the most critical moments are launch and landing due to the stressful conditions crew members are under in the spacecraft. In fact, human losses in space missions have occurred in those phases (Barratt 2019). Inside the spacecraft, the Environmental Control and Life Support System (ECLSS) maintains the atmosphere steady, normoxic, and normobaric while at neutral temperatures. However, the carbon dioxide concentration inside the cabin is on average 10 times higher than on the ground (0.3%–0.5%). The environment outside the spacecraft is the most hostile ever experienced before, nil barometric pressure, high levels of radiation, and extreme temperatures (−150°C to +120°C) (Komorowski et al., 2016; Barratt 2019). An immediate hazard is caused by a loss of cabin pressure (e.g., in case meteorite or satellite debris were to hit the station), fire, release of toxic substances, or malfunction of the ECLSS (Environmental Control and Life support System) (Kirkpatrick et al., 2005; Kirkpatrick et al., 2009c). In space, any of these events could potentially cause and aggravate a potential injury.

In space, numerous changes occur in human body physiology (Table 1). Some of these changes may particularly affect the body’s response to bleeding, mainly the cardiovascular system. The cardiovascular system is involved in response to a hemorrhagic event. The redistribution of body fluids toward the head is a well-known phenomenon in microgravity (Komorowski et al., 2016; Barratt 2019; Nowak et al., 2019). The fluid shift initiates at the launch position with the lower limbs raised above the thoracoabdominal coronal plane, a condition that continues during orbit, producing a displacement of blood and other fluids from the lower limbs to the torso and head (Williams et al., 2009; Nowak et al., 2019). When astronauts arrive in space, the gravitational pull that drives the circulation toward the feet stops working and fluids shift toward the head and torso (Alexander 2016). This shift and the compensation by the cardiovascular system can make the human body more subject to potentially harmful cardiovascular effects. The compensation for volume redistribution includes the activation of central baroreceptors (Convertino 2003; Di Rienzo et al., 2008; Panesar and Ashkan 2018) and suppression of the renin–angiotensin–aldosterone axis with the release of the atrial natriuretic peptide. Salt and water are excreted, with a reduction in plasma volume and a transient increase in hematocrit levels. A decrease in both erythropoietin secretion and red cell mass is also present, with a reduction in blood volume (Panesar and Ashkan 2018) (see Panesar and Ashkan (2018)) for the review of the literature). The decrease in cardiac workload in prolonged spaceflight may reduce the overall myocardial mass (Convertino 2009; Demontis et al., 2017; Panesar and Ashkan 2018), but despite the loss of contractile mass, ejection fraction and arterial pulse wave velocity are preserved. The human body is able to compensate the fluid shift through diuresis, with a reduction of extracellular fluid and plasma volume, an event that produces a decrease in body mass during the first 30 days (Panesar and Ashkan 2018).

Cardiac function adapts to the fluid shift and to the alterations by increasing cardiac output (Demontis et al., 2017; Panesar and Ashkan 2018). In spaceflight, the cardiovascular system is affected by one of the major alterations in human physiology. Over time, the shift of fluids from the lower body to head and torso produces loss of ventricular mass (cardiac atrophy) (Perhonen et al., 2001; Demontis et al., 2017; Evans et al., 2018), decreased sensitivity of the carotid-cardiac (vagal) baroreflex (Williams et al., 2009; Norsk 2014), and a greater responsiveness of sympathetic neural activity to inflight simulations of standing (Williams et al., 2009; Demontis et al., 2017). The effect is a decreased blood pressure and elevation of cardiac output throughout flight (Perhonen et al., 2001; Ertl et al., 2002a; Ertl et al., 2002b; Norsk 2014; Evans et al., 2018).

Vasodilation, present in space permanence, may reduce (Norsk et al., 2015; Norsk 2020) plasma volume and associated cardiovascular effects. This scenario is called cardiac deconditioning (Demontis et al., 2017), and decreased compensatory responses, exacerbated by relative hypovolemia and anemia manifesting during spaceflights (Nowak et al., 2019). However, increased levels of red blood cell platelets and higher hemoglobin concentration are reported in long duration flights, but these effects are probably linked to the plasma volume decrease occurring in space (Smith 2002; Kunz et al., 2017). The altered physiologic conditions of the cardiovascular system may result in a decreased ability to respond to blood loss in weightlessness. Hence, in case of hemorrhage, the time to intervene effectively is probably shorter (Kirkpatrick et al., 2009b; Williams et al., 2009) and rescue must be rapid, making fluid resuscitation a priority.

The hypothalamic–pituitary–adrenal HPA (axis) plays an important role in the adaptation to stress (Buckey and Homick 2002; Smith 2006; Welt et al., 2021). It is the most important interconnection between the nervous system and the endocrine system. The activation of the HPA axis leads to the secretion of glucocorticoids, which act on multiple systems and organs to redirect the energy resources necessary to meet a real need or even a possible need that could occur. The HPA axis response to stress is driven primarily by neural mechanisms, with responses that may be inhibited by feedback (e.g., production of glucocorticoid hormones). In a stressful situation, the axis mediates the effect of stress factors by regulating numerous physiological processes, such as metabolism, immune responses, and activation of the autonomous nervous system (ANS) (Chouker 2020; Tobaldini et al., 2020). In the presence of hypovolemic shock, there is an activation and release of adrenaline and noradrenaline by the adrenal medulla and glucocorticoid hormones by the adrenal cortex, in addition to glucagon from the pancreas (Smith 2006; Mandsanger et al., 2015; Herman et al., 2016; Crucian et al., 2018; Chouker 2020; Tobaldini et al., 2020; Kageyama et al., 2021).

ANS regulates the cardiovascular system and controls visceral functions in order to maintain homeostasis and the homeodynamic state of the body. It is also an interface between the body, the central nervous system (CNS), and external stimuli (Mandsanger et al., 2015; Chouker 2020; Tobaldini et al., 2020). Its sympathetic branch plays a role in the control of many activities, for example, cardiovascular, gastrointestinal, pulmonary, cutaneous, genitourinary, and immune. Despite being defined as an “autonomic” system, there are complex control mechanisms that act both centrally and peripherally (Mandsanger et al., 2015; Herman et al., 2016; Chouker 2020; Tobaldini et al., 2020) in pathological conditions such as hypertension, heart failure, and myocardial infarction stress (Malliani 2000; Wallin and Charkoudian 2007; Herman et al., 2016; Tobaldini et al., 2020). ANS plays an important role in the regulation of the vegetative state and also in the modulation of the responses of the immune system (Kirkpatrick et al., 2009b; Mandsanger et al., 2015; Chouker 2020; Tobaldini et al., 2020), metabolism, and inflammation (Kirkpatrick et al., 2009b; Chouker 2020; Tobaldini et al., 2020; Welt et al., 2021), suggesting an integration at different levels of control (Kirkpatrick et al., 2009b; Mandsanger et al., 2015; Chouker, 2020; Tobaldini et al., 2020).

When we talk about modifications present in space, we refer mainly to the studies conducted on parabolic flights. In them, there are short phases in which there is a change in severity. In this way, the effects of the different phases of flight on hemodynamics and the cardiovascular system were studied: 1) 1 g (before and after each parabola), 2) hypergravity during the ascending part, 3) microgravity phase at the apex of parabola, 4) hypergravity during the descending part of parabola, and 5) 1 g at the end of the parabola (Iwase et al., 2020).

In fact, these experiments simulate the hypergravity and microgravity characteristics of space missions (Criscuolo et al., 2020). These studies were born with the intent to explore the effects of different gravity levels (zero, lunar, and Martian gravity) on cardiovascular and autonomous control for missions to Mars in the near future. During the parabolic flight, the correlations between the level of gravity and the cardiovascular autonomic modulation have been at the center of many studies (Widjaja et al., 2015). Despite this, to the best of the authors’ knowledge, these effects have not yet been sufficiently studied to predict what might happen in the event of a severe hemorrhagic shock.

On the ground, the main indication in massive bleeding shock is surgery, i.e., damage control surgery (Ball 2017), which must be applied as soon as possible (Ertl et al., 2002a; Ertl et al., 2002b; Kirkpatrick et al., 2005; Wallin and Charkoudian 2007). Persistent hypotension after fluids administration (ATLS protocol) (American Committee for Trauma-American College of Surgeons 2018) is treated with vasopressors (epinephrine and norepinephrine) to improve systolic pressure. However, drugs (Standl et al., 2018) with different targets are available in case of failure of inotropic infusion. For example, dobutamine can be used in cardiogenic shock and in any type of shock with insufficient ventricular pump function. Other drugs (Standl et al., 2018) such as milrinone, levosimedan, vasopressin, glyceryl trinitrate, and sodium nitroprusside have found applications in different types of shock, mainly cardiogenic, with the exception of cafedrine hydrochloride and theoadrenaline hydrochloride that are used for neurogenic shock. However, a specific review for this topic should be the best option to discuss it in depth.

The ability to control hemorrhage after a traumatic injury in space is crucial in astronaut’s health care (Table 2). The crew must continue its mission autonomously, and any medical care is performed in a setting where resupply, evacuation, and communication are difficult (Hamilton et al., 2008). In space, medical systems as well as supplies, equipment, and crew training are limited.

It must be underlined that estimates of traumatic injuries are mainly based on terrestrial populations and do not include spaceflight data. They are extrapolated to the astronauts and referred to the environment of the International Space Station (ISS). In addition, estimates do not account for injury risks due to long duration surface operations under the influence of gravity, and for increased risks of acute radiation sickness (ARS) (Jones et al., 2019), both conditions are expected in Moon or Mars missions (Nowak et al., 2019).

In case of medical issues, stabilization and expeditious evacuation back to Earth are the present policy (Hamilton et al., 2008; Kirkpatrick et al., 2009c; Hodkinson et al., 2017) on the ISS, although standard advanced trauma life-support (ATLS) (American Commettee for Trauma-American College of Surgeons 2018), intravenous insertions for infusion, endotracheal intubation, and chest tube placement are practices that the crew medical officer (CMO) must know (Hamilton et al., 2008; Kirkpatrick et al., 2009c; Hodkinson et al., 2017). A major traumatic hemorrhage in space would be catastrophic. Hemorrhage can occur either externally, from open wounds, or internally, into closed anatomic spaces. It can be categorized as compressible and non-compressible, depending on the location (Kirkpatrick et al., 2005; Ball 2017; American Commettee for trauma-American College of Surgeons 2018). Non-compressible torso hemorrhage (NCTH), coming from the torso vessels, the pulmonary parenchyma, solid abdominal organs, or disruption of the bony pelvis, is occult and not treatable by simple compression and therefore be fatal (Ball 2017). On Earth, a blunt, polytrauma patient can be a challenge due to difficulty in detecting internal bleeding and could require advanced surgical skills and more dedicated devices than with external bleeding (Brenner et al., 2018; Cannon et al., 2018). Vice versa, in weightlessness, this type of injury can be devastating and seemingly impossible to treat, despite the help of ultrasound in diagnosis (Hamilton et al., 2008; Kirkpatrick et al., 2009c; Pletser et al., 2009; Alexander, 2016; Garrigue et al., 2018; Mashburn et al., 2019) It can absolutely drain a mission’s resources with no chance of resupply. The need for blood supplies in resuscitation is another major issue in space. It is known that morbidity and mortality resulting from hemorrhage decrease with the use of blood products and the derivatives of blood (Nowak et al., 2019). Therefore, blood transfusion, already a life-saving procedure on Earth, should be considered all the more important in space.

In an article, Nowak et al. (2019) reported on the need for research on alternative blood products in hostile environments. For example, lyophilized blood components like plasma that undoubtedly have advantages over liquid storage for mass, volume, and limited shelf life (Pusateri et al., 2016; Garrigue et al., 2018; Nowak et al., 2019).

Another possibility is the use of hemoglobin-based oxygen carriers (HBOCs) (Moore et al., 2009; Weiskopf et al., 2017; Nowak et al., 2019), which are artificial red blood cell substitutes able to deliver oxygen and provide volume expansion. They require little preparation; however, mass and volume are similar to red packed cells, occupying room in the space craft. Additionally, they are still experimental (Nowak et al., 2019).

In space, limitations due to mass, volume, and power (Nowak et al., 2019) affect blood storage capability which requires a significant use of refrigeration power. Refrigeration is also associated with a limited shelf life, 35 days at 1–6°C, while a trip to Mars lasts at least 6 months. However, to date, the most practical application for transfusion in space is fresh whole blood despite the limits set by circulatory physiology, resupply issues, and personal restraints in the spacecraft (Nowak et al., 2019). Other issues have to be taken into account in space (Nowak et al., 2019) such as the following:

-The need to restrain CMO and patients during spaceflights.

Additionally, in space, a severe hemorrhage may demand an immediate surgical intervention before diagnostics may have localized the source of bleeding (Kirkpatrick et al., 2001; Doarn 2007; Kirkpatrick et al., 2017a). A group of flight surgeons, trauma surgeons, and biomedical engineers emphasized that laparotomy could be required to stabilize a patient prior to further procedures (Doarn 2007; Ball 2014; Lamb et al., 2014; Kirkpatrick et al., 2017a).

Damage control surgery (DCS) (Doarn 2007; Ball 2014; Lamb et al., 2014) should be used to provide surgical control of hemorrhage. However, DCS should be performed in association with Damage Control Resuscitation (DCR) (Doarn 2007; Ball 2014; Lamb et al., 2014; Kirkpatrick et al., 2017b; Chang et al., 2017). This paradigm states that essential surgery is needed to preserve the physiological reserves of patients implementing only the necessary tasks by means of a few, selected procedures. Besides limiting the procedures to the essential, this method does not require large equipment outlays. A special protocol for austere environment is the Remote Damage Control Resuscitation (RDCR) (Kirkpatrick et al., 2017b; Chang et al., 2017), a treatment strategy for the severely injured trauma patient, designed to limit hemorrhage and produce or preserve adequate levels of physiological reserves for the DCS in the prehospital phase (Kirkpatrick et al., 2017b; Chang et al., 2017). For RDCR on Earth, the doctrine of permissive hypotension has been adopted (Lamb et al., 2014). This practice aims at limiting ongoing hemorrhage by reducing pressure while maintaining a “critical level” of vital organ perfusion. In this approach, few signs are necessary to evaluate the patient status such as the presence of a palpable radial pulse, mental status, and a systolic blood pressure (SBP) of 80–100 mmHg. Traumatic brain injury (TBI) needs a higher SBP to preserve cerebral perfusion pressure and avoid a secondary ischemic injury to the brain (Kirkpatrick et al., 2017b; Chang et al., 2017). However, applying this strategy during spaceflight would be difficult, especially in missions beyond low Earth orbit (LEO) due to the challenging issue of blood transfusion storage.

The early use of blood products, fresh warm whole blood, and other blood components, as well as other devices (hemostatic dressing, extremity tourniquets, junctional tourniquets, abdominal aortic and junctional tourniquets (AAJT), non-absorbable expandable, injectable hemostatic sponge (XSTAT), resuscitative endovascular balloon occlusion of the aorta (REBOA), intra-abdominal self-expanding foam, tranexamic acid administration, and expandable hemostatic sponges (Gordy et al., 2011; Jenkins et al., 2014; Bjerkvig et al., 2016; Rappold and Bochicchio 2016) is representative of DCR and RDCR. These protocols should be particularly useful in space missions where conditions are extreme rather than only austere. In fact, despite the numerous experiments on the feasibility of emergency procedures in microgravity (Campbell 2002; Dawson 2008; Kirkpatrick et al., 2009c; Alexander 2016; Panesar and Ashkan 2018; Robertson et al., 2020), the complex pathophysiology of hemorrhagic shock is mostly still unknown.

Space missions, in any case, may not allow all the procedures we are accustomed to on Earth, for example, the use of a “massive transfusion” protocol with fresh frozen plasma in conjunction with blood and platelets for a severe ongoing bleeding.

ATLS (Ball 2017) protocols have been adapted to the unique pathophysiological mechanisms (Panesar and Ashkan 2018; Nowak et al., 2019) present in space (Kirkpatrick et al., 2009c), but it is still not known how a severe bleed or cardiac failure might affect the hemodynamic state secondary to microgravitational fluid shifts (Kirkpatrick et al., 2009b). Plus, prolonged fluid infusion may have the effect of draining most of the limited supplies of the crew, adversely affecting the clotting profile and/or induce hypothermia (Kirkpatrick et al., 2009b; Panesar and Ashkan 2018). For limb and extremity trauma, tourniquets or hemostatic dressings may be adequate (Rappold and Bochicchio 2016; Panesar and Ashkan 2018). On the contrary, the region of the trunk cannot be treated by external pressure to control hemorrhage and, so far, hemorrhagic shock. Hemodynamic deterioration may prove difficult to address, owing to homeostatic decompensation, the fact that there is no access to facilities and equipment, or due to the lack of trained staff. As a result, DCS has been introduced also in space (Doarn 2007; Ball 2014; Lamb et al., 2014; Kirkpatrick et al., 2017a). In the exploratory phase, hemostasis and/or control of endogenous bacterial contamination must be achieved.

On the ISS, the only resuscitation fluids available are 4 L of normal saline (Nowak et al., 2019), and methods to generate crystalloids in flight are under investigation (Kirkpatrick et al., 2001; McQuillen et al., 2011). On the other hand, response to reduced gravity on other planets such as Mars, or on the Moon is largely unknown, and no appropriate protocols are available to date.

As already stated, blood transfusion in space depends on, among many conditions, limited vehicle dimensions (Summers et al., 2005; Hamilton et al., 2008; Alexander 2016; Nowak et al., 2019). In fact, during a spaceflight, mass, volume, and the necessary power to preserve stored items are known constraints. In addition, blood transfusion in the microgravity environment presents numerous difficulties. For example, although intravenous cannula infusions, phlebotomy and catheterization are possible, in weightlessness once the CMO and the patient are restrained, liquids have a different behavior than on Earth. Blood collection in microgravity should be possible with the use of a vacuum, syringe, or pump. Infusion could be accomplished with a pressure bag or a syringe (Hamilton et al., 2008; Nowak et al., 2019).

It must be remembered that on deep space exploration missions, communication with mission control may be delayed or impossible and the possibility of evacuation will be largely dependent on distance and trajectory from Earth. Therefore, the crew should be more able to function autonomously (Hamilton et al., 2008; Alexander 2016; Nowak et al., 2019) because even on the ISS in low Earth orbit, emergent evacuation could take more than 24 h (Summers et al., 2005; Hamilton et al., 2008; Alexander 2016).

The improved understanding of the coagulation process has produced a growing number of hemostatic agents that can be topically applied (Alexander, 2016; Chiara et al., 2018; Huang et al., 2020; Tompeck et al., 2020). In a systematic review in 2018, Chiara et al. (2018) selected four categories: 1) adhesives (liquid fibrin adhesives and fibrin patch), 2) mechanical hemostats, 3) sealants, and 4) hemostatic dressings (mineral and polysaccharides). Each one of them is described according to their employment and scientific foundation.

Despite their different utilization and activation modality, it must be generally underlined that the first concern of the surgeon is the state of the patient’s endogenous coagulation system. A mechanical agent after surgical hemostasis or packing is the right choice in case of normal coagulation. If the patient’s coagulation cascade is not reliable, the hemostat of choice should be an agent that may be effective even when coagulation factors are not, for example, adhesive products (Chiara et al., 2018). In the case of ongoing arterial or high flow bleeding, a patch-supplemented adhesive agent is indicated, as it is directly applicable under pressure on the site of the bleeding. A sealant agent is useful when the bleeding source is an organ like the liver, pancreas, and kidney, or to close a lung wound. Finally, hemostatic dressings should be considered in junctional and non-compressible hemorrhages, for example, in the neck, groin, or axilla (Chiara et al., 2018).

All these hemostats should be available in hospital service because of their different usages and indications. On the ground, tourniquets, conventional bandages, and advanced hemostatic dressings should be available to stop the bleeding in complex situations (Chiara et al., 2018).

New hemostats (nanotechnology) defined as self-assembling peptide nanofibers and chitosan nanofibers have also been used in clinical applications (Corwin et al., 2015; Chaturvedi et al., 2017; Chiara et al., 2018; Estep 2019; Huang et al., 2020; Tompeck et al., 2020).

Artificial red blood cell substitutes (hemoglobin-based oxygen carriers (HBOCs)) are under study to find a way of providing oxygen delivery and volume expansion in such extreme environmental conditions as deep space missions (Kirkpatrick et al., 2009c; Nowak et al., 2019). Originally, their application was studied to prevent transfusion reactions and/or bloodborne disease transmission. Other issues related to HBOCs need to be mentioned. For example, religious motives against transfusions or the need for a rare blood type. In addition, HBOCs may be used as an alternative to blood products in areas where the usual form of blood donation is not available, such as in space missions far from the Earth’s orbit (Moore et al., 2009; Corwin et al., 2015; Weiskopf et al., 2017; Estep 2019; Nowak et al., 2019). Although HBOCs have many advantages as they can be stored at room temperature and require relatively little preparation, they are liquid and have a mass and volume similar to packed red blood cells. Although Moore et al. (2009) published a systematic review showing there is no statistical difference in the mortality rates of shock patients with placebo and HBOC-treated patients, adverse events have been present, and these substitutes are still under review (Nowak et al., 2019).

As reported by Nowak et al. in 2019, plasma is the only lyophilized blood component in clinical use (Pusateri et al., 2016; Garrigue et al., 2018; Nowak et al., 2019). It has the advantage to be stored in a powder form at ambient temperatures for up to 2 years, and at the moment of transfusion, it can be reconstituted for infusion within a few minutes. In this way, it is advantageous with respect to the limited shelf life of other products and also with respect to the reduced mass and volume of the lyophilized component. In addition, lyophilization may provide storage of autologous blood products with lower risks for infection and transfusion reaction. However, to date, lyophilization of red blood cells and platelets is still experimental.

Bacterial translocation: To date, the theory suggesting that the gut, when suffering from oxygen debt, starts to leak endotoxin and bacteria systemically which then initiates an inflammatory reaction, has not been studied in space (Lord et al., 2014). On Earth, the severity of organ damage that starts in this way depends on bleeding severity and shock duration. The mesenteric lymphatics seem to be the major conduit for the transport of gut-derived bioactive factors into the systemic circulation (Diebel et al., 2012). Organ damage starts depending on bleeding severity and shock duration. Vital organ hypoperfusion usually begins in the gut and progresses to the kidney, liver, and lungs. The emission of large amounts of damage-associated molecular patterns (DAMPs) in polytrauma, systemically circulating, affects the patient’s whole body as initiators of systemic inflammation that is an exaggerated defense response with consequent organ failure (Wutzler et al., 2013; Huber-Lang et al., 2018; Matheson et al., 2018; Relja et al., 2018; Relja and Land 2020).

The endothelium while the linkage between oxygen debt and traditional organ failure (renal, hepatic, lung, etc.) has been long recognized; two additional highly dynamic tissues should be considered: the endothelium and the blood. These can be thought of as an integrated organ system, and are strongly related to oxygen delivery in the body (Lord et al., 2014). Microcirculation approximately represents an area of 4,000–7,000 m² with endothelium being a major target for trauma induced hemorrhage and hypoperfusion damages. When endothelial damage is present, hemorrhage and hypoperfusion therapy can produce damages (reperfusion damages) in the epithelium. In this case, the primary goal in trauma care should be the fast mitigation of oxygen debt (Jenkins et al., 2014).