Pathways to Reduce Late Mortality of Hemorrhagic Shock

Abstract

Patients with progressing hemorrhagic shock (HS) die rapidly of cardiac arrest by insufficient venous return or within days by second-hit multiple organ dysfunction/failure (MOD/MOF). Once earliest source control has been effectuated and macro-hemodynamics is normalized, only three variables affect mortality, namely microcirculation, temperature, and oxygen. Late, non-immediate, mortality is usually preceded by a period of cryptic shock, essentially a disease of microcirculation in the midst of a seemingly functional macrocirculation. The persistence of the effects of ischemia-reperfusion toxemia (IRT) underlying a subclinical cryptic shock is the fundamental pathogenetic factors for clinical observed second hit deterioration. Rewarming a hypothermic hemorrhagic patient and administration of supplementary high dosages of oxygen are standard practices for the management of hemorrhagic shock in acute phase. A complete shift of paradigm prospects an answer to the above tactics’ limitations, drawbacks, and contra-indications. Mild-to-moderate hypothermia, titrated supplementary oxygen, and timely-given vasodilators should instead be given during damage control surgery (DCS) for advanced shock with the aim of reducing ischemia repercussion injury (IRI) e microcirculation dysfunction. A new strategy is suggested: preoperative hypothermia and titrated oxygen before hemorrhage source control, and intra-operative vasodilation and anti-inflammatory tactics after source control.

1. Introduction

Quoting Singer and Matthay [1], “Many advances in medicine have been achieved through challenging established dogma with revolutionary thought and novel practices. Each and every specialty is reinvigorated by regular re-evaluation of processes and practices in the light of new evidence and fresh conceptualization. Challenge can galvanize fresh thinking and new approaches, yet may also reinforce and strengthen traditional paradigms if the prevailing orthodoxy is subsequently revalidated.”

1.1 Changing the paradigms

Once earliest source control has been effectuated and macro-hemodynamics is normalized, only three variables affect mortality, namely microcirculation, temperature, and oxygen.

Microcirculation optimization is crucial for prognosis of HS; hypothermia is still seen as an enemy and high flow oxygen advised in advanced HS till recently.

Can the interaction between the three variables be manipulated for improving prognosis of advanced unstable progressing HS?

2. Hypothermia in hemorrhagic shock

In hemorrhagic shock, re-warming the patient with normothermic/warm fluids and devices like the Bair Hugger is standard practice, assumedly and principally to prevent accidental hypothermia from blood loss, general anesthesia, and environmental exposure of open cavities and cold fluids [2].

Spontaneous hypothermia in hemorrhagic shock is not an independent risk factor for complications or mortality, which is correlated rather with the severity of the injury [3, 4].

Surely warming makes the patient more comfortable and prevents or stops the shivering accompanying hypothermia [5, 6], but is this practice really worthy, not to say safe [7]?

Cold increases α-adrenergic vasoconstrictive response; likewise heat increases beta-agonist response, with changes that are independent from the activity of metabolizing enzymes affected by temperature [8].

Hypothermia decreases blood flow to all organs of the body in different manner, the skeletal muscle and extremities being the most sensitive to the reduction, followed by the other internal organs, the lungs as the last. The metabolism of all drugs, in particular opioids and muscle relaxants, is slowed, and the lower is the temperature the lower and more distanced dosages are required [9].

The increase or normalization of temperature neutralizes the initial compensatory vasoconstrictive phase conveniently contributed by hypothermia, predisposing to a faster passage to a decompensated phase; moreover, hypothermia reduces the amount of fluids necessary to maintain pressure following vasoconstriction [10]. Since Hippocrates time and in World War I, it was noted that shocked patients had a higher survival when exposed to cold rather than warm environment, due to the vasoconstriction effect of cold [11].

The rationale for preventing or delaying the onset of hypothermia-related coagulopathy [12] is rather weak argument when compared to the beneficial effects on hemodynamics and metabolism in the overall computation. Hypothermia-induced coagulopathy is clinically significant at around 32°C, indicating a terminal stage of shock [5], while coagulopathy in early stage is determined by hypoxia and trauma itself, compounded by iatrogenic intervention and dilution of coagulation factors [13, 14]. Even at lower deep levels, coagulopathy remains a reversible phenomenon. In experiments on animals, spontaneous mild hypothermia does not affect coagulation in a model of controlled hemorrhagic shock [15] as predictably instead does hypothermia induced with intravenous cold solutions in uncontrolled hemorrhage models, where dilution of coagulations factors and the increased volume-driven pressures of the extra fluids become a contributing factor [16].

There is overwhelming convincing experimental evidence in animals of different size, proving the increased survival with induced intravenous and surface hypothermia compared to normothermia. This is not achieved without problems with both methods. Surface hypothermia is rather uncomfortable and intravenous fluids induce dilution coagulopathy, decreased DO₂ due to Hb curve shift to left, and must be accompanied by pharmacological control of shivering. Another drawback of surface cooling is that may accelerate death during severe hemorrhage shock because it causes reflex vasoconstriction that increases arterial pressure and bleeding speed before cooling down metabolism, which preserve cell functions [17]. For all these reasons, the systemic intravenous not-hematic fluids and surface hypothermia have been abandoned. The basic benefits of hypothermia in respect to normothermia were otherwise evident.

The experimental models of controlled hemorrhagic shock in small and big animals have confirmed the historical observations in war surgery and, ominously, the indisputable fact that hypothermia supports arterial pressure, decreases heart rate and oxygen consumption, and prevents lactate levels’ rising [18, 19, 20, 21]. It appears also to be in prospective more advantageous in advanced, uncontrolled hemorrhagic shock stages [21].

Very few studies have looked into the relation between hypothermia and hemorrhage in humans, on the claim coagulation increases bleeding by interfering with coagulation.

There is no evidence that mild hypothermia-induced coagulopathy increases mortality by increasing the rate of bleeding in elective surgery with patients kept at 36–34°C [22, 23] or in trauma patients [24], nor is evidence it increases mortality as early coagulopathy or as late coagulopathy [25, 26].

It can be postulated that the increased bleeding in the initial stages of hypothermia is consequence of vasoconstriction increasing pressure, hence bleeding rate speed, whereas in the late stages, both the vasoconstricting effect prevailing on the fading hemodynamic pump pressures and the positive effect on metabolism actually decrease mortality by preventing, slowing, or blocking further blood loss and maintaining cellular metabolism to a minimum.

A limit of the experimental studies lies in extrapolating conclusions from results obtained in laboratory on rats, dogs, and pigs, who have, respectively, much less and more fat mass than average humans, a different response to catecholamines, and a different surface-to-volume ratio. Finally, the cognitive functions tested after extracorporeal circulation are incomparable with the ones in humans [21, 27].

The main reason for the bad reputation of hypothermia in hemorrhagic shock has been the confusion between the early dynamics of spontaneous accidental hypothermia and the late metabolic hypothermia of advanced shock, between the various causes of hypothermia, and between early and late hypothermia.

Accidental, environmental, hypothermia respond to external rewarming; metabolic and cellular hypothermia does not, and only oxygenation with restoration of the capacity to produce adequate adenosine triphosphate (ATP) can reverse the latter.

2.1 Cellular effects of hypothermia

2.1.1 Protection from ischemia

ATP preservation is the essential life-preserving mechanism. ATP content is decreased in hemorrhagic shock but is regenerated once blood flow is restored in time. Cellular function remains viable up to a limit (warm ischemia period) depending on mitochondria function and up to a certain point can be re-established with restoration of perfusion [28, 29, 30].

Hypothermia diminishes the oxygen demand of the body (6–7% per 1°C cooling), protecting the most oxygen-dependent organs of the body, brain, and heart, against hypoxic damage [31]. The drop in body temperature in response to hypoxia, due to energy depletion, and a drop in heat production, unlike the ventilatory response to hypoxia, do not depend on the activation of peripheral chemoreceptors. This is the cause of metabolic hypothermia occurring in advanced HS [32].

Preservation of adenosine triphosphate (ATP) and glycogen stores in the ischemic myocardium areas, and of creatine phosphate in the non-ischemic areas appear to be as the determinant mechanisms for the benefit of hypothermia in ischemic myocardium [33, 34].

In brain cells, hypothermia reduces basal cellular metabolism by reducing oxygen uptake and consumption, with consequent shift of Hb-O₂ dissociation curve to the left and preservation of ATP content in all cells by stopping its breakdown [35, 36] and at some extent lactate and acidosis increase [37].

Ischemic neurons release neuroexcitory amines, especially glutamate, which in turn activates N-methyl-D-aspartate (NMDA) channels; once the channels are activated, calcium enters the cells and accumulates activating multiple destructive enzymes, with result of neuronal death. Hypothermia reduces the release of glutamate and another neuro-transmitter glycine needed for the NMDA receptor activation and prevents calcium entry restricting membrane permeability [38, 39, 40], so preventing cell death [41]. The reduction of calcium and lactate pathways accounts for the cell preserving effect of hypothermia in the brain.

3. Protection against ischemia-reperfusion

Hypothermia creates ischemic tolerance by several mechanisms: metabolic depression, reduced need for oxygen and energy, blundered immune and inflammatory response, and increased cell membranes tightening. Even more important is its protection from ischemia-reperfusion injury [42, 43].

Heart protection. Despite local hypothermia at 32–34°C in AMI reduces infarct size and ischemic/reperfusion damage, maintains ventricular performance and long-term remodeling, and prevents the no-reflow phenomenon, without though improving the overall outcome, its findings are ominously translatable in the prevention of IRT [44, 45].

The protective of hypothermia, whether induced or spontaneous, on I/R injury in the heart bases on the protection mitochondrial permeability transition pores, reduction of calcium overload, regulation of cellular signaling (Akt pathways, heat-shock proteins, extracellular-regulated kinase, etc.), and an overall reduction of the inflammatory response.

These events were observed when hypothermia was induced during the ischemic episode and disappeared after reperfusion [44, 45], hence the crucial importance of installing any form of therapeutic hypothermia before reperfusion.

This effect of hypothermia is timing/speed of onset-dependent. If hypothermia is present before ischemia installs can be life saving, otherwise it is not beneficial and may actually accelerate exitus. If tissue metabolism and heat production capacity is preserved by hypothermia before heat loss from ischemia occurs, then hypothermia is lifesaving [46, 47, 48].

Neuroprotection. The prevention and attenuation of the direct ischemic insult and the protection against ischemia-reperfusion (I-R) and ROS injury by tightening cell membranes and decreasing capillary permeability and edema in the intestinal capillaries, the most permeable in the body together with the liver and kidney ones [42, 43], are particularly useful if not crucial for brain cells IR injury or damage (IRI/D) during ROSC after successful CPR [49, 50, 51, 52, 53] and in neonatal encephalopathy [54, 55, 56, 57].

Systemically induced therapeutical hypothermia (TH) at a core body temperature of 33–35°C has been shown to be beneficial not only for neonates with ischemic encephalopathy but also for comatose adults post out-of-hospital cardiac arrest with both shockable and non-shockable rhythms [54, 55, 56, 57]. Acute brain damage from ischemia-reperfusion may further lead to other distal organ IRI [58].

Current clinical practice to prevent IRD with systemic therapeutic hypothermia involves whole-body cooling at core temperatures not below 34°C, threshold that can lead to severe complications [59, 60, 61].

Therapeutic mild hypothermia (≤34°C) reduces neurologic disability and cerebral palsy in neonatal hypoxic encephalopathy without statistically significant reductions in mortality during the neonatal period, infancy or later childhood, or in seizures at any age. Mortality at 18–24 months was though more reduced in high-income countries and not in low-income ones. The treatment should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischemic encephalopathy, initiated early (within 180–360 min), and be protracted ≥48 hours [62].

Hypothermia in organ preservation. Therapeutic hypothermia (4–10°C) has been standard procedure to protect donor organs against the harmful effects of ischemia/hypoxia after surgical removal from the donor. On its own it is not enough as it increases blood viscosity, contributing to red blood cells occluding the microvasculature (“sludging”) and causing detrimental microcoagulopathy. Even hemodilution did not resolve the problem [63].

This drawback stimulated the development of specialized storage solutions, integrating the hypothermic effect [64, 65].

Cellular swelling from intracellular edema at deep hypothermic levels can be explained by the temperature-dependent decrease in the activity of the Na/K-ATPase pump causing an increase in cytosolic Na + concentration and subsequent water retention. The increase of iron, ROS, and cytosol Ca++ in the first few hours of hypothermia accounts for the swelling [66, 67].

Survival in elective surgery on non-cardiovascular patients has been reported with induced temperatures down to around 5°C, around 10°C for cardiac surgery patients [68].

3.1 Clinical effects

The beneficial effects of hypothermia on heart oxygen consumption are more, the sooner the wanted temperature is reached [69].

Following the experience with deep hypothermia in thoracic aorta, a temperature target of 20°C can be seen as a safe limit for both heart and brain safety in models of extracorporeal circulation for cardiac arrest by exsanguination [70, 71]: It is safer and faster to reach than the 10°C reached with experimental big animals at a speed of 2°C/min [72].

Two-thirds of patients with trauma present with mild hypothermia, and a 10% with moderate one [73]; deep hypothermia <32°C occurs in a quarter of hypotensive shocks.

The 32°C temperature is the threshold below which significant coagulopathy occurs [5, 12, 15].

Below 26°C a rise of systemic and pulmonary vascular resistance can be noted [74].

Below 29°C dysrhythmias appear; below 24°C CA is a rule; no survival is normally the rule below 9–10°C of core temperature of spontaneous hypothermia [75].

Hypothermia decreases blood flow to all organs of the body in different manner, the skeletal muscle and extremities being the most sensitive to the reduction, followed by the other internal organs, the lungs as the last. The metabolism of all drugs, in particular opioids and muscle relaxants, is slowed so lower and more distanced doses are required, the more the lower is the temperature [9].

In ischemic hearts during mild hypothermia, the heart rate decreases while cardiac contractility is preserved, thus reducing myocardial work and oxygen consumption; the cardiac output is decreased, but the stroke volume and blood pressure are maintained.

In normal hearts, the increase in vascular resistance is caused by the increase in catecholamines release yielding to an increase of cardiac output, oxygen demand, tachycardia, and tachypnea.

With advancing hypothermia and concomitant slowing of metabolism cardiac, the cardiac output and oxygen demand decrease. Despite the protective role of hypothermia on tissue survival, profound and prolonged cooling eventually leads to circulatory failure by a direct effect on coronaries and microcirculation.

Hypothermia at 32°C in healthy coronary arteries slows coronary blood flow and increases microvascular resistance; furthermore, by increasing NO release, it exacerbates endothelium-dependent vasodilatory response. The alteration of the NO endothelium-dependent vasodilatory response makes patients with chronic ischemic heart disease and chronic heart failure prone to ischemic damage [76].

“In this pathogenetic mechanism, however, is a space for a preventive therapeutical intervention aimed to counteract coronary vasospasm and deranged excitability at core temperatures <30–29°C.”

With the deepening of hypothermia, the heart slows down pumping, dysrhythmias with high risk of cardiac arrest (CA) are common with hypothermia at ≤29°C, and dysrhythmic CA with very few anecdotal exceptions is a rule <24°C. Dysrhythmias and coronary vasoconstriction is what causes CA in accidental hypothermia.

The microcirculation stagnation (no flow phenomenon) and the hemoconcentration (decreased plasma volume), due to a leakage of plasma in capillaries, cause an increase of blood viscosity and concentration and aggregation of RBC with rouleaux formation in the microcirculation, in the end contributing with the effect on the coronaries and/or myocardium to the patient’s demise.

3.2 Drawbacks vs. benefits of therapeutic hypothermia

Shivering. A common drawback of hypothermia is muscle shivering: Shivering is a compensatory mechanism aimed to increase heat production. It increases oxygen demand and consumption, metabolic rate and sympathetic tone, which increase heart rate and cardiac output, and in the same time. Depleting ATP, whose hydrolysis is what produces heat. The faster the cooling is reached, however, the lesser the shivering and the oxygen consumption [77]. Shivering occurs during hypothermia induction at temperatures between 35 and 37°C and less likely at mild hypothermia between 32 and 34°C; thus, shivering may delay reaching lower target temperatures of 32–34°C and offset the therapeutic effects of hypothermia for I/R injury, pre-requisites of the therapeutical use of hypothermia [9]. Shivering disappears at temperatures <33°C [78]. Selective surface heat to hands and face, areas with the highest density of cutaneous temperature receptors, could be given in lieu of a pair hugger. The author recommends instead 0.3–0.5 mg/Kg of pethidine iv as safe anti-shivering drug, a sub-analgesic dose with no hypotensive effect—pethidine is already the least ventilation-depressing opioid. Morphine also settles the discomfort and has a lesser hypotensive effect and a superior sedative effect than pethidine, but has the unwanted vasodilating heat-losing effect from histamine release. Pethidine, on the other hand, has a central anti-cholinergic effect terminating rapidly the shivering that other synthetic opioids do not have; besides, rigidity and muscle spasm can show with the latter group of drugs. Interference between the drugs is a potential pitfall in terms of potentiating reciprocal side effects, for example, hypotension, drowsiness

Rewarming shock. Another drawback is the rewarming shock. A rewarming time > 0.25°C/h is recommended for the reheating after cardiac arrest occurring in accidental hypothermia that must be done within 6 hours. If rewarming was attempted after 5 h, experimental animals died as soon as core temperature reached 25–28°C [75]. Rewarming shock is a not well-understood complication of fast rewarming from accidental hypothermia, characterized by collapse with hypotension and tachycardia and by not progressing decrease of acidosis reverse trend. In its fulminant form, rewarming shock occurs during or shortly after rewarming and is unrelated to the occurrence of ventricular dysrhythmias. The first clinical sign is the no increase or reduction of cardiac output during rewarming, or shortly after, which is unrelated to any obvious cause, followed later by a rapid fall in blood pressure, caused by a sudden lowering of total peripheral resistance. During the process, hyperkalemia, hypoglycemia, and a rebound of increased intracranial pressure in TBI are expected.

The collapse is fatal if left untreated, but it can be buffered temporarily by interventions aimed at increasing peripheral resistance [79, 80]. It occurs only during rewarming in accidental hypothermia and does not occur during rewarming and weaning of the CPB appears.

Actual and potential benefits. If two-thirds of patients with trauma present with mild hypothermia, a 10% with moderate one [73], to bring up internal temperature up to 36°C, can be done intra-operatively fast enough in almost all patients. In experimental conditions on animals with different sizes than humans, the recommended rewarming speed from extreme temperatures of 10–15°C under CPB after induced exsanguination is 0.5°C per minute [81]. In the overall computation, hypothermia is not an enemy and has the only drawback in the shivering, causing lack of comfort in the early stages and in stopping microcirculation in advanced stages when paradoxically also a synchronous and crucially protective effect as long as the stagnation is not allowed to persist for longer than 1 maximum 6 hours [75]. Moreover, both shivering and the rewarming shock are solvable problems as is the protection of myocardium during the deepening of spontaneous accidental hypothermia when ischemia to the heart from the arrest of the pump ≤30–29°C is unwanted before deeper protective hypothermia has taken place. There is a window of therapeutical space to protect myocardium <32–30°C with rewarming and vasodilatation. The drawbacks should not hinder its beneficial applications. Hypothermia is such a relevant factor for survival at any stage of shock that no method of extreme form of resuscitation cannot disregard induced hypothermia as essential therapeutic component. Any association of causality between accidental hypothermia and mortality cannot be asserted without information on the contribution of metabolic hypothermia, that is, the level of macro- and micro-hemodynamics on impact, the different effects of hypothermia on macro- and microcirculation, and the timing of measurements especially in relation to the initial management of the shock and correlated hypothermia [82]. Hypothermia associated with HS is per se not lethal, and even its most ominous metabolic-hypoxic type, caused by hypoperfusion, could be managed with re-perfusion and intra-operative active re-warming and microcirculation vasodilatation after source control. If properly interpreted, controlled, or induced, it can only be beneficial in HS.

Timing of temperature manipulation is crucial for its benefits, as diriment is the synchronous reading of shock progression and dynamics and the distinction of the cause of hypothermia.

Moreover, systemic hypothermia with CPB is the major contributing factor to prevent or control systemic IRI [83].

The only study on the effects of hypothermia on microcirculation confirms that mild hypothermia at 34°C either protects or does not affect microcirculation. In an experiment on sheep, one group was kept in normothermia and another sent in hypothermia at 34°C with gastric circulation of cold water, both were made to bleed in a controlled volume hemorrhage. Microcirculation parameters were measured at hemodynamic stability and shock: Cortical renal, intestinal villi, and sublingual microcirculation were assessed with incident dark field illumination (IDF) video-microscopy; intestinal and renal blood flows were measured by an ultrasonic flowmeter, and mucosal PCO₂ was measured by air tonometry. Mild hypothermia does not worsen the microcirculatory derangements induced by hemorrhagic shock in the three most hit beds, with peritubular capillaries most sensitive to changes of regional and tissue perfusion than intestinal and sublingual beds [84].

4. Oxygen and hemorrhagic shock

The administration of oxygen at normobaric levels via a bag-mask with reservoir or an ETT with a FiO₂ of 1 (100% O₂) has been a common empiric practice in advanced shock.

It is commonly assumed that 100% oxygen, that is, a fraction of inspired oxygen (FiO₂) of 1 in pre-hospital setting on a patient with hypotensive hemorrhagic shock requiring intubation or the administration of 80–100% with a re-breathing mask with reservoir is good therapeutics.

There is no evidence of increased survival or of benefits with concentrations at a FiO2 > 0.4–0.5 in an uncontrolled hemorrhagic shock before source control, contrarily to moderate or mild hypothermia [85, 86, 87] or in controlled shock without hypoxemia [88].

As a matter of fact, hyperoxia has the opposite effect: The ischemic CNS response and the chemoreceptor response get in fact neutralized by hyperoxia in uncontrolled hemorrhage before or without source control, especially if a blood transfusion “giving a lift to that oxygen” is also running.

This might be as important reason for the better results of the “scoop and run” policy in humans and the scarce or no interference with hemodynamics before source control [89].

Oxygen in those scenarios is often given empirically without endotracheal intubation with masks with an average FiO₂ of ≤0.6, therefore not affecting significantly PaO₂ at the extent of neutralizing the two lifesaving reflexes.

In decompensated hypotensive shock and in absence of post-traumatic respiratory failure not requiring intercostal drain, for example, severe pulmonary contusion, patients should initially be kept at concentrations not higher than 40% FiO₂. Subsequently, 10% increases titrated to a SaO₂ of 90-94% can be effected according to arterial blood gases.

Even in a fainted patient—fainting per se has no correlation with HS degree, though is expected to occur often in advanced shock—PaO₂-titrated FiO₂ is required.

Total intravenous anesthesia with solely ketamine has in fact been safely done on not hemorrhagic or shocked patients and on patients with severe hemorrhages on spontaneous ventilation, breathing only oxygen-air, with no intubation or sophisticated monitoring other than clinical observations (pers. obs.).

Preoxygenation with 100% O₂ is only advised by several anesthetic societies to provide enough time during endotracheal intubation and prevent periods of hypoxia potentially occurring like difficult airway scenarios at expenses of temporary absorption atelectasis. It is also advised in CA resuscitation until ROSC.

5. Cryptic hemorrhagic shock

5.1 Ischemia-reperfusion and systemic inflammatory response

Ischemia-reperfusion phenomenon represents the continuation, local reverberation, and systemic amplification of the effects of ischemia to tissues.

Acute ischemia yields to nitrosative-oxidative stress with accumulation of by-products such as reactive oxygen and nitrogen species (ROS/RNS) that disrupts the mitochondria’s enzymatic pathways and membranes, provoking an unduly intracellular accumulation of calcium, eventually leading to cell death via several mechanisms [90].

The stressed or dying cell itself, when reperfused, triggers an accentuation of local toxicity by calling inflammatory cells, which reverberate further damage and other cells’ death. With the restoration of the circulation, toxic and inflammatory mediators are spread to remote organs [91, 92]. Preferred targets of the toxemia are the lung, the brain, the heart, the liver, and the kidney, due to their microcirculation peculiar anatomical structure.

The inflammatory mediators released as a consequence of reperfusion appear also to activate endothelial cells in remote organs that are not exposed to the initial ischemic insult. This distant response to I/R can result in leukocyte-dependent microvascular injury that is characteristic of the multiple organ dysfunction syndrome [93].

The impaired endothelium-dependent dilation in arterioles enhanced fluid filtration and leukocyte plugging in capillaries, and the trafficking of leukocytes and plasma protein extravasation in postcapillary venules.

The level of hypotension is a major determinant of the systemic inflammatory response arising during hemorrhagic shock [94]. The experimental works of Douzinas have proven the nexus between the level of ischemia and the IR-triggered inflammatory response, after previous indirect studies had correlated the level and duration of ischemia with the level of the inflammatory response [95, 96].

The phenomenon is very similar to a crush injury evolving in crush syndrome or to the toxemia and inflammatory shock following an ANP [91, 97, 98].

The gut is normally resistant to ischemia [27] but when is hit, as for its permeability, it acts as a rebound platform for a systemic spread of toxins, necrotic or inflammatory factors, and bacteria translocation even in the absence of sepsis. In a systemic IR toxemia (IRT), like the one induced by a HS, the gut is a formidable multiplier of toxemia augmented with the local bacteria translocation in addition to the inflammatory and toxic cascade. Furthermore, intestinal I/R increases luminal epithelial permeability yielding to ingress of bacteria and exit of bacteria and enterotoxins in the circulation, which can result in sepsis and multiple organ failure [99, 100].

An analogue situation occurs when the primary ischemic site is the gut itself such as in acute mesenteric ischemia or a gangrenous colon volvulus [101].

Another organ with highly permeable microcirculation, hit in any inflammatory, septic to toxic shock is the lung.

Endotoxemia in the absence of infection predisposes to infections in distant organs in the first postoperative week.

The IR local injury and systemic toxemia is not the only side effect of late inadequately treated ischemia.

A direct blunt trauma if significant or massive can give a post-traumatic inflammatory response (PTIR) of a SIR sepsis-driven, with the same endotheliopathy as underlying main pathophysiological mechanism [93, 98].

A master review describes the molecular intracellular damages induced by PTIR or post-trauma SIR after blunt trauma [102].

A reverberation and persistence of inflammatory response and endothelial dysfunction of arterioles is the underlying pathophysiological mechanism triggering a cascade of events leading to death in the first week or so.

No restitution ad integrum of endotheliopathy in the arterioles indicates irreversible shock [93, 98].

The resulting in increased microcirculation permeability with localized and distant organ fluid loss into the interstitial space, cytokine systemic storm and an inflammatory cascade reactions that can lead to reversible or irreversible end-organ dysfunction. Impaired endothelium-dependent dilation in arterioles, enhanced fluid and protein extravasation, platelets and leukocyte plugging in capillaries account for the clinical effects. At microcirculation capillary level, extravascular fluid hampers the transport of oxygen and decreases substrates availability, affecting all energetic processes including would dealing [102]. The reverberation between intracellular, local, regional, and systemic damage by specific intracellular and external molecules, activated in a trauma, especially a blunt one, and acting as intermediary and messengers for the SIR fuse, nonetheless the involvement ab initio of our innate immune system, have been postulated and prospected in a review by Pape [102].

5.2 What is cryptic shock?

The persistence of the above inflammatory, immunosuppressive, toxic, and catabolic dynamics is the reason for late, non-immediate, mortality.

Mortality after the first 6–24 hours is related to the speed and efficacy of source control, and in the first week to first month, mortality is MOD/F driven with or without sepsis [103].

The commonly used term “second hit mortality” is valid and acceptable if referred only to the timing peak of mortality. The underlying pathophysiological mechanisms are in fact a continuum [91, 98, 104, 105].

Cryptic (subclinical, persisting, silent, latent, unresolved, insidious, and refractory) hemorrhagic shock (CHS) ensues is an untreated or inadequately or late treated shock [91], carrying a 50–60% mortality [106, 107].

CHS is essentially a disease of microcirculation, where a normal macrocirculation, CaO₂, and DO₂ do not guarantee adequate VO₂ after source control or source elimination.

A situation of subclinical shock that will abut in MOD/F is then present and should be prevented, identified, and managed early before evolves in exitus.

Monitoring of the solely macro-hemodynamics variables may lack sufficient predictive value on the evolution of a critical patient. Often in ICU macro-hemodynamics variables are seen within normal range; nevertheless, patients still deteriorate and die all of a sudden, hit by a rapid onset multiple organ dysfunction/failure (MODS/MOF) despite reassuring values [91, 106]. It is what kills in ICU patients with normal macro-hemodynamic variables.

When macro- and microcirculation are in evident dys-synchrony [108, 109], it is essential to address the crucial role of the microcirculation/tissues interaction and hence restore physiological levels of CaO₂, DO₂, and VO₂.

Despite restoration of the macrocirculation, the sublingual microcirculation is seen impaired for at least 72 hours in hemorrhagic shock [107].

5.3 Characterization of cryptic hemorrhagic shock

Whereas in a septic or toxic shock the persisting anomaly is the persistence of sepsis factors, mediators or by-products and in a toxic shock is the underlying systemic presence of toxic and necrosis by-products [93, 98]; cryptic hemorrhagic shock is characterized by the presence of an underlying persisting ischemia-reperfusion toxemia (IRT), persisting acidosis and a dysfunctional microcirculation, and endotheliopathy in advanced stages, when the arterial gate system suffers itself of hypoxia (Table 1) [27, 91, 93].

• Trend towards tachycardia, not explained otherwise

• MODS/MOF with normal macro-haemodynamics

• Presence of inflammatory or toxic mediators in the blood

• ↓SvO2/ScvO2 < 65–70%

• NBE > 4 mmol/L

• Lactic acid >4 mmol/L

• Microcirculation imaging (spread hetereogenity of capillaries, reduced capillary density,microcirculatory flow reduction, tissue edema).

Table 1.

Characterization of cryptic shock [91].

Acidosis, a direct function of ischemia/hypoxia/hypoperfusion, is monitored with the rising levels, in temporal order, of NBE, LA, and pH [91, 110, 111]. Whereas ischemia-reperfusion phenomenon depends on the entity and duration of tissues relative ischemia before the index operation, acidosis is a direct function of hypoxia or infection or indicates the presence of a ischemia-reperfusion toxemia.

Different abnormalities can be observed with direct visualization of the sublingual microcirculation with hand-held vital microscopes or HVMs [orthogonal polarization spectral (OPS), sidestream dark field (SDF), and incident dark field (IDF)] in a situation of cryptic shock: spread heterogeneity of capillaries, reduced capillary density due to hemodilution and anemia, microcirculatory flow reduction due to vasoconstriction or micro-tamponade, and tissue edema [112, 113].

Other methods, such as near-infrared spectroscopy (NIRS) sublingual capnometry and cerebral oxygen saturation and skeletal muscles oxygenation, have also been used in ICU to assess microcirculation in hemorrhage, cardiac surgery, and trauma [114, 115, 116, 117, 118, 119, 120].

NADPH fluorescence levels are the nearest method to measure visually tissue oxygen content [121].

“Clinicians never know whether optimization of the microcirculation and tissue oxygenation is actually achieved after macrovascular hemodynamic optimization. The use of automated analysis and the future possibility of introducing artificial intelligence into analysis software could eliminate observer bias and provide guidance on microvascular-targeted treatment options” [122].

6. Prevention of second hit mortality

To prevent or limit the ischemia-reperfusion toxemia, to prevent and buffer the effects of endotheliopathy in the arteriolar system, and to adjust amount of oxygen entering the life units [98] is essential management for preventing the second hit MOD/F morbidity and mortality.

Management, therefore, must be multidirectional.

While acidosis is managed by reversing hypoxemia and rapidly controlling or eliminating the sources (stop hemorrhage in a hemorrhagic shock and remove all infected necrotic ischemic gangrenous contaminated tissues/fluids in septic shock/inflammatory shock), or optimize cardiac output (cardiogenic shock), and only at extreme levels require bicarbonate buffering, IR toxemia dynamics allow space for therapeutical strategies and manipulations in pre- and post-source control and in postoperative period.

The strategy proposed to prevent second hit IRT MODS/F can be summarized in the following: (i) the earliest or an early timed surgery preventing early mortality and the incidence and level of a second hit MOD/F; (ii) appropriate application of damage control surgery (DCS) (Table 2); (iii) awareness in postoperative phase of the signs characterizing the status of a cryptic subclinical shock heralding the second hit; (iv) exploiting the benefits of hypothermia preoperatively (cold blood and blood components (plasma, RBC, platelets, and no reheating)), and shivering control, (v) hypoxemic or normoxemic reperfusion post-DCS; (vi) plasma in the presence of SIR syndrome or post-traumatic inflammatory response, for example, in blunt trauma; (vii) reheating and vasodilatation, which has shown to be beneficial in experimental animals, intra-operatively during DCS soon after source control and pressure restoration, except if there is co-presence of severe TBI; postoperative adjuncts pro re nata (high doses oxygen, NO inhalation, permissive hypoxemia, cortisone/vit A, and heparin).

Timing

Time from from injury to source control > 90-120 min in patients with haemodynamic instability

Hypotension

i Fluid-resistant hypotension or temporary (20-30 min) response to 500-1000 ml rapid infusion elicited after 2 hours from onset of a haemorrhage

ii in presence of signs of cardiac or brain ischemia

Acidosis (metabolic)/tissues hypoxia

i ScvO2 < 65–70%; (ii) NBE > 6–8 mmol/L; (iii) pH < 7.2 - (values in trends).

Intra-operative reasons

i Convenience for the surgeon before transfer, ii) Unreachable bleeding, e.g. terminal ICA, high IJV, sacral vessels, retro-hepatic veins iii) Intra-Operative Hypotension, iv) Operation lasting more than 60 min on patients hemodynamically unstable before operation, v) co-presence of fecal peritonitis or of gangrenous tissues/fluids anywhere in the body, vi) tension or gap between gut and abdominal wall margins, vii) high risk of anastomosis/abdominal wall healing failure (edematous, ischemic, congested, cyanotic, not oozing margins).

THAI (timing, hypotension, acidosis, intra-operative) criteria

Table 2.

Indications for DCS [110, 111].

Once earliest source control has been effectuated and macro-hemodynamics is normalized, only three variables affect mortality, namely temperature, oxygen, and microcirculation.

6.1 Managing microcirculation

While upstream circulation derangement’ correction is effected with an early or the earliest intervention of source control and venous return optimization, it is the effect of the hypoxemia distally to the tissues that determines the prognosis [123, 124].

In a progressive shock, microcirculation is put under distress and decompensates at three different moments.

First, when Crit-HbO₂ level is reached, bleeding source/s control and blood replenishment or judicious blood component restoration have not yet been accomplished.

Second, being HS, likewise CS, a vasoconstricting shock with the arteriolar reflexes system aiming to keep blood in the macrocirculation at expenses of microcirculation and tissue perfusion, when exogenous vasoconstrictors are used in the situation of a progressing hypotensive shock not responding to fluids during THR Stage III, in a phase of arterioles unresponsiveness Stage IV, or postoperatively in ICU, more distal hypoxia occurs [27, 110, 125].

Third, when circulation all of a sudden is restored and the nitrosative/oxidative stress products are enhanced and reverberated locally, and amplified systemically with damage to other organs, provided with specific special microcirculation, namely lung, liver, and kidney—the ischemia–-reperfusion injury (IRI), which can become systemic ischemia-reperfusion toxemia (IRT), leading to the second hit of MODS/F.

6.2 Vasodilatation

In late phase septic shock, when vasoconstriction takes over the initial vasodilation [93], NO donors protect also against hypothermia and hypoxia/acidosis [126].

Nitroglycerin decreases systemic vascular resistance (SVR), heart work, and oxygen consumption in severe heart failure and cardiogenic shock, a vasoconstricting situation [127].

In experimental studies on small animals, low dose nitrites and other extrinsic NO donors in low doses (extrinsic acetylcholine, sodium nitroprusside, and nitroglycerin) have also shown to enhance microcirculation flow and perfusion, reverse arteriolar vasoconstriction, and increase capillary perfusion and venous return, improving central cardiac function and prevented further tissue ischemia, when administered in early, reversible, and vasoconstrictive phase of hemorrhagic shock and detrimental in late stages [128, 129, 130, 131].

This is interpreted with the major chances of temporary timed benefits, when the arteriolar system is not in advanced hypoxemic derangement. Experimental studies were done also with animals filled with fluid after control hemorrhage and did not study a situation of pre- and post-source control. In the author’s view, source control is the cut off for a rational use in humans, after restoration of pressures.

The timing of administration is therefore the key factor for a beneficial usage of vasodilators in HS.

Understanding the hemodynamics of shock (vasodilator type the septic shock in the initial phases, vasoconstrictor types the hemorrhagic, the cardiogenic and the advanced septic shock) [93] is diriment for a safe use of vasodilators.

NO donors can be administered intra-operatively, after source control and with an optimal venous return and SAP of ≥90 and MAP of ≥60 mmHg, under continuous real-time monitoring.

No hypotension should be allowed to occur intra-operatively or postoperatively.

Dosages should be titrated to maintain mean an arterial pressure (MAP) > 65–70 mm Hg under real-time continuous monitoring and a detectable response in the microcirculation. The safety of VD in SS and CS points toward a benefit in HS.

CS and HS are microcirculation vasoconstriction shocks, due to the occurring reflex response, whereas SS is vasoconstricting only un advanced stages, being a vasodilating in the initial reversible stages as for its direct effect on endothelium [93].

Intravenous infusion of vasodilators in physiological conditions has proved safe and generally beneficial in all vasoconstricting shocks, namely advanced septic shock and cardiogenic shock. In HS, intra-operative iatrogenic vasodilation soon after source control is a therefore potentially beneficial, despite a not clear mechanism.

A potential benefit of systemic infusion of nitrites or NO donors is the protective effect on patients with coronary artery disease by counteracting the vasoconstriction effect of drugs (e.g., noradrenaline) and deepening hypothermia on heart and coronaries.

The benefits of a systemic vasodilatation with nitrites and NO donors have also been confirmed by NO inhalation, with its anti-inflammatory effect in preventing and counteracting the IRI to the lung, manifesting in postoperative period with secondary acute lung injury by vasoconstriction or by I-R from splanchnic organs such as gut and liver by NO [132, 133, 134].

A reduction of I-R damage in the liver from any etiology, whether primarily inflammatory or secondary hemorrhagic with NO eNOS-produced has also been noted [135].

The timing of administration with beneficial effects of iNOS inhibitors in the vasodilative phase and of NO inhalation during the vasoconstrictive phase emphasizes again the crucial importance of timing and synchronous monitoring of its effects. Areas that are lacking iNOS have less NO-induced vasodilation and become underperfused.

Vasodilation creates also an optimal micro-hemodynamics for oxygenation and removal of CO₂ buffering of acidosis and milieu normalization and IR inflammatory and toxic product removal.

Intra-operative internal and external warming under full oxygenation and after source control helps or can substitute vasodilators action. The same strategy can be applied in HS.

External warming can be added soon after source control and in postoperative period.

To bring up internal temperature up to 36°C can already be done intra-operatively. In experimental conditions on animals with different sizes than humans, the recommended warming speed from extreme temperatures of 10–15°C in large size animals is 0.5°C per minute [81].

6.2.1 Addressing ischemia-reperfusion

Systemic hypothermia and the hypoxic/ischemic post-conditioning strategy, despite the lack of clinical data pointing to a decrease in HS mortality, remain to date the best therapeutical assets available to prevent or attenuate the damage of IRI.

The benefits of hypothermia at mild moderate levels have been delineated experimentally [21].

Besides the prevention and attenuation of the direct ischemic insult, hypothermia gives protection against free radicals in I-R injury and protects against inflammation by tightening cell membranes, decreasing capillary permeability, leukotriene production, and edema [42, 43].

This effect is exploited in preventing IRI on the brain during ROSC [50, 51] in decreasing the size and performances of myocardium post-infarction [44, 45].

6.3 Systemic hypothermia pre-source control

Despite local hypothermia in AMI reduces infarct size and IRI without improving the overall outcome, its findings are ominously translatable to HS with global ischemia situation and low DO₂.

If local or regional hypothermia prevents the escalation of IR damage to heart and brain even before ischemic infarction installs, even more so systemic hypothermia may decrease the level IRD/I in HS systemic hypoperfusion and hypoxemia.

Hypothermia can be conveniently exploited preoperatively either not counteracting spontaneous accidental hypothermia or by inducing a mild-moderate level.

It should be controlled or brought and kept at the least to >30°C for drugs be effective, > 32°C to avoid the nuisance of coagulopathy requiring packing and consuming time for completion of the index operation, and below 36°C core temperature to avoid the negative effects of unnecessary high temperature in tissues that have already suffered a condition of relative hypoxia and exploit its beneficial effect on buffering IRI.

Practically, if present ab initio, hypothermia should not be counteracted or brought to normothermia by any means, and it should be lowered at mild-moderate levels by infusion of cold whole blood, or fresh-frozen plasma and cold RBC if the patient is normothermic.

Clinical experience with cold stored low-titer whole blood (LTWB) has been seen not to confer disadvantages on hemodynamic and safety aspects compared to normothermic blood, with the advantage of healthier platelets up to 2 weeks and higher retention of Hb at 24 hours [136, 137, 138, 139, 140, 141].

If hypothermia is used as part of the treatment in HS, the entire strategy should change starting from preoperative management and anesthesia.

There is overwhelming convincing evidence in animals of different size, proving the increased survival with intravenous and surface-induced hypothermia compared with normothermia. This is not achieved without problems. Surface hypothermia would be more uncomfortable, and intravenous fluids induce dilution coagulopathy and decreased DO₂ due to Hb curve shift to left and must be accompanied by pharmacological control of shivering and in its accidental form not to be counteracted, resorting to small doses of pethidine for shivering.

Therapeutic hypothermia, after reperfusion following resuscitation with fluids, predictably cannot prolong survival in volume-controlled HS [142].

Normothermia is predictably beneficial after source control and resuscitation [143]. During surgery after source control, it is rewarming, in fact, that increases survival, and not hypothermia; likewise, it is hypothermia, which is beneficial and increases survival before source control.

In a study under volume-controlled induced HS on medium-sized animals spontaneously breathing under a GA with a vasodilating agent such as halothane, hypothermia induced after exsanguination with extracorporeal shunt cooling at 35+/−0.5°C resulted in an improved survival compared to normothermia [144]. The study was biased by the beneficial effect on the vasodilating halothane. In any case, postoperative hypothermia is not an acceptable situation or a possible iatrogenic tactics in HS. It remains beneficial in normovolemic conditions such as post-CA ROSC period or neonatal encephalopathy.

For an indirect proof of the beneficial effect of cold blood and blood components global ischemia scenario is CPB. Systemic hypothermia with CPB is the major contributing factor to prevent or control systemic IRI [49]. The different outcomes between pre- and post-source control hypothermia can be explained only by the global and more uniform distribution of hypothermia with ECLS, method not practical or convenient in postoperative period when the comfort of the patient is a main therapeutic target.

The key universal word to HS management, together with a rapid or earliest source/s control, is timing.

The protective effect of hypothermia from ischemic damage, whether induced or spontaneous, is timing/speed of onset-dependent. If hypothermia is present before ischemia installs is or maybe lifesaving, otherwise it is not beneficial and may actually accelerate exitus. If tissue metabolism and heat production capacity is preserved by hypothermia before heat loss from ischemia occurs, then hypothermia is lifesaving, as seen in CA from accidental hypothermia [46] and in cardioprotection post-AMI [47].

6.4 Oxygen-titrated reperfusion

Besides hypothermia, ischemia and hypoxemia have been studied to test the effects of their variations on the IR dynamics.

Excess of O₂ therapy during significant hemorrhage intensifies the physiological compensatory responses of vasoconstriction and blood flow redistribution [145]. Therefore, compared with room-air breathing, high flow or high concentration O₂ therapy deteriorates both hemodynamics and tissue/cellular hypoxia, in spite of the significantly higher arterial blood oxygenation.

Moreover, the abundance of oxygen supply in the initial phase of reperfusion produces a burst of ROS generation. This opens to the question of how possibly attenuating IRI by manipulating the oxygen content and titrate it to the cells needs.

“Ischemic preconditioning” is an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion. Ischemic preconditioning (local or remote) plus antioxidants and scavengers [hypoxia-inducible factor-1α (HIF-1α) antioxidant N-acetylcysteine (NAC) antioxidant MitoQ Glutathione (GSH)] aim to prepare cells to better respond to the forthcoming stress, are difficult to apply in clinical settings, and lack effectiveness when they are applied after or during reperfusion/resuscitation [146].

The opposite tactics, “ischemic post-conditioning,” consist in intermittent ischemia applied during early reperfusion alternating with brief periods of reperfusion [147].

A closely related technique involves initiation of transient episodes of ischemia in a remote tissue or organ at the time of reperfusion (remote ischemic post-conditioning). Though not advisable in HS and cardiovascular ischemia, remote “ischemic post-conditioning” confirms the advantages of ischemic/hypoxic post-conditioning in buffering, decreasing, or counteracting the side effects of IRI [148]. Resuscitation from hemorrhagic shock resulted in acute lung injury with enhanced oxidative and inflammatory pulmonary responses. However, the degree of injury correlated only with the extent of oxidative aggression [149].

A variation from the alternating cycles of ischemia-reperfusion is “hypoxic post-conditioning,” characterized by reperfusion under normoxia alternated with periods of hypoxia. The tactic was found to reduce the formation of reactive oxygen species (ROS), lipid membrane peroxidation, and intracellular and mitochondrial Ca(2+) overload [150].

“Hypoxemic resuscitation” with PaO₂ at 35–40 mmHg compared to normoxemic resuscitation with PaO₂ at 95–105 mmHg has been seen attenuating lactate production, lower ROS production, lesser oxidative and inflammatory stress [151], and pulmonary capillary endothelial dysfunction in respect of normoxemia in medium-size animals such as rabbits, following induced volume-controlled HS [152].

Hypoxemic reperfusion consists in gradually increasing initially during reperfusion the FiO₂ of the reperfusate from a lower level at PaO₂ levels of 30–35 mmHg to PaO₂ levels of 95–105 mmHg at the end of the resuscitation period. At a PaO₂ range between 35 and 130 mm Hg no significant metabolite concentration changes are seen [153]. Though tested only in experimental settings, the new conceptual development, revamped from a combination of the experimented “hypoxic post-conditioning and hypoxemic resuscitation” tactics, represents the most conceptually optimal method for oxygenating tissues without increasing the IRI [154].

The advantage of ischemic position is in the possibility to modulate PaO₂ using different levels of FiO₂ without compromising perfusion. In this way, ROS and the intracellular pH are kept at a minimum, at the same time oxygen is available to mitochondria for ATP generation/storing, and metabolic waste is not slowed.

Another potential advantage of hypoxemic reperfusion compared to the use of antioxidants is that it aims to prevent ROS production rather than eliminate their deleterious effects.

Moreover, hypoxemic reperfusion may be advantageous compared to post-conditioning strategies since blood flow is restored offering better replenishment from metabolic wastes.

Two experimental studies highlight the relevance of oxygenation on the perfusion in determining IRI and overall prognosis in resuscitation of a progressive hemorrhagic shock.

In a study, tissue oxygenation (PO₂ e tPO₂) improved at a FiO₂ of 1 in normovolaemia and at blood volume losses of less than 20%. Instead, at significant, for more than 50% blood volume losses, high inspired oxygen admixtures lead to precipitous reduction of tissue oxygenation, similar to that of animals breathing in-room air. An even worse outcome was observed by inducing hypoxemia (breathing at FiO₂ = 0.15) without resuscitation; all parameters deteriorated, and the animals had an earlier death. Hypoxemia combined with hypoperfusion accelerated the tPO₂ fall considerably [155].

An experiment in vitro on cardiomyocytes from explanted heart has shown that exposure to hypoxemic and room oxygen levels over a 72-h period results in significantly lower amounts of pro-inflammatory cytokine release than intermittent or continuous hyperoxia. Cardiac myocytes obtained from the explanted hearts were exposed to constant hyperoxia (95% O₂), intermittent hyperoxia (alternating 10-min exposures to 5 and 95% O₂), constant normoxia (21% O₂), or constant mild hypoxia (5% O₂), using a bioreactor. Constant and intermittent hyperoxia induced inflammation and cytotoxicity soon after exposure, which was the greatest after constant hyperoxia and even brief hyperoxic episodes [156].

In the last 7 years there has not been any study or in vivo application of hypoxemic reperfusion tailoring oxygen administration to HS level.

Only one study has showed that the more advanced is shock, the lesser oxygen is required. In it, where rats were made to bleed 70% of their TBV in a controlled HS experiment, a 3-week-old hypoxically stored RBCs, made hypoxic using an O₂ depletion system, scored like fresh RBC and better than conventional 3-week-old stored RBC in terms of hemodynamics and organ injury, during resuscitation, and in terms of oxidative stress, RNA/DNA injury, and lipid per oxidation, following reperfusion [157].

6.5 Normothermic plasma

Trauma causes a systemic inflammatory response, which, contrarily to sepsis and inflammatory shock [91, 98] where is regularly and primarily hit, in trauma with or without hemorrhage is more present in severe blunt trauma, due to the relative increased response for the relative increase of soft tissue injuries in respect to a penetrating one where the inflammatory reaction is present only mainly along the track of the offense weapons trajectories. Moreover, SIR messengers and factors are lost in a relative bigger amount in a penetrating trauma than a blunt one where tissue contusions are universally present compared to a penetrating trauma. Endothelial cell damage and glycocalyx shedding of capillaries and arterioles are the main target, yielding to coagulopathy, further inflammation, increased vascular permeability, and dyslexia that may lead to death. The microcirculation derangement is mirrored by worsening of flow, density, and heterogeneity of capillaries within microvessels, as seen with sublingual incident dark field video-microscopy [158].

The vascular endothelium plays a central role in maintaining organ homeostasis through its regulation of vascular tone, coagulation, inflammation, and barrier function and the vital interaction with the distal tissues on gas exchange. Dysregulation of normal endothelial function occurs during major injuries with severe tissues trauma, hemorrhagic shock, and burns, where it gives rise to systemic microvascular thrombosis, inflammation, loss of barrier integrity, coagulopathy, and respiration dysregulation. The endotheliopathy of trauma involves a complex interplay between the glycocalyx, von Willebrand factor (VWF), expressed on its surface, and platelets. Upon exposure to subendothelial proteins such as collagen, VWF binds platelets to the injured vasculature. The endothelium, which provides an anticoagulant and platelet-repellent surface in the resting state, becomes highly procoagulant and attracts platelets and leukocytes when its protective glycocalyx is depleted. Hyperadhesive VWF also binds leukocytes to normal ECs remote from the injury site [159].

Normothermic FFP is the most effective fluid in restoring the endothelial glycocalyx and junctions, in reducing endothelial permeability, and in attenuating the early inflammation/coagulation response. The mechanism is not clear but is likely due to the effects of the several components of FFP as the same beneficial effects have been seen also with plasma-derived products such as prothrombin complex concentrate (PCC) and lyophilized and spray-dried plasma. The protective effects of FFP are diminished by post-thaw storage at 4°C for 5 days and are time sensitive with most efficacy with the first 3 hours post trauma [160].

A decrease of 30 days mortality was found with plasma when compared to no plasma, but only in blunt trauma [161]. In some blunt trauma, such as a predominantly orthopedic blunt poly-trauma a variable post-traumatic inflammatory response ensues. In these scenarios, the inflammatory cascade has more chance of being retained inside circulation, damaging the endothelium and microcirculation, than a penetrating trauma where the inflammatory avalanche gets lost with the blood loss. Presumably, following the loss of inflammatory or toxic mediators and factors with the blood loss, there is a notable absence or a comparably lesser amount of SIR and IRT in penetrating injury, while the post-traumatic inflame response is very much present and longer lasting in a blunt injury where viable but damaged tissue contusions or hematoma continue being a source of SIR or IRT. This explains why plasma has benefits in blunt injury when added to blood.

Another advantage of plasma in blunt trauma is that it helps the release of VWF from ECs. This action is prevented by the anti-fibrinolytic agent tranexamic acid, providing a direct link between endotheliopathy and fibrinolysis during acute trauma [162].

These findings make normothermic plasma an important fluid in postoperative management of a HS from a blunt poly-trauma. An advantage can further come in decreasing plasma amenable coagulopathies, if already present and missed.

6.6 Postoperative therapeutic adjuncts

Cortisone is the perfect drug for curbing lung inflammation in the initial stages of secondary ALI by any etiology as well as any inflammatory microcirculation derangement of kidney and liver.

Cortisone has two major potentially negative side effects in the immediate postoperative period: healing interference and impairment, and curbing the inflammatory response to IRI/T. While healing is not impaired if given in the first 3 days, not anyway enough to interfere with healing processes of an anastomosis or abdominal/chest wall union, and can anyhow be counteracted by high doses of vitamin A, its anti-inflammatory property is a major problem. Its use with intent to prevent or curb the IRI to lungs kidneys and liver needs to be well pondered.

Heparin until mobilization remains another option practicable with a predictive and preventive therapeutical role in early IRI. Heparin small doses could be added to dissolve microthrombi in microcirculation especially in the lung we have seen to be an important pathogenetic mechanism for the VQ mismatch of interstitial pneumonia or ALI/ARDS occurring in second hit MOD/F. This effect must be plot against wound mucosal anastomosis oozing in patients with mild or moderate TBI [25, 26].

Therapeutic oxygen at concentrations above FiO₂ of 0.6 in a HS has to be considered as normobaric hyperoxia and avoided, in both preoperative and postoperative periods. It has been seen that 40–50% equals 100% in terms of oxygenation without the side effects of hypoxemia; 60% is therefore the maximum that should be given in a HS for oxygenation purposes. Higher concentrations should be considered only for special purposes, for example, CA initial resuscitation until ROSC or concomitant acute respiratory failure by added pulmonary trauma. Despite a proven anti-inflammatory and anti-infection property in experimental settings [163], it is not clear as to which patients and or which conditions would benefit of hypoxemia to decrease postoperative surgical site infections’ rates [164]. Certainly, oxygen is necessary for healing and prevention of infection: Oxidative bursts of neutrophils require molecular O₂ [165, 166]. Oxygen in high doses PaO₂ > 60% can be necessary, if the tiO₂ and VO₂ could be reliably calculated prn. VO₂, in fact, is not an accurate index of tissutal PaO₂ under conditions of tissue hypoxia [167]. A possible benefit on post-operative infections’ prevention cannot be excluded either.

The damages to lung alveoli microcirculation and structure due to vasoconstriction and the excess of ROS at superior normobaric doses are the drawback to avoid.

Hyperbaric oxygen is not an option too.

Inhaled NO can be used in ICU for preventing secondary ALI or the lung microcirculation vasoconstriction [131, 132, 133, 134].

6.7 Permissive hypoxemia

Mild permissive hypoxemia (PaO₂ 55–80 mmHg; SpO₂ 88–92%) results in improved outcomes also in patients at risk or with actual early acute lung injury, included those with ARDS or with ARF from other causes. Preliminary results with low FiO₂ at 0.5 in a mix population have confirmed the safety and therapeutic efficacy of a “permissive hypoxemia” tactics, with improvement of in-hospital mortality, a longer ventilator-free day period, and an improvement of the 28-day mortality in an ARDS subset and a worse outcome in high or hypoxemic concentrations [168].

7. Perspective

On these bases, a strategy can be drawn for timely application before or soon after source control in an advanced shock requiring DCS [111], when IR toxemia and cryptic shock are very likely to install and determine prognosis (Table 3).

Table 3.

Strategies.

The framework conceptualized by Convertino of a similarity between extreme physical exercise requiring increasing VO₂ and the need to ensure sufficient VO₂ after normalization of CaO₂ and DO₂ [169] as well as the conclusions of a study by Gutierrez et al. showing clearly high FiO₂ cannot compensate for the low cardiac output and absence of tissue perfusion and O₂ transport does not necessarily correlate with sufficient or optimal VO₂ that is in fact limited only by the diffusion of oxygen from capillaries to cells [167] and address the crucial questions and research directions to follow, if we want to diminish late HS mortality by preventing, buffering, and managing the pathophysiological mechanisms leading to exitus.

The real-time in vivo monitoring of microcirculation [122] remains essential in the first three-hour days postop, when full-blown cryptic shock installs develop and can be timely managed.