Review Article

Hemorrhagic : The “physiology approach”

Fabrizio Giuseppe Bonanno Trauma Directorate, Chris Hani Baragwanath Hospital, Johannesburg, South Africa

ABSTRACT A shift of approach from ‘clinics trying to fit physiology’ to the one of ‘physiology to clinics’, with interpretation of the clinical phenomena from their physiological bases to the tip of the clinical iceberg, and a management exclusively based on modulation of physiology, is finally surging as the safest and most efficacious philosophy in hemorrhagic shock. ATLS® classification and recommendations on hemorrhagic shock are not helpful because antiphysiological and potentially misleading. Hemorrhagic shock needs to be reclassified in the direction of usefulness and timing of intervention: in particular its assessment and management need to be tailored to physiology.

Key Words: Classification, hemorrhagic shock, management

INTRODUCTION management of a scenario or of a problem [Table 1]. ATLS® classification of hemorrhagic shock (HS)[1] is not sensitive It has always been puzzling trying to understand and accept the and specific enough to help decision-making in reference to rationale and benefits of the ATLS classification[1] especially after the timing of management, being based only on the amount having replaced Holcroft more sensible classification,[2] as for the of blood loss that may or may not be rightly estimated, and difficulty of practical implementation with reference to timing and it is unhelpful and difficult to apply too.[9] The previous optimal management. Both classifications were consequences of physiological classification[2] had advantages overlooked and not experiments done on animals that do not have the same adrenergic re-captured by the ATLS® one, namely the progression of the receptors distribution and amount on humans, which further varies effects of a hemorrhage on the different organs and systems, from individual to individual,[3,4] and a misinterpretation of Shires a more reliable indicator than the amount of blood itself in studies in the 1960s,[5,6] deceptively corroborated by the improvement guiding timing of intervention. Nevertheless, the physiological in renal failure statistics in the Vietnam war with the overload of classification, despite being more functional and useful does not crystalloids, incidental with a coincidental increase of ARDS.[7,8] keep in account the pre-existent different organ physiological reserves or can foresee the level at which hypotension, crucial A more useful classification of hemorrhagic shock (HS), individual parameter signaling decompensation, occurs. By recommending physiology-tailored and therapeutic/decision-making friendly, which is the fluid-load of 2 L crystalloids load for adult patients to test based on the above two classifications of shock, has been elaborated. the reliability of compensatory mechanisms, as recommended up to recently, classical ATLS® guidelines actually delay the timing of intervention as source control when testing is not CLASSIFICATION OF HEMORRHAGIC SHOCK required and more crucially end up increasing the ongoing or spontaneously stopped . The only novelty of the Classifications are meant to summarize the assessment and classification is the cutoff at 30% blood loss as level of blood loss always manifesting with hypotension, per se not enough Address for correspondence: useful information to guide decision making. Dr. Fabrizio Giuseppe Bonanno, E-mail: [email protected] The new classification [Table 2], which may well be called Access this article online the “physiological HS classification” or “therapeutical HS Quick Response Code: Website: classification’, is based on a decision-making that keeps in account www.onlinejets.org hard practice and basic physiological considerations, such as the significance of fluid-blood resistant hypotension and body

DOI: natural hemostatic mechanisms, the right definition of shock 10.4103/0974-2700.102357 nonetheless the relevance that hemorrhage triggered I-R and SIR have in critical illness scenarios as secondary insult from ischemia.

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Table 1: Classical clinical classifications of complications; improve the healthy or moderately sick patient haemorrhagic shock before surgery by optimizing or reinforcing patient physiology Holcroft* with a view to reduce or prevent complications. So, sicker the Mild <20% Skin changes patient, the earlier more rapid and aggressive the intervention Mod >20% <40% Kidney, Gut, Lung, Liver dysfunction - Hypotension has to be; the less sick the patient more time has to be taken Severe >40% Brain and Heart involvement for improvement before intervention. Patient biological and ATLS** I: blood loss <15% physiological reserves (immunity, nutrition, exercise and age- II: blood loss >15% <30% related cardiovascular reflexes and specific organs homeostatic III: blood loss >30% <40% autoregulatory compensatory mechanisms), pre-existing IV: blood loss >40% systemic diseases or derangements (chronic renal failure, *BV diverted towards noble organs in a reverse hierarchy response; **Hypotension is consistently present when > 30% TBV loss. It may or may not be present with blood hypertension, diabetes, chronic liver disease, and chronic heart loss of < 30% TBV. Hypotension signals decompensation.; ***Persisting with disease), and concurrent drug intake (alcohol, antihypertensive, normalised systolic after fluid load signals partial compensation (stably unstable); ****Persisting Tachycardia and hypotension after fluid load signals severe life anti-arrhythmic, β-blockers, steroids, vasodilators, inotrops, and threatening Physiology (unstably unstable); BV: Blood volume; ATLS®: Advanced trauma insulin) play different significant roles in the overall prognosis life support; TBV: Total blood volume of the critical illness by delaying detection, limiting the physiological reserve of the different organs and complicating Table 2: Therapeutical/physiological classification of recovery. HS and first line management of source control Critical HS Shock with heart and brain involvement or > 40% TBV loss Timing of intervention for source control in HS depends on (impending CV collapse) → Stand-by surgery for source the clinical severity and degree of compensation that in normal control individuals reflects the level of blood loss, and on the response Severe HS Shock with hypotension not responding to blood/fluid load-test (unstably unstable) → Rapid surgery for source control to fluids load. TBV is 70 ml/kg body weight in adults, 80 ml/kg Moderate/ Moderate shock is hypotensive shock responding with in infant age and 80–90 ml/kg in newborns. HS at the extremes Mild HS normotension and reverse tachycardia trend to blood/ of life is more serious than at the age in between as for the not fluid overload (unstably stable); mild shock is normotensive tachycardic from start → Investigate, Ponder surgery, developed (newborns and infants) or less responsive (elderly) Interventional radiology/ Non-operative intervention vascular reflexes. Elderly patients as a matter of fact can have *hypotension may occur at ≥ 20% and is always present at ≥ 30% TBV loss; **by response shock at seemingly normal of 120 mmHg due is meant reverse tachycardia trend and normalization of pressure; HS: Haemorrhagic to atherosclerosis, hypertension, and less functional reflexes shock; TBV: Total blood volume; CV: Cardiovascular maintaining relatively high pressures for perfusion.[10,11]

In “critical shock”, in fact there is no much of circulating volume, HS in pregnant women does not manifest with shock signs until and brain and heart internal circulations are barely holding as a 30–35% TBV is lost due to the increase of plasma and cardiac result of the systemic vasoconstriction from chemoreceptor and output. The supine position neutralizes the advantages of those central nervous system receptors stimulation, while in “severe preparatory changes to forthcoming intravascular volume-losses shock” there is sufficient blood volume to potentially maintain as for the uterus compressing on the IVC and impairing VR, perfusion despite endogenous compensatory capacity in terms of phenomenon avoidable by always maintaining a left-oblique vasomotion/vasoconstriction has been lost; in moderate shock positioning when lying down. compensatory capacity instead has not been lost; and mild shock indicates only some blood loss. Acute blood loss and hypotension with brain and heart disturbances or a blood loss >40% of TBV (critical HS, unstably The ‘physiological–therapeutical’ classification must be unstable) require stand-by surgery to stop bleeding; persisting distinguished from the prognostic one, i.e. reversible or hypotension not responding to blood or fluids load (severe irreversible shock and implicitly photographs the levels of shock shock) with stable normalization of systolic and reversed HR within a time-frame of reversibility. It must also not be confused trend (stably unstable), also requires emergency surgery to stop with the two hit-model of physiological deterioration either, bleeding. which describe the time-peaks of clinical downfall. Heart and brain circulation in “critical shock” are holding because RATIONALE: TIMING OF INTERVENTION—THE of still functional regional vasomotion, but they have already “ PARADOX” passed the critical extraction point as by definition ischemic signs are already present. Timing is everything. The main stem of treatment of shock is removal of the causa prima (source optimization in cardiogenic No response to small volumes of hypertonic/colloid fluid load shock (CS), source control in HS, and source elimination in in “severe shock” signifies a deranged vasomotion due to loss of inflammatory shock (IS). The timing for treatment of HS can endogenous compensation as the beginning of a physiological be summarized in a “therapeutic paradox”: Intervene soon in a slope with continuing hemorrhage at a rate in which reflex very sick patient to prevent death and accepting the inevitable compensatory vasoconstriction cannot maintain pressures.

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Anything else other than a fast run to theater and swift anesthesia experience had told us that hypotension, clot formation, and induction will kill patients in the above two scenarios. To push vessels retraction were the reasons for patients’ survival after extra fluids fast or in great quantity will disrupt the balance by arterial damage or injury, that an untreated arterial injury or counteracting life-saving hypotension, vasoconstriction, vessel killed rapidly or was savageable if spontaneously stopped, while retraction, and clot formation, with the end-result of killing the a venous injury had to rely only on clot formation to stop. patient or in the less pessimistic scenario causing heart attack or This implies, paradoxically, that major venous injury can be a cerebrovascular accident.[12] more lethal than arterial one in sites such as mediastinum and retroperitoneum where it cannot be compressed.[14-17] The mechanisms accounting for the worsening of the situation before or in the absence of source control in critical and severe Thus, pushing fluids and hyperoxia and the maintenance— HS are multiple and act in combination evolving in a vicious though temporary—of the actual mean arterial pressure (MAP) circle of accelerated exitus. in critical shock and severe shock before source control, is in principle and de facto deleterious to patient’s physiology and

The chemoreceptor response to low PaO2 at levels of pulse outcome. Delay and standard resuscitation with oxygen and pressure of 70–80 mmHg increases BP by direct stimulation of fluids will paradoxically result in an earlier ischemia of the two the vasomotor centers in the reticular activating substance of the organs than the one that would occur if no transfusion and early medulla oblongata and lower pons, increasing arterioles tone via surgery were instead implemented. sympathetic nervous system stimulation. At some stage, without or before source control and in the presence of supplementary The fluid-load test is consequently a wasteful and damaging fluids and oxygen or hyperoxia, the vasoconstricting reflex gets exercise in ‘critical hemorrhagic shock’ as is any delay to fast dampened; eventually, with HbO2 reduced to minimal terms from source control. the unarrested bleeding and CO reduced from the decreased venous return, and with dissolved PaO2 that cannot sustain CaO2 In all other cases of hypotensive shock with no heart or brain at a level to maintain sufficient perfusion (DO2), the reflex gets ischemia the fluid-load test should be carried out as it tells us triggered. By the time the chemoreceptor is triggered though, on the status of compensation present and, importantly, allows

HbO2 will have reached minimal levels, and so the DO2, and brain distinction between severe and moderate shock, i.e. between and heart are already suffering of relative hypoxia (critical shock). a rush to theater or temporizing on further diagnostic or

Coronaries have a very high O2ER at basal conditions (75% vs. therapeutic strategies. Hypotensive shock without heart or brain 25% of most of the other organs) and are already in pathological involvement, independently whether the loss is 20% (not always supply dependence in critical shock, dangerously near the accompanied by hypotension) or 30% (always accompanied by critical extraction level beyond which anaerobic metabolism and hypotension) of TBV, which responds to blood/fluids overload potentially devastating further ischemia ensues.[13] Adjunctive test with normalization of blood pressure and reverse trend in hyperoxia will paradoxically accelerate the physiological slope, tachycardia (moderate shock), indicates reliably the presence particularly if combined with blood or fluids increasing bleeding still of a certain physiological reserve in terms of compensatory rate before source control. mechanisms. Such scenarios do not require immediate or rapid surgery but can be investigated before surgery or interventional As importantly, the ischemic CNS response to pressures <60 radiology and considered for conservative management. No mmHg with decreased DO2 delivery, as signaled by an already investigation should be entertained in the presence of critical clinically impalpable level of systolic pressure, would also be or severe shock. counteracted by fluid administration with the paradox of having a situation, otherwise kept compensated by the two reflexes, being Investigations should be allowed only in not-hypotensive, instead decompensated by fluids and oxygen administration. compensated mild-to-moderate HS, and should be aimed only to identify the origin of the bleeding/s and concomitant pathologies Moreover, the increase of intravascular volumes with fluid worthy or essential to be picked up before surgery. History, transfusion before source control previously advised would clinical assessment, logistics and equipment dictate the timing further decrease perfusion as it counteracts the three natural of intervention and investigations in compensated shock or physiological mechanisms of hemosthasis, i.e. arterial retraction/ consideration for conservative not-operative management. Blood spasm, hypotension, and clot, ending up increasing bleeding and transfusion in these not emergency cases should be given within decreasing pressures. maximum 4–6 h from insult to prevent I-R complications, till a level judged satisfactory (Hb ≥ 7 g/dL with Hct >21–24%) in Since World War I in fact it has been known that: hypotension, healthy patients and ≥9–10 mg/dL with Hct ≥27–30% in cardiac vasoconstriction, vessel retraction, and clot formation prevented patients, keeping in account SvO2 minimal levels of 70%, and continuation of bleeding after wounding; blood or plasma normalized values of BE and LA in the absence of infection.[18-19] transfusion before surgery was a wasted resource that could cause re-bleeding; and surgery with control of hemorrhage Moderate HS responds well to crystalloids and PRBC i.v.; mild was the most effective resuscitation. The insight of war surgery shock can be treated with oral fluids, or i.v. fluids.

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For stabilization to be considered established, besides normal BP and reverse or normal pulse, patients must be seen with normal or improved complexion, mental status, urinary output, and comforting indirect signs of perfusion such as PaO2 and SaO2.

PITFALLS IN HEMORRHAGIC SHOCK RESUSCITATION

The loading fluid test of 2 L of crystalloids previously recommended by ATLS® was de facto antiphysiological and deleterious especially when indiscriminately implemented and did not bring increase of survival,[20] but an increase in mortality and postoperative complications when compared to no-fluids or less-fluids resuscitation.[21-24] Experimental evidence confirmed the deleterious effects of the crystalloid bolus.[25,26]

Figure 1: Effects of VR manipulations on haemodynamics in At normal heart conditions and healthy valves and myocardium, patients with normal cardiac reserve any increase of venous return will effectively increase MAP which will increase actual bleeding by counteracting hypotension, any experiment or study in a more physiological manner. The the physiological vasoconstriction, and the clotting attempts, real message from Shires works is that replenishment to be which are the three natural mechanisms the organism uses to effective and accurate can only be done after source control stop hemorrhage. Vasodilatation and decreased viscosity from where the solution of continuity is repaired and compensatory- hemodilution also trigger the same chain of events, leading to physiology restored. Only then fluids infusion will equilibrate increased, continuous or recurrent bleeding. These considerations the three fluid compartments. It is true that combinations of [25-36] [20-22,37,38] and observations were tested in animals, humans, crystalloids, plasma, and blood in the Vietnam war, increased [39] and computer simulations and confirmed that (i) too much survival and decreased renal failure at expenses of ARDS fluid infusion causes hemodilution of platelets and clotting (former Da-Nang lung), but that cannot be attributed to the factors, increase of blood pressure, decrease of blood viscosity, combination fluids blood 3:1 more that it can be attributed vasodilatation, all factors thus leading to a blow out of the to blood only.[7,8] The ratio 3:1 is not only inaccurate in its hemostatic plug with accentuation of ongoing hemorrhage or/ conception, amount and priority of transfusion but also for its and secondary hemorrhage; (ii) blood loss causes hypothermia, indiscriminate use, i.e. whether shock is compensated and with which causes coagulopathy; (iii) in patients with penetrating or without source control. Moreover, patients’ selection was trunk injury and hypotension and uncontrolled vascular injury, not done in terms of categorizing them with different classes if no fluids in standard fashion are given in prehospital setting of shock and the decrease of renal failure is likely to have before theater, survival is increased, complications decreased and represented a natural selection occurred in survivors with not hospital stay shortened compared to standard fluid resuscitation; critical/severe shock cases, eventually some of them evolving in (iv) surgical hemosthasis is the key therapeutic act for uncontrolled ARDS. Besides the negative effects on bleeding and on viscosity hemorrhage; and (v) limited or moderate resuscitation is superior of microcirculation, the classical approach does not make sense to aggressive resuscitation in uncontrolled vascular injury. Same intuitively either. If blood loss is the primitive derangement, it is hemodynamic and hemostasis derangements occur if hypertonic expected blood replacement to be the main and most important saline instead of crystalloids is used [Figure 1].[25-27,30,33-34,36] corrective action. In other words, blood should be given first and crystalloids should follow once the fluid component of the Moreover, the principle first-crystalloids-then-blood, even plasma shifts toward interstitial-intracellular spaces and increases worse in a 3:1 ratio, was based on the assumption that blood hematocrit.[40] The infusion of crystalloids would then noncorpuscolated plasma, the fluid part of plasma, has replace the lost intravascular component and restore hematocrit. first to replace the interstitial–intracellular shifts occurring It is simple deduction that unless there is a loss of continuity left during hemorrhage. Shires studies[5,6] were accurate on the unrepaired in the circulation system, which is a closed system, assessment of fluids shifts, not in the way to manage them. The any fluid shift from cells-to-interstitia-to-intravascular space homeostasis of water bidirectionally in the cell-interstitia-blood would be reversed in the opposite direction by reproducing the pathways will be obviously deranged in not-compensated shock dynamics backwards (Claude Bernard homeostasis concept). whereby definition the grasp on maintaining blood pressure by In hemorrhage it is blood that is lost and blood needs to be arteriolar vasoconstriction fails and the ratios in the Starling replaced, at least to minimum physiological levels when blood equilibrium in the capillaries default. It is intuitive that only loss trespasses them. An indirect advantage of this shift of policy by restoring vasoconstriction capacity the shifts can re-occur. would be the shortening of time of clot formation compared to This assumption was missed when the 3:1 ratio was postulated the first fluids—then blood current policy that has dominated as the right one, confirming the need to categorize shock for decades of practice in trauma with deleterious effects.[41]

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In hypotensive shock Ringer’s lactate should therefore be used only after blood or blood components therapy in an amount tailored to balance osmolality electrolytes and hemathocrit.

Another drawback of an excess of fluid transfusion is RV/LV cardiac failure or CS if the two halves of the heart have pre- existent decreased functional reserve due to valvular or myocardial pathology. Two problems would then be faced—overload and low cardiac output—with treatment of one condition worsening the other one [Figure 2]. Direct inotropic support would then be required in conjunction with blood replenishment and aggressive ICU monitoring of the cardiac output.

Furthermore, excess treatment with fluid or blood overload is deleterious whether is effected before source control or afterwards, as it may cause secondary intra-abdominal Figure 2: Effects of VR manipulations on haemodynamics in compartment syndrome,[42-44] with changes that trigger a patients with diminished cardiac reserve second hit SIR or I-R syndromes and ALI helped by SIR and vasodilatation, if resuscitation is done late, or worsened by In HS AVP has been found to reduce the fluid requirement vasoconstriction with serious effects on abdominal organs and improve neurological outcome and cardiopulmonary [52] perfusion, ventilation, kidney function and venous return, if parameters. Vasopressin as bolus (0.4 U once or twice) and/ resuscitation is done early and in excess. Gut edema and increased or infusion (0.04–0.1 U/min) reverses intractable or prolonged intraabdominal pressure till abdominal compartment syndrome hypotension in the late phase HS or intraoperative HS with and [53-59] level will ensue, due the increase of capillary net-filtration- without cardiac arrest. Vasopressin vasoconstrictive effect results from inhibition of K channels and inhibition of nitric pressure (cNFP) secondary to increased intracapillary pressure ATP result of the increased pressure upstream from increased volume. oxide-induced accumulation of cGMP. Replacement of depleted Starling law ruling the permeable capillaries net filtration pressure stores of vasopressin in the neurohypophysis may also contribute [60] states: NFP = [capillary pressure – (interstitial fluid pressure to reversal of shock. ADH may cause problems at higher [61] + plasma colloid-osmotic pressure) + interstitial fluid colloid- dosages or when given for several hours. osmotic pressure]. Noradrenaline (NE) is a potent alpha-adrenergic agonist with Inadequate or delayed resuscitation is the other side of minimal β-adrenergic agonist effects. NE increases MAP due inappropriate treatment of HS. Cardiac arrest can occur as a to its vasoconstrictive effects with little change in the heart primary hit for insufficient venous return and coronary ischemia rate and stroke volume, and by doing so increases indirectly due to the dependence of coronary perfusion from blood flow the cardiac output as well. Doses of NE going from 0.2 µg/ during the diastole phase, which is decreased following the kg/min titrated to response up to 3.3 µg/kg/min are used to decrease of the stroke volume. The compensatory tachycardia maintain CO and BP. Its drawbacks are an increase of workload only worsens the situation accelerating heart ischemia. Post-HS and oxygen consumption plus coronary vasoconstriction. NE should be used early as neurohormonal augmentation therapy SIR or I-R phenomenon is the second serious consequence supporting hemodynamic function, rather than as a late rescue of inadequate or deficient resuscitation leading to increased therapy to treat shock.[62] morbidity and mortality.[45,46] Both NE and ADH combined with hydroxyethyl starch improve STRATEGIES AND TACTICS cerebral perfusion pressure, oxygenation and metabolism in HS, with AVP being the faster of the two.[63,64] The combination AVP Adjuncts in treatment + NE is an effective treatment for uncontrolled HS at the early Compensation of HS occurs by reflex arteriolar vasoconstriction stage after hemostasis, if blood is unavailable.[65] sympathetic-mediated with catecholamines acting on α1 receptors. At some stage hyporeactivity to endogenous catecholamines NE should be added to AVP if the latter is ineffective, and must installs, signaling decompensation, which becomes paralysis when be discontinued before ADH.[66] a complete lack of responsiveness occurs even to exogenous vasoconstrictors signaling irreversible shock. Likewise in SS, the combination of low doses NE and ADH, or ADH on its own, can be administered from presentation Besides its proven benefits in (SS), vasopressin alias and categorization of critical or severe HS till before source arginine vasopressin (AVP) alias anti-diuretic hormone (ADH) control as a vasoconstriction-maintaining, vasomotor collapse- has shown beneficial effects in CS and in cardiac arrest. [47-51] delaying, drug.

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Once arterial pressure is brought to a systolic of at least 90 <90 mmHg by titrated prn hourly bolus of 250 ml of RL or HTS; mmHg and a MAP >65–70 mmHg, and CO still would be low, skin complexion and consciousness level direct resuscitation in intravenous dobutamine may take over. In normal hearts there is a conscious patient. however scarce need for inotropic support in the postoperative ICU phase. The presence of associated head injury that is not mild (GCS ≤ 12) compounds the clinical picture because of the Dopamine may also be useful in patients with compromised difficulty or impossibility to use level of consciousness as systolic function, low CO, and MAP. At doses of approximately an indicator of the level of blood loss and compensatory 10–20 µg/kg/min, the prevailing α-adrenergic effect leads to mechanisms efficacy, and the unpredictable loss of the capacity arterial vasoconstriction and elevation in blood pressure. The of flow self-regulation following trauma. Patients with HS and problem with dopamine however is that before the cardio-vascular HI need therefore a moderate resuscitation in between permissive system responds to vasoconstricting high dosages it has to pass hypotension and standard resuscitation, i.e. systolic of ≥100 through low and medium concentrations that may temporarily mmHg particularly in view of the fact that the brain loses its worsen the situation by increasing the heart rate and regional circulation self-regulatory capacity at variable levels of HI.[69,70] vasodilatation in a moment where there is not much blood in circulation; furthermore dopamine predisposes to dys-rhythmias. Experimental evidence and clinical experience in civilian and military setting have shown benefits and safety of boluses of Titrated hypotensive resuscitation 250 ml of fluids, whether crystalloids, colloids, or hypertonic Too late, too little, too early too much, too late and too much saline at different concentrations, as effective and safe initial are all harmful resuscitation strategies. To which level then management of patients with HS[67,68,71-73] HTS should be given should resuscitation be maintained before imminent surgery not more than 250, maximum 375, ml/h to maximize its merits or temporarily before surgery or as the only treatment if a and diminish its drawbacks on bleeding by interference with conservative nonoperative approach is adopted? This should coagulation and more importantly following increase of pressure be a level of blood pressure sufficient enough to maintain as direct hemodynamic effect. perfusion without risking either continuation of bleeding or re- bleeding. These targets are reached with “Titrated Hypotensive In a recent study on humans, the no-difference of mortality in Resuscitation” [Table 3]. patients who received either HTS 7.5%–Dextran 70 at 6% or HTS 7.5% administration boluses of 250 ml compared to NS “Hypotensive resuscitation” is an old concept introduced by 0.9% 250 ml as initial fluid treatment before source control,[74] Cannon around the First World War,[14-17] but implemented associated to an increase of mortality in the subgroup who only by Crawford in late 1980s for the treatment of ruptured did not receive blood transfusion in the first 24 h, appears to abdominal aortic aneurysm before surgery,[38] recently re- contradict some of the conclusions of previous experiences. The introduced as “permissive or titrated hypotension” by the Israeli inclusion, in the study, of patients in HS with SBP ≤70 mmHg Defense Force[67,68] for transported patients with HS where or with SBP between 70 and 90 mmHg + HR ≥110 bpm would resuscitation monitoring and titration are difficult to achieve fit the profile of critical and severe shock categories if brain or and a small volume of infusion is logistically convenient. The heart were involved and a known loss <40% had occurred, or systolic pressure was kept less than 90 mmHg to maintain a no consistent response to the fluid bolus was noted; moreover, consciousness level or at the palpable pulse level, i.e. ≥70 and the observations made in the group with no-blood transfusion indicate patients in whom type and amount of fluids would not Table 3: HS: too much too early, too little and too have made difference. The study only emphasizes the need of a late. What is the ideal or perfect resuscitation? more accurate and useful categorization of HS. Resuscitation in defect or delayed or omitted • Primary cardiac arrest for insufficient venous return, massive heart or cerebrovascular accident “Hypotensive resuscitation” and “permissive hypotension • “Primary hit” IHD, CVA, acute overlapping ischemic or on demand” or “titrated hypotension”, more accurately failure • “Secondary hit” ischemia-reperfusion, SIR, endotoxaemia and bacterial “Titrated Hypotensive Resuscitation” (THR), remains the ideal translocation (hitting lungs and kidneys) resuscitation and the way to go as standard initial resuscitation Resuscitation in excess particularly during transport of patients with critical or severe HS • Secondary compartment syndrome, cardiac failure, cardiogenic shock, pulmonary oedema, persistent or recurrent bleeding independently on the scenario, whether civil or rural or military. What is then the Ideal or Perfect Resuscitation? • “Standard Resuscitation?”. No, not any more flat resuscitation! It is just a guess Emergency protocols: The “physiology approach” work and increases morbidity and mortality. • Titrated Hypotensive Resuscitation? Yes! It should be the standard for transport In ‘critical shock’ with a known TBV loss of ≥40% or the of patients with critical or severe HS. presence of brain and heart ischemic changes there is no • Damage Control? Yes! In specific situations. proven effective strategy of resuscitation out-of-hospital that • Conservative /Non-operative intervention ? Yes! In specific situations. NOI is a form of DC would not contemplate heroics like in situ extreme-outdoor- IHD: Ischemic heart disease; CVA: Cerebro-vascular accident; SIR: Systemic inflammatory resuscitation (EOR) by small operative units with or without response; NOI: Non-operative intervention; DC: Damage control suspended animation-fastly induced hypothermia techniques.

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Such techniques with portable femoro-femoral CPBP/ECMO been conceptualized. Likewise general anesthesia should too be without hypothermia have given dismal results outdoors in CA titrated to pain/autonomic stimulation response (autonomic or CS before refractory CA in normovolemic not-exhanguinating controlled—anesthesia) under the comprehensive concept of patients even when applied with beating heart, and a survival ‘physiology approach’. of 20-30% indoors.[75-76] In trauma scenarios with solution of continuity in the vascular tree and decreased blood volume Etomidate, S(+)-ketamine or alfentanyl induction and S(+) EOR with the method of suspended animation can only be ketamine or remifentanyl continuous-intravenous anesthesia effective with hypothermia induced by cold saline aortic flush (CIVA) titrated to response is the author’s suggested method for via emergency sternotomy/thoracotomy.[77] anesthetizing critical and severe shock patients.[98-100]

Until methods and techniques of EOR and suspended Emergency protocols based on a “Physiology approach” animation- hypothermia are optimized or perfected, only three comprehensive strategy, i.e. the “Therapeutical Classification options are so far available. ‘One’ is a life-saving run to the nearest medical facility for rapid source control with continuous Table 4: Decision making in Critical HS: A blood transfusion running in high capacity/flow cannulae, well comprehensive management knowing it is destined to get lost. ‘Two’ is to run at the nearest Critical HS medical facility with no fluid-treatment whatsoever at all leaving Out-of hospital: NO-resuscitation until source control - or titrated hypotensive to the patient natural balancing mechanisms to do their best resuscitation ± AVP iv boluses x max 2 followed by AVP infusion, + NE infusion if ADH on its own is ineffective. without iatrogenic interference until rapid/swift anesthesia/ In-hospital: Stand-by surgery for source control under CIVA with Etomidate surgery for source control. “Three” is THR. In the author’s or S(+)-Ketamine or Alfentanyl as induction followed by Ketamine view no-resuscitation or THR are the most sensible options to and/or Remifentanyl infusion for maintenance. Followed after source control use as initial resuscitation before source control in patients with by hypotensive HS both indoor and outdoor while rushing on the Fresh whole blood transfusion (0 neg or 0 pos or grouped or cross-matched blood, way to a medical facility. The no-resuscitation option may indeed according to immediate availability) [21] or be the best option. PRC/FFP/Platelets + Anticoagulopathy regimen (rFVIIa, Cryoprecipitates, Fibrinogen, Prothrombin Complex concentrates, antifibrinolitics, Desmopressin) THR should also be used in ‘severe’ HS after the initial bolus empirically or ad hoc following routine coagulation tests and thromboelastometry within 10-15 minutes from the blood sample of the fluid-load test discriminates it from the ‘moderate’ one; and if shock turns out to be moderate with normalized systolic and Crystalloids as Ringer’s Lactate to balance osmolality, electrolytes and reversed tachycardia trend, no further fluid should be given until hemathocrit after blood/blood components transfusion in an inverse ratio from previous recommendations i.e. blood or blood components/fluids ratio > 1 source control. HS: Haemorrhagic shock; NE: Noradrenaline; ADH: Anti-diuretic hormone, alias AVP: Arginine vasopressin; CIVA: Continuous intravenous anaesthesia; PRC: Packed red cells; Which fluid to use in “critical HS” in pre-hospital phase and FFP: Fresh frozen plasma; rVIIa: Reconbinant factor viia; prn: Pro re nata (when there is need, when need rises); ad hoc: (specifically, for a specific situation) which fluid should be used for load-test in severe HS?

It should be the fluid one would like to use as bridge infusion Table 5: Decision making in Severe HS: A until source control if blood were unavailable: hyperosmotic– comprehensive management hyperviscous solutions (HHS), HTS or RL combined with Severe HS alginates, and conjugated albumin solutions appear so far to Out-of hospital: Titrated hypotensive resuscitation + AVP iv boluses x max 2 be excellent choice. There is overwhelming evidence on the followed by AVP infusion, + NE infusion if ADH on its own is importance of maintaining microcirculation function with aim ineffective. In-hospital: Rapid surgery for source control under CIVA with Etomidate or to optimize perfusion in HS by using apt fluid with specific S(+)-Ketamine or Alfentanyl as induction followed by Ketamine characteristics and composition, particularly viscosity more than and/or Remifentanyl infusion for maintenance. colloid-osmotic and oncotic properties, and, in parallel, on the Followed after source control by irreplaceable function of blood from microhemodynamics and Fresh whole blood transfusion (0 neg or 0 pos or grouped or cross-matched blood, oxygen-transport end-points.[78-94] according to immediate availability) or PRC/FFP/Platelets + Anticoagulopathy regimen (rFVIIa, Cryoprecipitates, Fibrinogen, To show predictable benefits of THR on mortality and Prothrombin Complex concentrates, antifibrinolitics, Desmopressin) empirically or ad morbidity,[85,95] specifically in preventing the installing of hoc following routine coagulation tests and thromboelastometry within 10-15 minutes cryptic shock abutting in a I-R MOD/S clinical picture in the from the blood sample and [96] postoperative period, trials should be done on patients in Crystalloids as Ringer’s Lactate to balance osmolality, electrolytes and hemathocrit hypotensive shock classifiable as ‘severe’ or ‘critical’.[97] after blood/blood components transfusion in an inverse ratio from previous recommendations i.e. blood or blood components/fluids ratio > 1 HS: Haemorrhagic shock; NE: Noradrenaline; ADH: Anti-diuretic hormone, alias AVP: It is under the same principle of the least interference with arginine vasopressin; CIVA: Continuous intravenous anaesthesia; PRC: Packed red cells; physiology during that tactics and strategies such FFP: Fresh frozen plasma; rVIIa: Reconbinant factor viia; prn: Pro re nata (when there is as THR, damage control, and damage control resuscitation, have need, when need rises): ad hoc: (specifically, for a specific situation)

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severe postoperative coagulopathy in trauma patients with hemorrhagic 107. Schoechl H, Nienaber U, Maegele M, Hochleitner G, Primavesi F, Steitz B shock: preliminary results of a randomized controlled trial. J Trauma et al. Transfusion in trauma: thromboelastometry-guided coagulation factor 2011;70:652-63. concentrate-based therapy versus fresh frozen plasma-based therapy. Crit 104. Lustenberger T, Talving P, Kobayashi L, Barmparas G, Inaba K, Lam L et al. Care 2011;15:R83 Early coagulopathy after isolated severe traumatic brain injury: relationship 108. David JS, Marchal V, Levrat A, Inaba K. Which is the most effective with hypoperfusion challenged. J Trauma. 2010;69:1410-4. strategy: early detection of coagulopathy with thromboelastometry or use 105. Greuters S, van den Berg A, Franschman G, Viersen VA, Beishuizen A, of hemostatic factors or both? Crit Care 2011;15:433. Peederman SM et al. Acute and delayed mild coagulopathy are related to outcome in patients with isolated traumatic brain injury. Crit Care 2011;15R2. How to cite this article: Bonanno FG. Hemorrhagic shock: The "physiology approach". J Emerg Trauma Shock 2012;5:285-95. 106. Kashuk JL, Moore EE, Sawyer M, Le T, Johnson J, Biffl WL et al. Postinjury coagulopathy management: goal directed resuscitation via POC Received: 30.03.11. Accepted: 13.04.11. thrombelastography. Ann Surg 2010;251:604-14. Source of Support: Nil. Conflict of Interest: None declared.

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