ADVANCES IN RESUSCITATION STRATEGIES

Abstract

Shock, regardless of etiology is characterized by decreased delivery of oxygen and nutrients to the tissues and our interventions are directed towards reversing the cellular ischemia and preventing its consequences. The treatment strategies that are most effective in achieving this goal obviously depend upon the different types of shock (hemorrhagic, septic, neurogenic and cardiogenic). This brief review focuses on the two leading etiologies of shock in the surgical patients: bleeding and sepsis, and addresses a number of new developments that have profoundly altered the treatment paradigms. The emphasis here is on new research that has dramatically altered our treatment strategies rather than the basic pathophysiology of shock.

2. Hemorrhagic shock

Exsanguination is one of the leading causes of death following trauma^{1, 2} and prompt hemorrhage control along with adequate fluid resuscitation are the key components of early trauma care. Similarly, hemorrhage is often encountered in non-trauma patients as a complication following major surgeries. Despite hemorrhage being a common problem, the optimal resuscitative strategy remains controversial, with vigorous ongoing debates about issues such as the type of fluid, volume, rate, route of administration, and end points of resuscitation.

a. Futility of current methods/adverse effects of aggressive resuscitation

Although it is widely believed that early aggressive fluid resuscitation is beneficial, clinical and basic science literature fails to provide conclusive supporting evidence ^{3, 4, 5, 6, 7}. As a matter of fact, the basic rationale for administering intravenous fluids in patients with ongoing bleeding has been challenged repeatedly for almost a century⁸. Theoretically, fluid resuscitation in the absence of (or prior to) hemorrhage control can exacerbate bleeding due to the disruption of early soft thrombus, coagulopathy, and hemodilution^{9, 10, 11, 12}. A systematic review of 52 animal trials concluded that fluid resuscitation appeared to decrease the risk of death in models of severe hemorrhage (RR=0.48), but increased the risk of death in those with less severe hemorrhage (RR=1.86)¹³. Furthermore, hypotensive resuscitation (targeting a lower blood pressure), whenever tested, reduced the risk of death (RR=0.37). Similarly, a critical review of the literature failed to find any evidence that pre-hospital advanced life support improved outcomes in trauma patients¹⁴. In a study that has generated vigorous debate since its publication in 1994¹⁵, hypotensive patients with penetrating torso injury were randomized to routine fluid resuscitation, or resuscitation was delayed until bleeding had been surgically controlled. The results of this study demonstrated a survival advantage in the delayed resuscitation group (70% versus 62%, p=0.04). Despite all the controversy, the most impressive finding remains that withholding fluid resuscitation until hemorrhage control did not increase the mortality. The issue of timing and volume of fluid resuscitation in bleeding patients has also been addressed by The Cochrane Database of Systematic Reviews¹⁶. Only six randomized clinical trials met the inclusion criteria, and a careful review failed to provide any evidence in support of (or against) early or large volume intravenous fluid administration in uncontrolled hemorrhage. Based upon all this information, it is reasonable to conclude that fluid resuscitation is not a substitute for early hemorrhage control. Low volume, careful resuscitation is reasonable, especially when trying to get a dying patient to definitive care. However, early aggressive fluid resuscitation, in the absence to hemorrhage control, can’t be justified.

In addition to the impact of resuscitation on bleeding, resuscitation fluids have profound cellular effects. It is now widely recognized that resuscitation fluids are not completely innocuous, and they may actually potentate the cellular injury caused by hemorrhagic shock¹⁷. This concept of “resuscitation injury” has steadily gained attention since a report by the Institute of Medicine (1999) described in detail the wide spectrum of adverse consequences that can follow resuscitative efforts¹⁸. Historically, the concept of large volume crystalloids resuscitation was a product of seminal work by Shires, Moyer, Moss and others during the 1960s^{19, 20, 21, 22}, and it became common practice during the Vietnam conflict. Their work suggested that infusion of large-volume isotonic crystalloids improved survival, and resuscitation fluids were needed not only to replace the intra-vascular volume loss, but also to replenish interstitial deficits. Therefore, these investigators recommended fluid replacement equal to three times the volume of blood loss (and as high as 8:1 for severe shock). At that time the emphasis was on restoration of intra-vascular and interstitial fluid deficits, without much importance attached to the cytotoxic effects of crystalloid fluids. Isotonic fluids were used widely in Vietnam and it was during this period that the appearance of “shock lung/Da Nang lung” (later termed acute respiratory distress syndrome or ARDS) was first described in soldiers that received massive crystalloid resuscitation. Today, ARDS and Multiple Organ Dysfunction Syndrome are major causes of delayed mortality in trauma patients. An ever-increasing basic science literature supports the new paradigm that cellular injury is influenced not only by shock, but also by our resuscitation strategies. Today, with the easy availability of advanced cellular research techniques, we can study the effect of resuscitation fluids on the biological systems in much greater detail. Review of the literature suggests that commonly used resuscitation fluids (especially racemic lactated Ringer’s solution) can exaggerate the post trauma immune activation²³. Therefore, in addition to the immediate side effects (worsening of hemorrhage), delayed complications of fluid resuscitation such as systemic inflammatory response, fluid overload (leading to compartment syndromes, pulmonary edema etc), anemia, thrombocytopenia, electrolyte/acid-base abnormalities, and cardiac and pulmonary complications must also be kept in mind²⁴. Excessive fluid resuscitation increases the chances of developing abdominal compartment syndrome in critically ill surgical/trauma, burn, and medical patients^{25, 26, 27}. Similarly, in a multicenter study of burn patients, administration of excessive fluids (in excess of 25% of predicted) increased the odds of ARDS (OR 1.7), pneumonia (OR 5.7), multiple organ failure (OR 1.6), blood stream infections (OR 2.9), and death (OR 5.3)²⁸.

b. New developments

It is now being appreciated that resuscitation fluids, like other drugs, have indication for appropriate use, safe therapeutic doses, potential side effects and complications. Despite a paucity of good randomized controlled trials (RCT) in this arena, clinical practices are rapidly changing. In general, large volume aggressive fluid resuscitation is becoming increasingly rare, and low volume, carefully guided resuscitation is more common. A few of these issues are discussed in more detail below:

i. Controlled hypotensive resuscitation

In appropriate patients (e.g. in young victims of penetrating trauma) limiting the rate and volume of fluid resuscitation prior to hemorrhage control is rapidly becoming routine practice in large trauma centers. Blunt trauma patients with associated head injury are still resuscitated to a higher blood pressure, in an attempt to maintain adequate cerebral perfusion, but early use of blood products and vasopressors is replacing large volume crystalloid infusion. Prompted by the recommendations of some consensus conferences^{29, 30, 31, 32}, and due to the unique logistical challenges of the battlefield, the resuscitation strategies being utilized by the US military have changed dramatically: resuscitation is selective, emphasizing low volume and practical endpoints, and the use of fluids with logistical advantages (e.g. hetastarch) is preferred. The endpoint of resuscitation is not a normal BP, but simply a palpable radial pulse and normal mental status (in the absence of head injury). Thus, IV fluids are given only selectively, and in much less volumes. Also, early hemorrhage control is prioritized over aggressive fluid resuscitation. It is difficult to determine the direct impact of these new strategies on combat casualty outcomes, but is very encouraging to note that for the first time since the Crimean War, the killed in action rate has markedly dropped below the historic 20% to around 10–14%³³. Hypotensive resuscitation can be performed by infusing fluids to achieve a desired goal (e.g. target blood pressure), or at a predetermined fixed rate. Pre-clinical data shows that resuscitation to target mean arterial pressure (MAP) of 40mmHg, as opposed to 80mmHg or higher not only results in decreased blood loss but also in better splanchnic perfusion and tissue oxygenation³⁴, less acidemia, hemodilution, thrombocytopenia, and coagulopathy³⁵, decreased apoptotic cell death and tissue injury^{35, 36}, and improved survival^{35, 36}. However, others have shown in large animal models that prolonged duration (8 hours) of hypotension increases metabolic stress, tissue hypoxia, and mortality^{37, 38}. Still the majority of the pre-clinical data favors MAPs between 40–60mmHg or systolic blood pressure (SBP) between 80–90mmHg. Furthermore, in each of these studies, hypotensive resuscitation with crystalloids was beneficial compared to non-resuscitated controls. An alternative means of hypotensive resuscitation, particularly useful in pre-hospital or austere environments where accurate blood pressure measurement may not be feasible, is by fluid infusion at a pre-determined rate (carefully selected to avoid over resuscitation). In animal studies, empiric rates of infusion have shown promise. Slow infusion rates with crystalloid have been shown to reduce organ injury³⁹, causes faster recovery of hemorrhage suppressed cell mediated immune function^{40, 41} and reduce mortality. Overall, the data suggest that hypotensive resuscitation at a fixed rate of 60–80cc/kg/hour generally maintains controlled hypotension to a SBP of 80–90mmHg (MAP of 40–60mmHg) and that this empiric control of infusion rates is beneficial in hemorrhagic shock. Regardless of which approach is selected (goal directed vs. fixed volume), these pre-clinical data combined with the clinical evidence ^{15, 16} argues strongly against routine large volume crystalloid resuscitation. The best approach for an urban trauma services (short transport times) appears to be “scoop and run”, where unnecessary field interventions are avoided and the focus is on fast and efficient transport of the patient to the hospital⁴².

ii. Hypertonic Saline

Another new development is the renewed interest in hypertonic saline (HTS), not just as a volume expander but also as an immune modulator. The use of HTS for resuscitation from hemorrhage was first described in 1980, when Velesco et. al⁴³, and DeFelippe et. al⁴⁴, reported in separate studies that hypersomotic sodium chloride rapidly expands plasma volume after major blood loss. Because of its ability to mobilize interstitial fluids into the vascular space, 250 ml of 7.5% saline can achieve results comparable to resuscitation with 2–3 liters of 0.9% saline. Since the original reports, HTS or hypertonic saline combined with dextran (HSD) have been tested in a number of RCTs, without showing a clear survival advantage⁴⁵. A meta-analysis evaluated HSD as the initial treatment for hypovolemic shock by reviewing the original records from six trials (and 604 subjects)⁴⁶. Overall discharge survival rates were better with HSD resuscitation as compared to conventional resuscitation. HSD resuscitation was particularly effective for the sub-group of patients that had sustained head injury with a discharge survival rate of 38%, as compared to a rate of 27% for the control group receiving saline. All of these trials had used HTS as a volume expander, but a more advantageous effect of HTS administration may be the attenuation of immune mediated cellular injury. A number of pre-clinical studies have demonstrated that HTS has the potential to modulate the immune response, with an overall attenuation of immune mediated cellular injury^{47, 48, 49, 50, 51, 52, 53, 54, 55, 56}. A small RCT has also shown that initial treatment of trauma patients with HSD inhibits neutrophil adhesion molecule expression and favorably modulates the inflammatory response⁵⁷. The recently established Resuscitation Outcome Consortium (ROC)⁵⁸, funded by the National Institutes of Health and the US Department of Defense initiated two multicenter trials of hypertonic resuscitation in blunt or penetrating trauma patients in hypovolemic shock, and severe traumatic brain injury. Both studies were designed to have three randomized groups comparing hypertonic saline/dextran (7.5% saline/6% dextran 70, HSD), hypertonic saline alone (7.5% saline, HTS), and normal saline (NS) as the initial resuscitation fluid for the pre-hospital setting. In addition to the primary endpoints, comprehensive data about the immunologic consequences of hypertonic resuscitation would also be collected. Unfortunately, the interim analysis of the data was not favorable, HTD treated patients experienced higher early mortality and no overall benefit compared to the control arm (the full analysis remain unpublished at the time of this writing)⁵⁹. Despite the much lauded laboratory effects of hypertonic saline, this fluid has not been the magic bullet hoped for by many researchers. Based upon these clinical data, HTS cannot be recommended for resuscitating trauma patients outside an approved trial. Another fluid that remains controversial is albumin. A recent report [post hoc analysis of patients from the Saline versus Albumin Fluid Evaluation (SAFE) study] suggests that albumin should be avoided in patients with traumatic brain injury, as it was associated with a significant increase in mortality⁶⁰.

iii. Damage Control Resuscitation

An idea that is gaining momentum due to the ongoing war (Iraq and Afghanistan) is the concept of hemostatic/damage control resuscitation⁶¹. Trauma patients are often coagulopathic due to shock and tissue injury, and this coagulopathy can be worsened by resuscitation with crystalloids and packed red blood cells (PRBC), as both are deficient in clotting factors. Observational data from civilian trauma centers and the battlefield seem to suggest that early administration of component therapy containing fresh frozen plasma (FFP) and platelets may be beneficial^{62, 63}. A recent retrospective analysis of mixed trauma patients requiring surgery and massive transfusion compared FFP:PRBC ratios of 1:1 and 1:4, and showed that only 26% of patients treated with the former ratio died while 87.5% of patients treated with the latter ratio died (p<0.0001). In this high risk group with an overall mortality of 55.5%, a 1:4 ratio of FFP:PRBC increased the relative risk of dying by 18.9 (p<0.001) when controlling for all other patient variables⁶⁴. Holcomb’s study of trauma patients at 16 trauma centers who required massive transfusion found that an FFP:PRBC ratio of 1:2 or higher (n = 252) compared to lower ratios (n = 214) was associated with improved 30-day survival (59.6% with high ratio vs. 40.4% with low ratio, p<0.01)⁶⁵. These conclusions have recently been questioned by a study that suggests that the observed survival differences between patients receiving high and low ratios in the first 24 hours may simply be due to the fact that survivors live long enough to receive component therapy (survivor bias)⁶⁶. Based on the battlefield experience, the US Army has instituted a policy of using a 1:1:1 ratio of PRBC:FFP:platelets in the battlefield for those that meet the criteria for massive resuscitation (expected to receive >10 units PRBC). However, no well designed randomized clinical trial has conclusively identified the optimal ratios of blood components. Our own institutional policy is to start FFP infusion as early as possible in massively bleeding patients, by activating a Massive Transfusion Protocols (MTP) which delivers PRBC:FFP in a ratio of 2:1, and administers 6 units of platelets for 10 units PRBC. Despite an ongoing debate about the precise ratios, there is general agreement that the blood products should be administered in the form of a MTP to optimize the processes of care and to improve outcomes. The often disorganized process of blood component transfusion in the face of massive hemorrhage benefits from an organized and standardized approach that delivers the needed blood products while avoiding their misuse. Despite these obvious attractive features, in a recent review Malone found only 10 such protocols published worldwide⁶⁷. The utility of MTP (using different ratios of blood components) has already been verified in some case controlled studies. Cotton tested the effectiveness of a Trauma Exsanguination Protocol (1:2:4 ratio of platelets:FFP:PRBC) by comparing patients treated with the protocol (n = 94 over 18 months) to a cohort of similar patients admitted during the prior 18 months (n = 117). The study found that implementation of the protocol reduced 30-day mortality (51% vs. 66%, p<0.03), decreased intraoperative crystalloid administration (4.9 liters vs. 6.7 liters, p= 0.002), and reduced post-operative blood product use (2.8 units PRBCs vs. 8.7 units, p<0.001; 1.7 units FFP vs. 7.9 units, p<0.001; 0.9 units platelets vs. 5.7 units, p<0.001)⁶⁸. Dente conducted a similar study of an MTP (1:1:1 ratio of platelets:FFP:PRBC), by comparing matched patients during one year period before and after implementation of protocol (73 protocol, and 84 matched controls). Implementation of the protocol was found to reduce mortality in the first 24 hours (17% with MTP vs. 36% pre-MTP, p=0.008), and at 30 days (34% vs. 55%, p=0.04), with a more pronounced impact in the blunt trauma patients⁶⁹. This study also showed that MTP patients required fewer overall transfusions of PRBCs and FFP after the first 24 hours (2.7 units PRBCS vs. 9.3 units, p<0.0001; 3 units FFP vs. 7.5 units, p<0.05). While further prospective research is needed to specify the exact ratios, there is convincing evdence that implementation of standardized protocols for blood component transfusion improves processes of care, reduces overall use of blood components, and improves outcomes.

iv. Red Blood Cell Substitutes

Although advances in viral screening have markedly decreased the risks of infectious transmissions, blood transfusion continues to be associated with numerous serious side effects. In trauma patients, transfusion of red blood cells (especially after prolonged storage) has been shown to disturb the immune system with an early immune activation resulting in Systemic Inflammatory Response Syndrome (SIRS), and a delayed immune suppression which predisposes the patients to infections⁷⁰. As a matter of fact, transfusion of PRBC remains an independent risk factor for increased infections, multiple organ failure, length of hospital stay, and mortality^{71, 72, 73, 74}. This has prompted many researchers to focus their attention on testing alternative oxygen carrying solutions⁷⁵. A detailed discussion about the history and the development of these products is beyond the scope of this article. However, all of these solutions contain some form of polymerized hemoglobin molecule and are thus labeled as hemoglobin-based oxygen carriers (HBOC). A common problem with the HBOC relates to the scavenging of nitric oxide by the free hemoglobin molecule, which results in severe vasoconstriction, a pro-inflammatory response, and end-organ injury. Different formulations differ in the mammalian source of the hemoglobin and how it is cross-linked, as well as in storage and length of shelf-life. Of the HBOCs tested thus far, only Hemopure or HBOC-201 (13g/dL glutaraldehyde polymerized bovine hemoglobin) has remained in contention for possible human use, while other formulations such as Polyheme (10g/dL glutaraldehyde polymerized human hemoglobin) and HemAssist (10g/dL diaspirin cross-linked human hemoglobin) have fallen out of favor due to negative phase III clinical trials. In Sloan’s multicenter randomized clinical trial (RCT) trauma patients in severe hemorrhagic shock reveived either 500ml of saline (n = 53) or HemAssist (n = 58) within 60 minutes of presentation. The study found a higher 28-day mortality in the treatment arm (47% for HemAssist versus 25% for saline, p=0.015)⁷⁶. In another multicenter RCT, trauma patients with severe hypovolemic shock were randomized to standard of care (n= 62) or HemAssist (n= 53) without any difference in 5- or 28-day mortality⁷⁷. Similar findings were reported with Polyheme in a subsequent RCT, where trauma patients in severe hemorrhagic shock were given either standard of care (crystalloid and allogenic blood transfusion, n=365) or up to 6 units of Polyheme (n = 349). Even after accounting for numerous protocol violations (17%), there was no mortality benefit in the treatment arm, and a higher rate of adverse events (93% for Polyheme versus 88% for controls, p=0.041)⁷⁸. A 2008 meta-analysis of 16 HBOC trials, including four trials of trauma patients receiving HemAssist or Polyheme, raised alarm as patients receiving HBOCs were noted to have a significant risk of myocardial infarction (RR, 2.71; 95% CI, 1.67–4.40), and mortality (RR, 1.30; 95% CI, 1.05–1.61)⁷⁹. This meta-analysis also included a single study data from a 2005 presentation to the U.S. Food and Drug Administration (FDA) on HBOC-201 use in surgical patients. HBOC-201 (Hemopure) has also been rested in a trauma patient population in South African study but the final results of this trial remain unpublished⁸⁰. HOC 201 has been extensively tested with good results in animal models (and is approved for veterinary use). It has also been tested in a large phase III clinical trial (n-688) in elective orthopedic surgical patients, where use of HBOC-201 resulted in less need for PRBC transfusion but a significant increase in serious adverse events⁸¹. A phase II multicenter trial in trauma patients entitled Restore Effective Survival in Shock (RESUS) was first submitted to the FDA for approval in 2005. However, after an initial positive response the FDA has repeatedly refused to allow the clinical trial to proceed due to concerns about patient safety, despite multiple revisions in the study protocol. Thus, based upon these current data, the use of any HBOCs can’t be endorsed at this time outside of well-designed, thoroughly vetted clinical trials.

3. Septic shock

a. Initial resuscitation

As opposed to hemorrhagic shock, early goal directed resuscitation has been shown to improve 28-day mortality in a single center, prospective, RCT⁸². Although the exact parameters used to guide resuscitation in that study have been challenged, the basic concept is clearly sound, as has been validated by a number of subsequent studies^{83, 84, 85, 86, 87}. For optimal results, the resuscitation protocol must be initiated as soon as shock is diagnosed and should not be delayed until admission to the intensive care unit (ICU). Due to venous dilation, and increased capillary leak, most of these patients require aggressive fluid resuscitation over the first 24 hours. During this period, in addition to ensuring adequate cardiac pre-load (e.g. central venous pressure, pulmonary artery occlusion pressure), parameters of tissue perfusion and oxygen delivery (e.g. serum lactate, base deficit, urine output, central/mixed venous oxygen saturation, cardiac output) should be carefully monitored. The SAFE study⁸⁸ has shown that albumin and crystalloids are equally safe and effective (except for patients with traumatic head injury). Surviving Sepsis Campaign has recently reviewed the literature and published updated and comprehensive guidelines to guide the resuscitation in adult and pediatric patients⁸⁹. These guidelines also provide evidence-based recommendations regarding a wide spectrum of supportive/adjunctive therapies (e.g. glycemic control, steroids, vasoactive agents, activated protein C etc).

b. Vasopressors and inotropes

Within reasonable limits, blood flow through the tissue beds is more important than blood pressure. However, during septic shock autoregulation is not normal and perfusion can become linearly dependent on blood pressure. Thus, after the initial fluid resuscitation (or concomitantly) hypotensive patients may require administration of vasopressors to keep the mean arterial pressure >65 mmHg (which has been shown to preserve tissue perfusion)^{90, 91}. Whenever possible, vasopressors should be started after providing adequate initial fluid resuscitation. There is no compelling, high quality evidence that shows one agent to be superior to another⁹². However, Surviving Sepsis Campaign recommends “norepinephrine or dopamine as the first choice vasopressor agent to correct hypotension in septic shock (Grade IC)”⁸⁹. According to them, norephephrine has some attractive features as it increases MAP (due to vasoconstriction), with little change in heart rate and some increase in stroke volume. Dopamine is another good choice, which increases MAP and stroke volume. However, it also increases heart rate, which may not be desirable. Other choices have some unattractive features. For example epinephrine can cause tachycardia, decreased splanchnic circulation, and hyperlactemia. Phenylephrine is a pure vasopressor and is least likely to cause tachycardia, but it decreases stroke volume. Vasopressin has recently gained popularity for treating refractory hypotension in septic shock patients, as there is a relative deficiency of this hormone in septic shock⁹³. However, a recent RCT-Vasopressin and Septic Shock Trial (VASST), which enrolled 778 patients failed to show a survival advantage of vasopressin (0.03 units/min) over norepinephrine, or a reduction in overall rate of serious adverse events⁹⁴. In addition to agents that restore the vascular tone, patients with documented or suspected decrease in cardiac function (elevated filling pressures and low cardiac output) should be given dobutamine as an inotropic agent⁸⁹. Administration of these agents should be guided by serial measurements of markers of tissue oxygenation, filling pressures and cardiac output, without making an attempt to achieve supra-normal levels⁸⁹.

c. Blood products

The optimal hemoglobin level has not been determined for severely septic patients. Rivers and associates in the early goal directed therapy trial⁸² used a target hematocrit of 30% in patients who continued to show low central venous oxygen saturation. In a more recent multi-institutional trail of mixed ICU patients (not necessarily septic shock patients) hemoglobin levels of 7–9 gm/dL and 10–12 gm/dL were associated with identical outcomes⁹⁵. Thus, it is reasonable to aim for target hemoglobin between 7–9 gm/dL if parameters of tissue oxygenation are adequate. But in cases of depressed tissue oxygenation or in patients with other co-morbid issues (e.g. coronary artery disease, stroke, etc), hemoglobin levels can be pushed up to 10–12 gm/dL to optimize the tissue oxygen delivery. However, this area remains controversial and evidence based guidelines have been proposed by experts in the field to steer the transfusion practices in these critically ill patients⁹⁶.

4. Future Directions

A number of new and exciting developments in the arena of resuscitation research have the potential of radically transforming clinical care in the near future. Two such areas of research are discussed here:

a. Pharmacologic therapy

Over the years, a number of pharmacologic agents have been tested as possible adjuncts to fluid resuscitation. These drugs cover a wide spectrum including neuroendocrine agents, calcium channel blockers, ATP-pathway modifiers, prostaglandins, sex steroids, anti-oxidants, anti-inflammatory agents, and immune-modulators. Although there is strong laboratory evidence of their beneficial effects on tissue perfusion, myocardial contractility, reticulo-endothelial function, cell survival, oxidative injury, and immune activation, majority of these agents are not yet in clinical use as resuscitative agents. A thorough discussion of the research in this area is beyond the scope of this article. However, a number of agents aimed at correcting the circulatory and immunologic derangements of hemorrhage are worth mentioning as promising pharmacologic adjuncts to resuscitation. Dr. Chaudry’s group has extensively studied the role of sex steroids in cytokine responses and neutrophil adhesion after hemorrhage; they have proposed estrogen and its analogs as possible beneficial treatments⁹⁷. Dr. Coimbra’s group has studied the phosphodiesterase inhibitor, pentoxyfylline, already widely used for vascular disease due to its rheologic properties, as a treatment for hemorrhage because it reduces neutrophil activation and adhesion⁹⁸. A Cochrane review recently analyzed data on the opiate antagonist Naloxone which has been studied based on the finding that central Mu, Epsilon, Kappa, and Delta receptors are activated during hemorrhagic shock and inhibit Ca⁺⁺ channels; the data suggested that further clinical trials are needed to determine if the beneficial effects on blood pressure by administration of Naloxone result in any durable improvements in survival⁹⁹. A common thread across all of these potential agents is that they are already in wide clinical use for other disorders. Thus, there is great hope that with more clinical evidence, these agents whose safety profile has already been tested for various non-trauma indications can be rapidly implemented as adjuncts to fluid resuscitation. Our group has been studying another group of drugs, also already in wide clinical use for non-trauma indications, in animal models of shock. Following hemorrhage, the stress of shock and resuscitation causes an immediate modulation of genes and proteins involved in a variety of cellular defense pathways through an alteration in their acetylation status^{100, 101}. We hypothesized that histone deacetylase (HDAC) inhibitors such as valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) may have utility in the treatment of shock through restoration of normal cellular acetylation. We subsequently have shown that HDAC inhibitors rapidly reverse shock induced alterations, restore normal histone acetylation, and improve survival in different models of otherwise fatal hemorrhagic shock and poly-trauma ^{102, 103, 104}. Impressively, this survival improvement was achieved without conventional fluid resuscitation or blood transfusion, which makes this approach very appealing for the logistically constrained pre-hospital and battlefield environments. It appears that HDAC inhibitors rapidly activate nuclear histones as well as numerous cellular proteins to create a “pro-survival” phenotype in hemorrhagic and septic shock^{105, 106, 107, 108, 109}. Unpublished data also demonstrate that this approach is very promising for the treatment of traumatic brain injury. A number of these HDAC inhibitors are currently being tested in phase I and II clinical trials (non-traumatic situations). We believe that additional research in this arena could ultimately lead to a potent pharmacologic adjunct to the treatment of hemorrhagic shock that works by promoting cell survival during periods of lethal stress.

b. Emergency Preservation and Resuscitation (EPR)

Up to 80% of trauma deaths occur in the early post-traumatic phase,¹¹⁰ with exsanguination as the dominant etiology¹¹¹. Profound shock from blood loss does not respond well to conventional methods of resuscitation¹¹². Even when the underlying cause can be treated and circulation restored, cerebral ischemia lasting 5 minutes or longer invariably results in severe brain damage. Often the underlying injuries are reparable but the patient dies of irreversible shock or severe brain damage. In this setting, strategies to maintain cerebral and cardiac viability long enough to gain control of hemorrhage and restore intra-vascular volume could be life saving. This requires an entirely new approach to the problem, with emphasis on rapid total body preservation, repair of injuries during metabolic arrest, and controlled resuscitation: Emergency Preservation and Resuscitation (EPR). Currently, hypothermia is the most effective method for preserving cellular viability during prolonged periods of ischemia. Although, no clinical studies have been conducted to test the therapeutic benefits of hypothermia in trauma patients, numerous well-designed pre-clinical studies clearly support this concept. It should be emphasized upfront that induced hypothermia and hypothermia secondary to shock are very different entities. Induced hypothermia is therapeutic in nature whereas hypothermia, seen in severely traumatized patients, is a sign of tissue ischemia and failure of homeostatic mechanisms to maintain normal body temperature. It is clear from the literature that rapid induction of deep/profound hypothermia (<15°C) can improve otherwise dismal outcome after exsanguinating cardiac arrest^{113, 114, 115}. Depending on the degree of hypothermia, good outcomes have been achieved with cardiac arrests of 15, 20, 30 and even 90 minutes in canine models^{116, 117}. Furthermore, the period of hypothermia can be safely extended to 180 minutes if blood is replaced with organ preservation fluids and low flow cardiopulmonary bypass is continued (as opposed to no flow) during the arrest period¹¹⁸. Although ground breaking, the clinical relevance of these original studies was somewhat limited by reliance on pressure-controlled models of hemorrhagic shock (or no hemorrhage), an absence of major injuries, and lack of surgical interventions. To fill these gaps, our team has utilized clinically realistic large animal models of lethal vascular injuries and soft tissue trauma to demonstrate that profound hypothermia can be induced through an emergency thoracotomy approach for total body protection, with excellent long-term survival and no neurological damage or significant organ dysfunction¹¹⁹. In a follow up study, it was established that lethal vascular injuries, above and below the diaphragm, can be repaired under hypothermic arrest with >75% long term survival¹²⁰. More importantly, it was shown that hypothermia could be used successfully even after 60 minutes of normothermic shock (transport time), and that the surviving animals were not only neurologically intact but also had normal cognitive functions. Subsequent studies have determined that to achieve the best results, profound hypothermia must be induced rapidly (2°C/minutes) and reversed at a slower rate (0.5° C/minutes)^{121, 122}. Induction of hypothermia has been shown to preserve various cell types in the central nervous system, while providing some immunological advantages, and modulating cell survival pathways ^{123, 124, 125}. The optimal depth of hypothermia is 10°C, and decreasing the temperature to ultra-profound levels (5°C) may actually worsen the outcome¹²⁶. If done appropriately, the safe duration of total body preservation in poly-trauma is about 60 minutes¹²⁷, and it results in no increase in post-operative bleeding or septic complications¹²⁸. Technically it is now feasible to induce hypothermia using small, battery operated, portable equipment (suitable for austere settings and pre-hospital environment)¹²⁹. This is associated with excellent “total body preservation” which may have significant implications not only for treatment of traumatic injuries but also for preserving organs for transplant¹³⁰. Induction of hypothermia not only modulates metabolism but also influences a vide variety of cellular and sub-cellular mechanisms¹³¹, including alteration in transcription of numerous beneficial genes¹³², the down-stream effects of which persists long after hypothermia. There is also some data from small animal models to suggest that similar metabolic arrest (and tissue preservation) can be achieved with other methods, such as inhaled hydrogen sulfide¹³³. It may sound futuristic, but the expertise to preserve the viability of key organs during repair of otherwise lethal injuries is now available¹³⁴, and a prospective multi-institutional clinical trial is scheduled to start later this year¹³⁵.

5. Conclusions

Treatments of shock have evolved over the last 50 years, but the changes over the last decade have been especially dramatic^{136, 137, 138}. Based upon contemporary data, early goal directed fluid resuscitation should be considered the standard of care for septic shock, along with additional supportive measures as advocated by the Surviving Sepsis Guidelines⁸⁹. The optimal approach for hemorrhagic shock is not as clear due to a relative paucity of level-1 evidence. However, according to my personal opinion the existing literature strongly supports some common sense recommendations for the treatment of hemorrhagic shock¹³⁹. . First, resuscitation is not a substitute for early hemorrhage control. From the moment of injury, all efforts to provide definitive control of hemorrhage as expeditiously as possible must be aggressively pursued. Second, large volume crystalloid resuscitation is deleterious and should be abandoned. Fluid resuscitation can be safely withheld in patients who have adequate cerebral perfusion (normal mental status in the absence of head injury) and a palpable radial pulse, especially if the pre-hospital transport time is expected to be brief. For situations where the time to definitive care is longer than 15–20 minutes, initiation of limited volume resuscitation is supported by the literature. Specifically, the goals should be to maintain either a SBP approximating 80–90mmHg, or clear mental status (in the absence of head injury) and a palpable radial pulse. At present, it seems that infusion of lactated Ringer’s solution (containing only the L-isomer of lactate) is the best option in the pre-hospital setting, whereas early use of blood products should be strongly considered once the patient reaches the hospital^{18, 23, 139}. While the ideal ratio of blood components is under investigation, there is a strong trend in favor of starting component therapy early and to administer higher ratios of FFP and platelets to PRBC. Newer methods for blood component preservation have improved their logistical profile, which may yield shelf-stable products for pre-hospital use in the near future^{140, 141}. The evidence strongly suggests that applying these ratios through an institutional protocol improves delivery of care and outcomes. When blood products are not an option, blood substitutes may have a role. However, at present, the data on blood substitutes are far too mixed to recommend their use outside of trials. Finally, pharmacologic adjuncts to resuscitation may ultimately play a role is reducing the deleterious immunologic and cellular effects of hemorrhage and resuscitation. This is an exciting area of future research but their use remains to be validated in robust clinical trials. For now, early and expeditious control of hemorrhage and modest, goal directed resuscitation should be the standard of care.