New concepts in shock management

SPECIAL COMMUNICATION

New Concepts in Shock Management David Alexander,

MD

Associate Medical Director of STAT MedEvac, Center for Emergency Medicine, Assistant Professor of Emergency Medicine, University of Pittsburgh, Pittsburgh, Pa Key Words: replacement

MAST,

sepsis,

shock,

volume

Address for correspondence and reprints: David Alexander, MD, Associate Medical Director of STAT MedEvac, 200 Meyran Avenue, Suite 500, Pittsburgh, PA 15213 This paper was presented at the Fourth Annual Clinical Care Conference, Care of the Critically Ill and Injured, March 8-9, 1996, Lake Tahoe, Nevada Copyright Associates. Reprint

0 1996

by the Air Medical

Journal

no. 74lll72313

Introduction Air medical crews are constantly being faced with clinical challenges. The patients being transported by critical care air transport are in die need of the services of tertiary referral centers. The transport personnel in whom these patients’ care is entrusted must have a wide knowledge base to care for these critically ill patients. These crews must be continually informed as to innovations in treatment modalities. This article is intended to provide a brief overview of important innovations in the treatment of shock. The sections included are hemorrhagic shock, uncontrolled hemorrhage, septic shock, and cardiogenic shock. It is hoped that this will encourage further reading on these new treatments. Hemorrhagic

Shock

To improve the outcome of patients with hypovolemic shock, control of hemorrhage and adequate volume restoration (with both crystalloid and red blood cells) are required. Mandatory to the control of hemorrhage is rapid operative resuscitation.1 The chief goal is the restoration of adequate tissue perfusion. This would include not only the control of hemorrhage but also the debridement of wounds, open reduction and internal fixation of long bone fractures, and excision of bums. As always the initial step is securing of the airway and providing ade quate ventilation and oxygenation. After the airway is secured, the next priorities are replacement of blood volume, restoration of tissue perfusion, and prompt control of hemorrhage. This is reflected in current training emphasized in the ABC’s (airway, breathing, and circulation) of prehospital treatment. The principal areas to be addressed in volume resuscitation in a patient are restoration of blood volume and red cell mass. The goal is to restore normal or Air Medical

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even acquire supranormal oxygen delivery.2.3The question arises as to how ade quate resuscitation can be monitored. Blood pressure by itself is an inadequate indicator of blood loss or resuscitation, especially in young patients.1 Indicators such as urine output (0.5 to 1.0 ml/kg/hr), heart rate, normalization of mental status, correction of base deficit, reversal of lactic acidosis, and restoration of normal blood pressure are more indicative of adequate resuscitation. The methods used to achieve these goals, such as volume infusion and vasopresSOTS, remain highly controversiall~4 Several studies, including Calvin and associates5 suggest that central venous pressure, pulmonary wedge pressure, and left atria1 pressure6 did not aid in evaluating the resuscitation of patients. Recent evidence suggests that base deficit and serum lactate may be reliable indicators of hypoperfusion. Davis and associates7 and Rutherford et al.8 have found that base deficit may be an indicator of hypoperfusion and oxygen debt and that the correction of the deficit may be an indicator of adequate resuscitation. Serum lactate seems to correlate with the degree of hypoperfusion and may even correlate with the outcome in trauma patients9 The choice of fluid to use with red blood cells has evoked much controversy over the years. Numerous studies’ have been done comparing the efficacy of colloid and crystalloid solutions in the resuscitation of patients in hemorrhagic shock. Equal survival has been shown using both crystalloid and colloid solutions.1 The ease of storage and substantial cost difference favor crystalloid solutions. Early Blood Administration Volume expansion by asanguinous fluid is probably reasonable for most patients 85

sustaining mild to moderate hemorrhage. Tachycardia, increased myocardial contractility, hyperventilation, and increased oxyhemoglobin desaturation permit considerable tolerance to acute blood loss without compromising tissue oxygenation.fo-1s Clinically, it has also been observed that patients with up to 20% blood loss do well without red cell replacement14 If blood loss is profound, aggressive volume replacement with crystalloid solutions may dilute the remaining red cell mass and decrease oxygen delivery. The preference for crystalloid therapy as a resuscitative tool has never been validated in a clinical or animal study.fsJo Recently studies have been performed to show the value of early blood administration to those with severe blood loss. Dronen and associates16 showed this in a porcine model of severe hemorrhagic shock. The results showed excellent survival using whole blood early de spite severe blood loss. Other clinical studies are currently underway to investigate the early use of blood in severe shock and the effects of hemodilution.17 Early analysis shows a significant impact on improving survival. The current standard transfusion therapy is to use packed red blood cells diluted with an equal volume of saline.15Jg21This allows the viscosity to decrease and permits more rapid infusion. Whole blood has a viscosity similar to diluted packed red cells and can be infused at a comparatively equally rapid rate.zz.23Both solutions have the same oxygen-carrying capacity and volume expansion. Prehospital use of blood as a resuscitation tool principally lies in air medical programs. Because of the storage and monitoring of the blood according to OSHA standards, blood use has been placed in hospital-based air transport programs. A survey of 130 programs in 1991 revealed only 40 programs using blood.24 The survey also indicated that physician crews were more likely to give blood. Hall and associates25 retrospectively studied blood use and showed a lower mortality and greater chance of being discharged home with early blood use. Further prospective trials should be undertaken.

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UncontrolledHemorrhage Recent studies have focused on the uncontrolled hemorrhage associated with penetrating trauma, abdominal aortic aneurysm rupture, or gastrointestinal bleeding. Evidence suggests a different approach should be undertaken in resuscitation of these victims. Cannon and as sociatesz6proposed that patients endure permissive hypotension until operative intervention to control hemorrhage. This “hypotensive resuscitation”27 or permissive hypotension is used to maintain a certain blood pressure (approximately 90 mm Hg) and hematocrit (approximately 40) but not to restore normal blood pressure. Numerous animal models indicated that fluid resuscitation or vasopressors in uncontrolled hemorrhage led to increased bleeding and reduced surviva1.2~30Recently Bickell and colleagues28 studied the effects of fluid restriction on outcome in victims of penetrating injuries. Intravenous fluid was withheld in one treatment group (until operative intervention), whereas the other group received intravenous fluids as currently practiced. The cohort receiving no preoperative fluid had a higher survival rate (70%vs 62%). Capone and associates31 suggest that complete restoration of fluid in the setting of profound hypotension caused by uncontrolled hemorrhage did not improve outcome, but careful fluid admink tration did improve long-term survival. This helped to avoid irreversible organ damage and to prevent an increased rate of hemorrhage. As previously mentioned, recent data suggest that early blood administration should be emphasized.16 Permissive hypotension should not be allowed to occur in patients with blunt trauma injuries. An adequate perfusion state must be attained to prevent multisystem organ failure. Buildup of lactic acid has a definite deleterious effect and must be avoided in patients with blunt trauma. This necessitates a near normal blood pressure. Also victims of closed-head injury need an adequate cerebral perfusion pressure to avoid secondary injury and should therefore not be allowed to remain hypotensive. Hypertonic Solutions Hypertonic or hypertonic/hyperoncotic solutions for the treatment of hemorrhagic shock have been recommended

on the basis of both clinical and animal studies.33 These solutions rapidly increase mean arterial pressure and cardiac output. They also will decrease heart rate,34 lower systemic vascular resistance,35 and increase myocardial efficiency.36Because of the hypertonicity of the solutions, intracellular fluid is shifted into the extracellular space, causing a further increase in plasma volume.37 Osmoreceptors present in innervated lungs may also mediate the hemodynamic response to hypertonic solutions. Lupes and coworkers38saw better survival in innervated dogs compared with dogs with blockaded cervical vagal trunks. Younes et al.39confirmed this in their work. The response of the lungs may be due to an afferentefferent reflex, resulting in selective musculocutaneous vasoconstriction.3839 Initial studies focused on high concentration salt solutions. De Felippe and associates40 reported the use of 7.5% NaCl in patients who were unresponsive to vigorous fluid replacement, dopamine infusions, and steroids. The hypertonic NaCl caused an immediate rise in arterial pressure, increased urine output, and re covery of consciousness. None of the 12 patients survived to discharge from the hospital. The problem was that the effects were short lived. The addition of dextran to solutions to create a hypertonic/hyperoncotic solution with longer lasting benefits has been studied and seems to be more efficacious.41-4s Kreimeier and associates44showed that the combination of dextran and 7.2% NaCl in small volume resuscitation increased cardiac output, improved renal blood flow, and increased pancreatic blood flow. Perfusion to the myocardium, brain, skeletal muscle, adrenal glands, and colon rose above baseline values, and all these effects lasted for at least 30 minutes. Several potential complications may arise with the use of these solutions. Hypernatremia and hyperosmolarity can re sult in disorientation, confusion, seizures, pulmonary congestion, heart failure, and brain cellular dehydration.45,46Those effects have not been seen to date in bum patients who have reached a serum sodium level of 160 mEq/L or serum OSmolality of 350 mOsm/L.47 De Fillipe et al.40 did not report any complications April-June

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with 7.5%NaCl resuscitation of refractory compared with resuscitation by crystal- displays pulmonary edema, cardiogenic shock. In animal studies no histologic ev- loid solutions. No adverse effects were shock, or penetrating chest injuries.1 idence of cerebral injury has been demonstrated in any of these studies. AIshown,45 and these solutions may even though these trials support the use of hy- TrendelenburgPosition aid in closed-head injury treatment by de pertonic solution in head-injured pa- The Trendelenburg position has been creasing intracranial pressure and im- tients, other subgroups of patients in long used as treatment for hypotensive proving cerebral perfusion pressure.da52 hypotensive hemorrhagic shock need to patients. Sibbald and associates75 have Theoretically, hypertonic solutions have be delineated. brought this procedure into question. the potential to cause local tissue damOther clinical studies have been done They showed that no consistent effect of age. Hands and coworkers53 showed no using hypertonic solutions in abdominal this position exists in normovolemic or histologic injury to infused veins. Rapid aortic surgery with fairly good re- hypovolemic patients. Placing the patient cardiovascular improvement was sults.67@ Results are even favorable for in this position may compromise pulachieved with either peripheral or central the use of hypertonic solutions in septic monary function and cerebral perfusion; vein infusion. shock.69970The combination of military the risk of aspiration exists as well.1 Dextran alone has been implicated in antishock trousers (MAST) and hyperanaphylactic reactions and in having the tonic saline has been shown in animal r-e Septic Shock potential for a bleeding diathesis.54,55 search to prolong the effects of increased Many new therapeutic modalities are Ljungstrom and associates56 reported mean arterial pressure and increased car- being used to deal with septic shock. the incidence of anaphylactic reactions as diac output for 2 hours.71 Despite exten- Sepsis with hypotension carries signifi0.025%. Dextran solutions cause a pro- sive clinical work suggesting improved cant mortality. Often, sepsis occurs after longed bleeding time, probably because resuscitation, the use of hypertonic/hya significant injury to a host (such as he of inhibition of platelet aggregation.54 peroncotic solutions still seems contro- morrhagic or cardiogenic shock) beThe prolonged bleeding time usually oc- versiall cause of multiple immunologic derange curs with large doses of dextran (1.5 ments. Clinical and animal studies also g/kg/day) or with prolonged infusions, Militay Antishock Trousers indicate that hemorrhagic shock impairs usually far exceeding the usual dose MAST were used extensively in the past. antibiotic efficiency7c78 and inhibits pro(~0.5 g/kg) used in combination solu- Their initial use in Vietnam seemed to phylactic antibiotics from preventing tions with hypertonic saline. Hypertonic improve outcomes in battlefield casual- wound infection.79 If a patient’s immune saline also has been shown by Reed and ties. MAST work to decrease the size of system can be restored after a significant associates57 to alter prothrombin time, the vascular bed peripherally, thus cam+ insult, he or she will be better able to partial thromboplastin time, and platelet ing an increase in peripheral vascular r-e combat sepsis. Current research is being aggregation at volumes several times sistance. Their clinical efficacy has yet to conducted using endogenous cytokines that of the small volumes needed to pro be proved. Mattox and colleagues72con- to help restore immune function or to duce hemodynamic improvement. Al- ducted a large prospective study on block the effects of cytokines that act as though potential complications do exist, MAST application, which demonstrated mediators of sepsis. they have yet to be observed in any ani- no difference in outcome.72A large retroCytokines are endogenously promal or clinical study.58 spective study demonstrated that se- duced proteins of small molecular weight Clinical studies have been performed verely hypotensive patients may benefit and multiple biologic effects. The cyin various settings, and the results seem from MAST.73 The study looked at the tokines interleukin-1 (ILl) , tumor necro to favor the use of hypertonic/hyperonoutcome of hypotensive patients from 16 sis factor (TNF), and interferon gamma cotic solutions. Cross and associate@ hospitals. They found that if the systolic play a critical role in the inflammatory re studied prospectively the use of hyper- pressure was less than 50 mm Hg and sponse to an acute illness. IL1 and TNF tonic saline in postoperative patients and MAST was applied, the survival rate in- may play roles as mediators of sepsis. found it to have good resuscitative quali- creased. This may be the cohort that Other cytokines that may play a role as ties. Pascual et al.60 used a swine model best benefits from the use of MAST. An- mediators of sepsis are interleukin-1, -4, to compare normal saline with hyper- other study using air medical transport -6, and -8. Blocking the effects of sepsis tonic fluids in hypovolemic shock and showed equivocal results on patients mediators may be a potential therapeutic demonstrated a far better outcome in the with systolic blood pressures less than 90 option in treating sepsis.Three classesof hypertonic resuscitation group. These mm Hg. This also was a small retrospec- agents to block the negative effects are studies were done with the usual 4 tive study of patients both with and with- being studied: (1) antibodies, (2) circulaml/kg. Other preoperative studies have out the use of MAST.74 Clearly, prospec- tory inhibitors, and (3) receptor antagoshown improved survival and reduced tive trials are needed. nists. Use of the more beneficial cymorbidity, especially in closed-head inMAST may also have a place in the tokines to restore immune function also juries.61-66Vassar and associates63~65~66treatment of ruptured abdominal aortic seems promising. have performed studies involving air aneurysm, septic shock, neurogenic Interferon gamma increases the medical transport. The rate of survival to shock, pharmacologic vasodilation, and macrophages’ response to antigens, inhospital discharge in patients with severe early stabilization of pelvic fractures. creases phagocytosis, and activates intrahead injuries was significantly higher MAST are contraindicated if the patient cellular killing of invading organisms. In Air Medical

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several studies interferon seems extremely promising in restoring a patient’s immune system after a signiticant insult (such as hemorrhagic shock) and in pre venting sepsis.79@TNF is produced by activated monocytes and has been shown to increase monocyte and neutrophil cytotoxicity and to regulate other cytokine production. TNF alpha used with interferon gamma may also aid in restoring immune function.83 TNF can also cause the hemodynamic, metabolic, and patho logic findings associated with septic shock.84 These effects include myocardial depression. This leaves interferon gamma as the best choice for biologic restoration of immune function. The finding that TNF is a potential mediator of septic shocks5,ashas led to research into using the antibody antiTNF as a treatment for gram-negative sepsis. Current trials have shown a transient improvement in left ventricular function and hemodynamics. As yet, antiTNF has not shown an impact on mortality,*sJs and further research is needed. IL1 is another polypeptide hormone similar to TNF. IL1 activates T cells, sup ports B-cell proliferation, and releases adrenocorticotropic hormone. Large amounts of IL1 are toxic to vascular endothelium and enhance tissue sensitivity to TNF.87 A naturally occurring protein IL1 receptor antagonist (1Llra) inhibits the effects of ILl. Numerous studies are underway to evaluate the efficacy of IL lra.s7-89A caveat to this treatment must be entertained. It has been noted that patients who have an inability to produce IL1 have a poorer prognosis than other patients with sepsis.s7,90This may reflect a breakdown in monocyte function, but IL1 may produce more harm than good. Monoclonal antibodies to bacterial endotoxins have also been espoused to treat sepsis, HA-lA and E5 are IgM antibodies to endotoxins from a variety of gram-negative bacteria.87 In the original study of HA-lA in the New England Journal of Medicine,91 HA-lA seems to be a safe and effective treatment. A reduction in mortality was also found in septic patients with high levels of TNF and B-6.92 Recent studies of HA-1A have not confirmed a decrease in mortality in patients with gram-negative bacteremia and may further suggest an increased mortality in patients with non-gram-negative bac88

teremia.gs-96 These studies suggested that as the number of organ system failures and the severity of the underlying disease increased, the mortality increased proportionately. Further study needs to be done to better stratify which patients may benefit from this therapy. Studies with E5 suggested that patients with gram-negative sepsis, who did not display refractory shock, had signiticantly decreased mortality.97,9* Both E5 and HA-IA need to be studied further as to the indications for their use. What is known is that to benefit from E5 or HA1A patients must have gram-negative sepsis and will require combinations of other pharmacologic agents to be effective.87 Another biotherapy proposed to prevent or treat sepsisis the induction of the heat shock response. The heat shock re sponse is the production of certain proteins that modulate the response to sep sis and prevent organ damage.sQg-102 Fever, chemicals, nervous stimuli, or ischemia are the elements that usually trigger the heat shock response.99 It seems that the febrile response to sepsis with the release of heat shock proteins is important in protecting the host against bacterial infections. Synthesis of heat shock proteins also seems to be promis ing therapy for the future.sQ~1o2 Naloxone has even been proposed as an adjunct in the treatment of septic shock. Swinburn and Phalanros first reported the use of this opiate antagonist in septic shock. Naloxone showed an increase in mean arterial pressure that lasted 45 to 165 minutes.104-107To date, no effect on mortality has been shown, but naloxone may serve as a temporizing agent in the treatment of septic shock.107 Septic shock can have profound myocardial depressive effects that have been demonstrated in several clinical studies.i@+llo Dobutamine is a synthetic catecholamine that exerts strong inotropic effects on myocardial tissue; therefore it could help to augment perfusion in patients with septic shock. Studies using dobutamine are scarce but do seem to indicate an improvement in he modynamic effects in patients with septic shock, and the drug is well tolerated.llr-113 Dobutamine should be considered when treating septic shock to help correct the severe hypotension along with the use of

vasopressors (dopamine, norepineph. rine, epinephrine) 113and volume resusci tation. Cardiogenic Shock Three percent to 20% of patients with an acute myocardial infarction will have their condition deteriorate into cardiogenie shock.114J15The mortality of cardiogenic shock was greater than 75%be fore balloon angioplasty and thrombolysis. Current treatment with sympathomimetic agents (dopamine, dobutamine, and norepinephrine) may increase the cardiac index but will also increase myocardial oxygen demand. Many recommend dobutamine as the inotrope of choice because it increases cardiac output without increasing the infarct size.lts,ll7 The hemodynamic effects may decline with continued use of dopamine and dobutamine. Phosphodiesterase inhibitors (amrinone, mihinone) have inotropic and vasodilating properties and should be considered when other therapies are ineffective.118 Intraaortic balloon counterpulsation @ABC)can also aid in hemodynamic stabilization. IABC increases coronary perfusion and decreases systemic afterload without an increase in myocardial oxygen demand.119 Controversy currently exists as to whether emergent coronary artery bypass grafting (CABG), primary percutaneous transluminal coronary angioplasty, or thrombolytic therapy is the preferred treatment in cardiogenic shock. Surgical intervention has the most impact in managing cardiogenic shock from mechanical defects (mitral regurgitation, ventricular septal defects, etc). Surgical CABG also seems to be beneficial in diabetic patients, patients with diffuse disease, or those not amenable to angioplasty. Primary angioplasty has successrates equal to thrombolysis in stable myocardial infarction patients and can be performed rapidly for patients in cardiogenic shock. For patients with hemodynamic instability and contraindications to thrombotic therapy or with a prior CABG, angioplasty is the treatment of choice.118At facilities without the availability of cardiac catheterization, patients may or may not receive thrombolytic agents and be stabilized with IABC and rapidly transferred to a tertiary care center.120 April-June

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Conclusion It is hoped that this article has stirred some academic curiosity and debate on the new concepts and treatments of these shock syndromes. This brief overlook is merely a glance at the innovations coming to the forefront of research into

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new clinical therapeutics for these crititally ill patients. Any comments are most welcome. Acknowledgment I would like to express my thanks to Andrew Peitzman, MD, Associate Professor

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of Surgery and Chief, Section of Trauma/Surgical Critical Care, University of Pittsburgh Medical Center; Rade B. Vukmir, MD, Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh Medical Center; and Renae Alexander, STAT MeclEvac.

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