Military Medicine: Wound Shock: A History of Its Study and Treatment by Military Surgeons

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Wound Shock: A History of Its Study and Treatment by Military Surgeons

Hardaway, Robert M

The treatment of wounds has received considerable attention from the time of the Trojan War. However, it was not until the American Civil War that shock was described as an entity distinct from the wounds themselves and that efforts were directed at more than just treatment of the wound. The need for fluid resuscitation in the treatment of hemorrhagic shock was first recognized in the Spanish American War, as was the association of sepsis with shock. World War I showed the need for blood in the treatment of "wound shock," a lesson that had to be relearned in World War II through bitter experience. Studies in the Korean War described the concept of disseminated intravascular coagulation and multiple organ failure, and the existence of disseminated intravascular coagulation was confirmed by studies in Vietnam. The treatment of hemorrhagic shock is now very effective, but the treatment of traumatic and septic shock remains unsatisfactory.

Introduction

Shock is the most common cause of death in noncardiac intensive care units.1 It has long been closely associated with wounds and in fact was called "wound shock" up until World War II. Shock has since been divided into hemorrhagic, traumatic, and septic categories, all of which frequently accompany severe wounds.

Early European Wars

During the Trojan War in 1200 BC, the first treatment for war wounds was recorded by Homer,2 who gave the mortality of war wounded as 77%. He offered the opinion that "Surgeons are worth more than armies to the public weal." Although he was probably overly enthusiastic, it is certain that the treatment of war wounded was carried out and considered important.

Over five centuries of Roman wars, Roman Legions always had a combat surgeon for each legion and maintained a surgical hospital at each legion fort. These were the first trauma centers. The foundations of these Roman military hospitals can still be seen in England and Germany. The concept of what actually caused wounded soldiers to die was vague and not thought about except perhaps to note that they could bleed to death.

During the European Wars of the 18th and 19th centuries, among the first to wonder why wounded soldiers died was the French surgeon Henri Francois Le Dran,3 who, in 1731, described a collapse of vital functions, which ended in death after being hit by a missile. He called it "secousse" (jar). Gross,4 in 1850, described shock as the "rude unhinging of the machinery of life."

Cooper,5 in 1838, in discussing gunshot wounds of the Crimean War, stated that many wounded soldiers died without significant loss of blood, severe pain, or serious injury. Surgeons "were in the habit of saying men died of shock." Shock was completely separated from hemorrhage. It was recognized that soldiers could bleed to death, but if there was little obvious hemorrhage, then death was attributed to "shock," a mysterious and indefinable death.

Early American Wars

After the British American War of 1812, Horner6 noted that the survival rate was higher in wounded soldiers whose amputation of a wounded extremity was postponed rather than performed at the first possible moment. Nevertheless, amputation as a prevention of gangrene and death persisted in the American Civil War. It was not until World War I that debridement replaced amputation for the prevention of infection in the war wounded. In spite of the fact that gangrene was a greatly feared cause of death, it was generally considered that shock itself was always secondary only to trauma. Septic shock was not thought of as shock until about 1898, during the Spanish American War.

The American Civil War of 1860 to 1865 saw the first efforts to treat "wound shock" as distinct from the injury alone. Infection and hemorrhage were the most common causes of death in the wounded. The possibility that shock and severe hemorrhage were the same was considered, but the concept persisted that they were different entities. In his history of the Civil War, written in 1876, Barnes, Surgeon General of the Army, stated "It is an open question whether a blow to the abdomen may produce death without an organic lesion. If pain is persistent and radiating from one spot, it may signify internal trouble and if collapse returns a few days after injury, it is supposed to mean internal hemorrhage. The collapse of bleeding, however, resembles syncope as distinguished from shock. Rest in bed, opium and warm fomentations constitute the treatment."7

It was during the Spanish-American War of 1898 that shock was first associated with sepsis. In speaking of the many wounded soldiers whose wounds were infected with Bacillus aerogenes capsulatus and gas gangrene, the Army Surgeon General stated in 1900, "Extreme degree of shock, with all its accompanying symptoms, was a marked feature of all of these cases." In this same report, it was noted how effective normal salt solution was in treating hemorrhage. "A soldier was stabbed in the neck, and the left common carotid artery and jugular vein were cut. He became exsanguinated and lost consciousness. The vessels were ligated and the patient given normal salt solution by enema and subcutaneous injection. The survival of this almost bloodless patient for 16 hours was attributed to the free use of salt solution. Patients in a state of shock were given normal salt solution rectally and subcutaneously, strychnine 1/60 grain, covered with blankets and kept warm."8

World War I

In World War I, in 1917, death was attributed to "wound shock." Hemorrhage was thought to be distinct from "wound shock" but was considered a complicating factor in the development of shock, "Complicating the wounds, there is usually some loss of blood. Under battle conditions especially there may be cold and exposure, lack of food and water and sweating which when combined with injury may bring about promptly the signs of wound shock."9 It was recognized that if a wounded soldier was not in shock, but was anesthetized with ether or chloroform, a calamitous fall in blood pressure might result. Venous pressure was found to be lower. This was an important observation and presaged the measurement and use of central venous pressure in Vietnam. From 1918 until 1964, however, venous pressure was not a serious consideration in treating shock.

A reference to "normal or increased erythrocyte count" was a remnant of the idea that shock and hemorrhage were separate conditions. The idea that wound shock was characterized by a high hematocrit value persisted through the years and played a great part in the emphasis placed on plasma as opposed to blood transfusion when the United States entered World War II.

A reference to "slight cyanotic appearance" presaged the findings of low oxygen tension (p02) in Vietnam casualties in 1964. Previous to this, the extremely precarious state of oxygenation in many instances of shock was not properly appreciated or documented.

Shock was blamed in part on a "toxic factor" arising from damaged and dying tissue and operation, which caused an increased permeability of the capillary walls and consequent reduction in blood volume by escape of plasma.9 Blalock,10 in 1930, "disproved" the toxin theory and blamed traumatic shock on extravasated blood in the tissues. A "toxic factor" was never found. Much later, during the Korean War, a toxin was again implicated in the production of disseminated intravascular coagulation and multiple organ failure.11

In World War I, there was a real appreciation of the time factor between being wounded and receiving adequate shock treatment. Santy12 noted that if the patient was treated within 1 hour, the mortality rate of nontransportable wounded was only 10%. This increased markedly with time, so that after 8 hours, the mortality rate was 75%. The need for fluid administration was well understood in World War I.9 However, the means of administering fluid volume were only partially developed. Although it was appreciated that the wounded were dehydrated and hypovolemic and needed water, it was thought that this water could, in most instances, be given orally or rectally. If the condition was more urgent, a subcutaneous clysis could be used. It was only in the most urgent cases that the intravenous (IV) route was thought necessary.

It was recognized that any fluid introduced intravenously would increase a low blood pressure. It was thought that this was only of temporary value when normal saline solution was used because of the leakage of the saline solution out of the circulatory system. For this reason, attempts were made to manufacture a colloid solution that would stay in the blood longer. The most common such solution was "gum salt," 6% to 7% acacia in 0.19% sodium chloride. Although used by a great many hospitals, the incidence of febrile and other adverse reactions was high, particularly in those with long-lasting shock and severe hemorrhage or infection. Most hospitals were not in favor of its continued use. Normal saline or Ringer's solution were considerably safer, but were thought to be only temporarily effective.

The administration of whole blood was thought to be extremely effective and was fairly widely used. It was stated that "blood can permanently raise arterial pressure, or gum salt solution can; but in addition [blood] contributes to the recipient a large increase of oxygen-carrier, the red corpuscles."9

Methods of processing and administering blood were relatively primitive. A transfusion apparatus for administering 600 mL of blood mixed with 100 mL of sodium citrate in 0.9% saline solution was most commonly used. Blood typing was done routinely. It was thought that more than 600 mL of blood was unnecessary, and more than this volume was seldom given. Blood was given immediately or within a few hours of being drawn from the donor. It was also thought that no matter what solution was given (blood, gum salt, or saline), the blood volume increased by only a fraction of the amount given due to the escape of considerable fluid into the tissue. This concept was based on blood volume measurements. This presaged the recognition years later in Korea that much more blood must be given than was lost to gain an adequate blood volume. The primary reason for this is still controversial, but is probably due to the pooling of blood in certain capillary beds with subsequent hemolysis and, in part, loss of fluid into the tissues.

In the standard treatment of shock as described in Army manuals, considerable attention was given to warmth, and special heating chambers were used, as well as blankets. However, it was appreciated that too much warmth would aggravate dehydration. The importance of elevating the feet in shock was also emphasized. The need for oxygen administration was intimated by the observation of a "slight cyanotic appearance," but the means for administering oxygen were not available during World War I.

It is interesting to note that vasoconstricting drugs such as epinephrine were condemned as causing a decrease in blood flow and tissue perfusion, and they practically disappeared from use during the war. This advanced concept was forgotten after World War I and was still not completely accepted in 1965. In 1918, it was thought that the "increased arterial pressure (after epinephrine) gave a wholly spurious impression of the state of circulation. Damming the blood in the arterial portion of the circulatory system, when the organism is suffering primarily from a diminished quantity of blood obviously does not improve the flow in the capillaries."9 We now know that the administration of vasopressors to a patient in hypovolemic shock will result in two very adverse effects: the onset of a severe acidosis with lactate levels of up to 131 mg percent and arterial pH of 7.0 or less, and elevation of central venous pressure to levels that preclude administration of IV fluids, which is what the patient needs.13 In fact, so dire were the consequences of vasopressors in this setting that, in Vietnam, they were dubbed "lethophed."

World War II

It is interesting that concepts of shock in World War I were quite advanced and in many ways superior to those of early World War II. The United States entry into World War II in 1941 began as a complete surprise and with complete unpreparedness. This lack of preparation is well illustrated by my own experience in October 1941, when I was assigned to the North Sector General Hospital. That was then the main Army hospital in Hawaii, having 1,000 beds and being much larger than Tripler, which was then a small wooden hospital at Fort Shafter. There, I was appointed Chief of Septic Surgery, a section of the surgical service treating trauma, infections, burns, and miscellaneous conditions not abdominal. I had about 100 beds on two wards and nearly that many patients.

The Japanese attack on Pearl Harbor on December 7, 1941 resulted in several hundred army wounded at Schofield Barracks and Wheeler Field.14 I operated on some 400 of them. About 160 of these were the result of bomb fragment and machine gun wounds from Japanese planes as they repeatedly strafed the barracks. Even the hospital came under fire, as it was located at the end of the row of barracks. Many more soldiers were wounded that day and in the days after by "friendly fire." Blackout was enforced immediately, and for several nights, any light or noise was a target. Wounded soldiers at Schofield Barracks were wounded within a mile of the hospital. Medical evacuation was swift, and the wounded were brought directly to the hospital for definitive treatment. This was fortunate, as casualties in North Africa and Europe were evacuated from much greater distances, taking far more time to reach a treatment facility. Hospital mortality figures at Schofield appeared to be unreasonably high compared with those arenas, however, precisely because more of the mortally wounded actually reached the hospital while they were still alive. These soldiers would have died in the field in North Africa and Europe, and would not have been added to hospital mortality statistics. Also contributing to the high hospital mortality in Schofield was the lack of IV fluids (blood and saline). I found that the dried plasma supply was so limited as to be almost useless. It came in 200-cc bottles into which 200 mL of distilled water was injected. Years later, it was discovered that much of the pooled dried plasma was contaminated with hepatitis virus. No other IV solutions were available at that time. Even normal saline had limited use due to the difficulty of its preparation. It was prepared from distilled water made by a small still in the operating room. A spoonful of salt was dissolved in it and the salt water was put in a Salversan flask, a glass cylinder about 12 × 1.5 inches with an outlet at the bottom to which was attached an old rubber tube and needle. The tube was sterile but so filled with pyrogens that a patient would often have a fever of 105 degrees or so if given this homemade solution.

At that time, shock was considered to be characterized by a low blood pressure and a high hematocrit. In fact, this was the official opinion of the National Research Council and the Army. Plasma was thought to be adequate, and blood was not recommended. There were not even any blood banks in the Army. Blood was given occasionally, usually to a patient with sepsis, and then only in small amounts (100 to 150 mL) by the direct method involving a syringe and three-way stopcock. The syringe was washed with a heparin solution, and then 30 mL of blood was pulled from the donor lying beside the patient. By turning the stopcock, the blood was then injected into the patient. Having both needles patent at once was always difficult.

It was soon evident that this misunderstanding of shock was a major problem. The result was a high mortality rate. The hospital mortality of soldiers admitted to the North sector General Hospital on December 7, 1941 was 20%,14 whereas that of combat wounded in Vietnam was 1.8%.15 It was a case of forgetting what had been learned in World War I, when it was recognized that shock and resuscitation were important, and that IV fluids and blood were required and should be given in large amounts. It was only much later, in 1942, during the African campaign, that Dr. Churchill, surgical consultant for the theater, saw the great need for blood in treating shock. His recommendation resulted in setting up the great blood transfusion program that proved so essential for the rest of the war.16

The first written documentation of resuscitation in World War II was a year after Pearl Harbor, in December 1942, from the 77th Evacuation Hospital in North Africa, as follows: "The wounded in action had for the most part either succumbed or recovered from any existing shock before we saw them. However, later cases came to us in shock, and some of the early cases were found to be in need of whole blood transfusion. There was plenty of reconstituted blood plasma available. However, some cases were in dire need of whole blood. We had no transfusion sets, although such were readily available in the United States; no sodium citrate; no sterile distilled water; and no blood donors."16

Hospital mortality was moderate, but many wounded died before getting to a hospital. The initial decision to rely on plasma rather than blood appears to have been based, in part, on the view held in the Office of the Surgeon General of the Army and, in part, on the opinion of the civilian investigators of the National Research Council that in shock, the blood was thick and the hematocrit high.

According to the Surgeon General's report during World War II, "The Army would likely discourage the use of blood banks. If war should come closer, they might want to use blood that could be transported by airplane. In more distant places where blood could not be procured locally, plasma (either plain or dried) would have to be used."16

Thus, the U.S. Army entered World War II considerably behind the standards of World War I, particularly regarding blood. In fact, on April 8, 1943, the Surgeon General stated that no blood would be sent to the combat zone.16 On November 13, 1943, the Surgeon General again refused to send blood overseas, citing three reasons: 1) His observation in overseas theaters had convinced him that plasma was adequate for resuscitation of wounded men; 2) From a logistics standpoint, it was impractical to make locally collected blood available farther forward than general hospitals in the Communications Zone; and 3) Shipping space was too scarce.

However, things soon looked up. Dr. Churchill, the Surgical Consultant in the North African Theater of Operations, reported on April 16, 1943 that "there is a need for whole blood transfusion in the treatment of a significant portion of wounded."16 He recommended that a system to provide whole blood to the combat wounded be established immediately. Dr. Douglas Kendrick organized the system. The story of the development of a system of whole blood distribution is one of the most important events of the medical history of World War II.

In general, the use of whole blood in World War II was to replace blood lost, volume for volume. This concept was later found to be inadequate in Korea and Vietnam, where it was soon recognized that it was necessary to give much more blood than was actually lost.

In World War I, shock was attributed to inadequate capillary perfusion, but this lesson was soon forgotten, and during World War II, the concept of inadequate arterial blood pressure was given precedence. The importance of timeliness in preventing and treating shock received a setback when it was stated by the Surgeon General, "There was no correlation between passage of time and shock encountered."16 This was very misleading. The reason there appeared to be no correlation was that most of the wounded who were in shock died before they arrived at a treatment facility, or they may never have reached the facility. If wounded arrive at a hospital in less than 1 hour, as usually occurred in Vietnam, many of them are saved. This is in spite of the fact that the mortality of those reaching the hospital in less than 1 hour is twice that of those who arrive after surviving an 18-hour delay. This, of course, increases the hospital mortality rate, even though many additional lives are saved.

Korean War

The Korean War (1950-1954) saw many advances in care of the wounded: whole blood was available in adequate amounts, plastic bags were used, helicopter evacuation became routine, and Ringer's lactate was used frequently to maintain vascular volume. The Mobile Army Surgical Hospital (MASH) concept was instituted for the first time. These advances were instrumental in reducing mortality from abdominal wounds from 21% in World War II to 12% in Korea and to 3.9% in Vietnam.15 Many of these advances were important in the station hospitals back in the United States, to which casualties were often evacuated within 48 hours. As Chief of Surgery at the Surgical and Orthopedic Center in Fort Belvoir, Virginia, I made great use of the new plastic blood bags and Ringer's lactate in treating hundreds of Korean war wounded. It was also during this war that disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) were first described.11

Vietnam

In the War in Vietnam from 1964 to 1972, 153,303 American wounded were admitted to military hospitals.17 As mentioned above, the hospital mortality was less than 2%. Blood and Ringer's lactate were often available and were administered at the battalion aid stations.15 Patients were frequently treated at a hospital in less than 1 hour, having bypassed the aid stations. The Vietnam War saw the beginnings of serious shock research in the Army, with the first description of shock lung,18 later called adult respiratory distress syndrome (ARDS). Intravascular clotting was proposed as the possible cause, and treatment with fibrinolytic enzymes was postulated. In support of this research, blood gases and pH, as well as central venous pressure, were measured for the first time in combat. Ringer's lactate also came into its own as the primary IV fluid in the treatment of shock. These findings were the result of research performed at the first shock-trauma unit, which was established at Walter Reed Army Medical Center in Washington, DC, in 1963, and in a duplicate unit in Vietnam in 1965.15,18,19 The unit in Vietnam was under the direct command of the following physicians in turn over a 6-year period: Dr. John A. Collins, Dr. Paul M. James, Dr. Terruo Matsumoto, Dr. Carl Bredenberg, and finally by Dr. R.L. Simmons. This unit, at the 3rd Surgical Hospital, treated and studied many of the most severely wounded,15,18,19 These studies indicated that "shock lung" and MOF could be caused by intravascular coagulation. The studies were continued over the next 30 years in animals, and culminated in a successful clinical trial of thrombolytics in 2001, based on data from these studies.20-24

Recent Developments

The past 30 years have seen a tremendous surge in the study of hemorrhagic and septic shock in the Army and elsewhere. A computer search for references on hemorrhagic and septic shock in 1999 revealed more than 40,000 entries. Many of these articles treat hemorrhagic shock and traumatic shock as a single entity, and their recommended treatments reflect this concept. A variety of IV fluids, including hypertonic saline and starch compounds, have been introduced. A delay in administering massive IV fluids until bleeding can be controlled may minimize blood loss, according to some. Emphasis has also been placed on warming IV fluids, especially blood, although the cooling of fluids may be effective in cases of high fever. The wide availability of artificial blood is on the horizon and will no doubt prove very significant in times of inadequate or tainted blood supply. The treatment of hypovolemic (hemorrhagic) shock without extensive tissue damage has proved very successful, approaching 100%, providing hemorrhage can be controlled. Pure hemorrhagic shock is always reversible with adequate and timely IV fluids. In fact, the problem of treating true hypovolemic shock has been essentially resolved.

Not so with traumatic and septic shock, which still have a high mortality. The mortality is due to MOF, especially ARDS. The only real treatment for ARDS is respiratory support, and many new methods of providing this support have been described. If this fails, however, the mortality approaches 100%. Despite extensive trials with a variety of drugs, mortality of septic and traumatic shock has not improved over the last 40 years. In fact, the incidence and mortality of septic shock has increased.25,26 Kraff27 states that the mortality of septic shock has remained at 50% or more despite intensive research. Death from septic shock in the United States increased from 35,000 in 1970 to 94,000 in 1980 to 198,000 in 1990.28 The death rate from septic shock per 100,000 population increased from 1.7 in 1970 to 4.2 in 1980 to 7.9 in 1993. According to Baue,29 "The frequency of infection, sepsis or inflammation in producing MOF led to clinical trials of so-called magic bullets for treatment of patients with sepsis. These trials have had either limited success or negative results despite evidence of efficacy or protection by such agents in experimental animals and in studies of normal human volunteers." Various anti-inflammatory therapies have failed to alter mortality.30

In the past, traumatic and hemorrhagic (hypovolemic) shock have been viewed as the same entity. Although these two may frequently overlap, they are in fact separate entities with different etiologies and treatment. Pure hemorrhagic shock is always reversible with the administration of adequate IV fluids, whereas traumatic shock is not. Research based on studies of the wounded in the Vietnam War and later has demonstrated that DIC occurs in traumatic and septic shock.15,18,19 It is the resulting occlusion of the microcirculation of any or all organs, particularly lungs, liver, kidney, and brain that produced the often fatal ARDS and MOF.15,18 Because the effects of DIC are not obvious until late in the disease process, this aspect has been neglected in the immediate treatment of septic shock, as efforts have been directed at agents of the secondary inflammatory response. However, if these microclots can be lysed early, before irreparable tissue damage has occurred, the lungs can return to normal function and the failure of other vital organs can be averted. Plasminogen activator24 and activated protein C31 have shown promise as safe and effective lytic agents in this setting. In view of the failure of other treatments to date, it is hoped that current and future research on septic and traumatic shock will address the problem of DIC in conjunction with other etiologies of this devastating condition.

References

1. Balk RA: Severe sepsis and septic shock. Crit Care Clin 2000: 16: 179.

2. Homer: The Iliad.

3. Le Dran HF: Observation de Chirurgie. Paris, 1731; 2: 253-4.

4. Gross SD: Systems of Surgery, quoted by Mann FC. Bull Johns Hopkins Hospital 1914; 25: 205-12.

5. Cooper A: The Principles and Practice of Surgery. Edited by Cox. London. 1836.

6. Horner: Surgical Skeleton Medical Examiner and Record of Medical Sciences, new series 9, pp 1-24, 1852.

7. Barnes JK: Surgical history of the medical and surgical history of the rebellion, part 2, Washington, DC, U.S. Army 1876; II: 15.

8. Report to the Surgeon General of the Army. 1900; 328.

9. Surgeon General, U.S. Army: The Medical Department of the United States Army in the World War. Surgery 1927; 2: 185.

10. Blalock A: Experimental shock: cause of the low blood pressure produced by muscle injury. Arch Surg 1930; 20: 954.

11. Hardaway RM, McKay DG, Williams JH: Lower nephron nephrosis (ischemic nephrosis). Am J Surg 1954; 87: 41-9.

12. Santy P: Marquis Moulinier, De shock traumalique dans les blessures de guerre: analyse d'observations. Bull Med Socchlr 1918; 44: 205.

13. Hardaway RM: Shock: The Reversible Stage of Dying, p 7. Chicago: Mosby Year Book Publishers, 1988.

14. Hardaway RM: The Army at Pearl Harbor. J Am Coll Surg 2000; 190: 593-600.

15. Hardaway RM: Care of the Wounded in Viet Nam. Manhattan, KS, Sunflower University Press, 1988.

16. Medical Department of United Slates Army: Surgery in World War II. Washington, DC, Office of the Surgeon General. U.S. Army.

17. Department of Commerce: Bureau of Census Statistical Abstract of the United States, 1995.

18. Hardaway RM: Shock lung. Int Surg 1972; 58: 311-5.

19. Hardaway RM, James JM, Anderson RW, et al: Intensive study and treatment of shock in man. J Am Med Assoc 1967; 199: 779-90.

20. Hardaway RM, Williams CH, Marvasti M, et al: Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med 1990; 18: 1413-8.

21. Hardaway RM, Williams CH: Prevention of multiple organ failure with plasminogen activator. Curr Ther Res 1991; 59: 721-22.

22. Hardaway RM: Traumatic and septic shock alias post-trauma critical illness. Br J Surg 1998; 85: 1473-9.

23. Hardaway RM, Williams CH, Vasquez Y: DIC in sepsis. Semin Thromb Hemost 2001; 27: 577-83.

24. Hardaway RM, Harke H, Tyroch AH, et al: Treatment of severe acute respiratory distress syndrome: a final report on a Phase I study. Am Surgeon 2001; 67: 377-82.

25. Stephenson J: Reflecting and regrouping after failed trials. Sepsis researchers forge on. J Am Med Assoc 1996; 176: 565-6.

26. Bone RC: Why sepsis trials fail. J Am Med Assoc 1996; 176: 565-6.

27. Kraff P, Fridich P. Pernerstorfer T, et al: The acute respiratory distress syndrome. Intensive Care Med 1996; 22: 519-29.

28. The World Almanac and Book of Facts 1995, p 163. Malwah, NJ, Funk and Wagnalls, 1995.

29. Faue AE: MOF, MODS and SIRS: why no magic bullets. Arch Surg 1997; 132: 703-7.

30. Zeni F, Freeman B, Natanson C: Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997; 25: 1095-2000.

31. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 29(Suppl 7): S53-S60.

Guarantor: BG Robert M. Hardaway, MC USA (Ret.)

Contributor: BG Robert M. Hardaway, MC USA (Ret.)

6121 Plnehurst, El Paso, TX 79912.

This manuscript was received for review in March 2003. The revised manuscript was accepted for publication in July 2003.