• Like

Loading…

Flash Player 9 (or above) is needed to view presentations.
We have detected that you do not have it on your computer. To install it, go here.

Transfusion and Shock

  • 1,306 views
Published

 

Published in Health & Medicine , Business
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
1,306
On SlideShare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
53
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. 1 TRANSFUSION AND SHOCK 2 FUNDAMENTALS OF MANAGEMENT IN SURGICAL PATIENTS 1 Page 1 of 119 2
  • 2. 1INTRODUCTION 2 Transfusion practices and shock are the topics chosen for this issue of Selected Readings 3 in General Surgery (SRGS). In the section dealing with transfusion practices we focus on risks 4 of transfusion, methods for salvaging blood and reducing transfusion volume, and manage- 5 ment of the patient who refuses blood and/or blood products. We then move on to a dis- 6 cussion of shock. Classifications of shock have evolved in the last five decades. Currently 7 shock states are classified as hemorrhagic/traumatic, neurogenic (spinal cord injury), cardio- 8 genic, obstructive (pulmonary embolus, pericardial tamponade), and distributive (septic, in- 9 flammatory). In this issue of SRGS, a discussion of shock from hemorrhage and/or injury, 10 and septic shock are offered. Other forms of shock have been discussed in previous issues 11 of SRGS dealing with trauma and venous disease. 12Transfusion in surgical patients—risks and current practices 13 Blood and blood products are life-saving substances and critically important tools used 14 by surgeons to manage critically ill and injured patients. Risks associated with blood product 15 administration include hemolytic transfusion reactions (which usually result from errors in 16 processing and administration), disease transmission, and transfusion-related lung injury. 17 Stored leucocytes may cause febrile acute transfusion reactions. Leucocytes also mediate 18 the process of alloimmunization to platelets. Furthermore, transfusions are associated with 19 immune modulation related to the duration of storage. Transfusion of older units of banked 20 red blood cells in patients with few risk factors for infection has been associated with an in- 21 creased risk of infection and mortality. Measures to reduce the number of leucocytes in 1 Page 2 of 119 2
  • 3. 1 banked blood have not been universally effective in preventing presumed leucocyte-medi- 2 ated changes in the immune system. 3 Because blood products are, for the most part, administered after acquisition from un- 4 related donors and stored for varying periods before administration to patients, functions 5 of transfused red blood cells, platelets, and coagulation proteins are not normal and may 6 not immediately correct abnormalities in oxygen delivery or clot formation. The pathophysi- 7 ologic effects of continued bleeding, combined with the need for multiple transfusions, lead 8 to a coagulopathic state. In this and following sections of the overview, we discuss these 9 problems. 10 The first article reviewed is by Goodnough1 in Critical Care Medicine, 2003. The article is 11 entitled “Risks of blood transfusion.” The author begins by noting that the rarity of serious 12 transfusion reactions and transfusion-related disease transmission has made estimation of 13 the risks of transfusion difficult. Mathematical models have been developed to predict 14 transfusion risk and these models assume that disease transmission is most likely to occur 15 when blood from infected donors is collected in the “window period” when the donor is in- 16 fectious but donor-screening tests are not positive. This assumption may lead to underesti- 17 mation of disease transmission risk. Another potentially hazardous assumption is related to 18 the fact that patients who receive blood have 1- and 10-year mortality rates ranging from 19 24%-52%. The patients may not survive long enough for the diagnosis of disease transmis- 20 sion to be made. Despite these limitations, Goodnough emphasizes that risks of transmis- 21 sion of viral diseases (mainly hepatitis B and C and human immunodeficiency virus) are low- 1 Page 3 of 119 2
  • 4. 1 er than at any time in the history of transfusion. He presents a table indicating a risk of hep- 2 atitis transmission of 1/220,000 transfusions to 1/800,000 transfusions, and a risk of human 3 immunodeficiency virus transmission of 1/1.4 million transfusions. Available data show that 4 risk continues to decline with improved practices of donor screening, particularly the re- 5 cently implemented practice of nucleic acid testing. 6 The author moves on to discuss specific aspects of viral disease transmission. He notes 7 that the first documented instance of transmission of human immunodeficiency virus in 8 banked blood occurred in 1982. Before screening blood tests were available, blood banks 9 began screening donors for specific characteristics and allowing donors to self-exclude their 10 blood after donation. This practice resulted in an immediate decline in instances of trans- 11 mission. With the implementation of antibody testing in March 1985, the rate of reported 12 transmissions of human immunodeficiency virus decreased from more than 700/year to 13 5/year. Additional small increments of progress occurred after the introduction of screening 14 for p24 antigen. Hepatitis B virus transmission declined markedly after the introduction of 15 third-generation tests for the hepatitis B surface antigen. Hepatitis B currently accounts for 16 only 10% of the instances of hepatitis transmission in transfused blood products. Hepatitis C 17 is an important viral disease that can be transmitted via transfusion. Transfusion-related 18 hepatitis C leads to chronic disease in more than 80% of cases. Twenty percent of infections 19 progress to cirrhosis; one to five percent of infections lead to hepatocellular carcinoma. The 20 mortality risk for hepatitis C over 25-30 years after transfusion-related infection is nearly 21 15%. 1 Page 4 of 119 2
  • 5. 1 Screening for human immunodeficiency and hepatitis viral disease is very effective. 2 Since 1999, worldwide, only two cases of human immune deficiency virus infection and one 3 case of hepatitis C have been reported where all screening tests performed in the donors 4 were negative. 5 Cytomegalovirus infection related to transfusion of blood products is an important 6 cause of mortality and morbidity in patients immunocompromised from treatment for ma- 7 lignant disease. The largest risk is observed in patients undergoing stem cell or bone mar- 8 row transplantation. The prevalence of cytomegalovirus infection in these patient groups is 9 60% and viral disease develops in up to one-half of the infected patients. Viral disease can 10 be reduced but not eliminated by using transfusions of blood cells from donors with nega- 11 tive serum tests of cytomegalovirus infection. The author cites data to show that granulo- 12 cyte transfusions from serum-negative donors resulted in seroconversion in 1%-4% of pa- 13 tients. Other data indicate that the risk of infection is not different with cells originating 14 from donors who are positive for cytomegalovirus infection compared with negative, but 15 the risk of clinically overt viral disease seems to be less when negative donor cells are used. 16 Cytomegalovirus infection is much less common in patients who undergo autologous stem 17 cell or bone marrow transplantation. This protection is observed despite equivalent rates of 18 serum assay conversion and urinary excretion of viral products in patients undergoing allo- 19 geneic or autologous bone marrow transplantation. Goodnough notes that 10%-50% of 20 blood donors test negative for cytomegalovirus infection. Leuco-reduction seems to reduce 21 the risk of cytomegalovirus infection also. Current recommendations state that patients re- 1 Page 5 of 119 2
  • 6. 1 ceiving allogeneic or autologous bone marrow transplants should receive blood products 2 donated by serum-negative patients; these products should undergo leuco-reduction. 3 Bacterial infection of banked blood products can cause rare but often fatal sepsis in pa- 4 tients who receive transfusion. Yersinia enterocolitica is the most common pathogen infect- 5 ing red blood cell units. The contamination rate is less than 1/million donated units but clini- 6 cal infection may become manifest during the transfusion and the mortality rate for clinical 7 infection is 60%. Platelets carry the greatest risk for bacterial infection because these units 8 are stored, for up to five days, at temperatures of 20-24°C. This means that stored platelets 9 are an excellent culture medium for bacteria. Goodnough cites surveillance data indicating 10 that bacterial contamination occurs in one of every 1000-2000 units. Because four million 11 platelet units are transmitted annually in the United States (25% of these are apheresis 12 platelets), estimates are that 300-1000 cases of bacterial sepsis may be expected each year. 13 Pooled platelets carry a higher risk than apheresis platelet transfusions. Liquid medium cul- 14 turing of platelets has been implemented in an effort to reduce the risk of infection. 15 Other infectious diseases that can potentially be transmitted by blood products include 16 leukemias caused by human lymphotrophic virus 1 or 2. Only a single case had been report- 17 ed at the time of publication of Goodnough’s article . Epstein-Barr virus disease, leishmania- 18 sis, babesiosis, toxoplasmosis, brucellosis, malaria, Chagas disease, West Nile virus, and pri- 19 on disease can be transmitted potentially by blood products, but such instances are ex- 20 tremely rare. 1 Page 6 of 119 2
  • 7. 1 Leucocytes in stored blood have been implicated in the production of febrile transfusion 2 reactions, postoperative infection, transfusion-related lung injury (discussed in SRGS, Vol. 3 35, No. 8), and increased recurrence risk for colon cancer. In an article by Bernard and coau- 4 thors2 (reviewed in SRGS, Vol. 35, No. 7), an increased risk for mortality and surgical site in- 5 fection was noted using an analysis of data from the NSQIP database. Currently universal 6 leuco-reduction programs have not resulted in significant protection against these compli- 7 cations. Another report by Weinberg and coauthors3 presents data on injured patients in a 8 retrospective study. These authors had previously observed an increased risk for mortality 9 and infectious morbidity in injured patients who received large volumes of transfused 10 blood. This association was particularly pronounced in patients who received blood with 11 storage age > 14 days. In this study, the authors focused on patients less severely injured 12 (injury severity score of less than 25) who did not receive early or large volume transfusion. 13 They documented an increased risk for mortality, renal failure, and pneumonia when these 14 less severely injured patients received any transfusion of blood with a storage age of > 14 15 days. The blood administered to these patients was leuco-reduced. These authors note that 16 transfusion carries a risk of mortality and infection related to the age of stored blood, and 17 this risk is not eliminated by leuco-reduction. Their data confirm a number of other analyses 18 of transfusion risk in injured patients. Goodnough cites additional data that indicate no re- 19 duction in the risk of infection after cardiac operations when leuco-reduced blood was used. 20 Another study noted no change in the risk of recurrence of colorectal cancer when a leuco- 21 reduction program was implemented. 1 Page 7 of 119 2
  • 8. 1 Additional evidence of immune system alterations occurring in patients transfused with 2 blood and blood products is found in an article by Dunne and coauthors4 in the Journal of 3 Trauma, 2008. These authors note that micro-chimerism, or the persistence of donor cells 4 in the circulation of the recipient, represents additional evidence of immune modulation oc- 5 curring after transfusion. These authors investigated the role of fresh versus banked blood 6 in producing micro-chimerisms in combat casualties. They studied 26 severely injured sol- 7 diers who had received fresh whole blood, banked blood, or blood plus platelets. Blood 8 samples from these patients were compared with blood samples from patients who had re- 9 ceived no transfusions. There was no evidence of micro-chimerism in the patients who had 10 not been transfused. Half of the patients who had received fresh whole blood had evidence 11 of micro-chimerism. A similar proportion of patients who had received banked blood or 12 blood plus platelets showed evidence of micro-chimerism. The authors cite data from other 13 studies that confirm the significant occurrence of micro-chimerism. The clinical significance 14 of this finding is unknown currently but micro-chimerism is known to be associated with 15 graft-versus-host disease in patients receiving bone marrow transplants. 16 Most of the morbidity from blood transfusion results from transfusion reactions associ- 17 ated with errors of cross matching or blood product administration. Goodnough1 notes that 18 errors in the blood bank or misidentification of recipients occur at a rate of 1/14,000-18,000 19 transfusions in the United States and Great Britain. Approximately two-thirds of these 20 events are the result of patient misidentification or failure to recognize a transfusion reac- 21 tion. One-third of the errors occur during crossmatching and blood labelling processes in 22 the blood bank. Approximately 10% of hemolytic transfusion reactions are fatal. The mortal- 1 Page 8 of 119 2
  • 9. 1 ity rate for error-related transfusion complications is roughly twice that for all transfusion- 2 related mortalities from infection. 3Editorial comment 4 Transfusion of blood and blood products is not without risk. To date, measures to estab- 5 lish the specific mechanism of transfusion-related immune modulation have not clearly 6 identified the factors responsible for these changes. Knowledge of these alterations has led 7 to the development of conservative transfusion protocols. It is now recognized that transfu- 8 sion can be safely withheld in stable patients with hemoglobin levels ≥ 7gm/dL. Higher 9 hemoglobin targets may be required in the critically ill and unstable, or in patients with se- 10 vere coronary artery disease. Blood and blood products are best used for specific indica- 11 tions; protocols that identify specific goals of blood product use and document evidence of 12 achievement of carefully chosen outcomes will provide surgeons the best means to achieve 13 effective use of blood and blood products. 14Current transfusion practices 15 Practice guidelines for the use of blood and blood products in the perioperative period 16 were developed and promulgated by the American Society of Anesthesiologists. A summary 17 of the practice guidelines is found in a report published in Anesthesiology in 2006.5 The 18 guidelines begin with a review of practical measures for detection of patients who might re- 19 quire blood or blood products. The initial evaluation includes, at a minimum, review of med- 20 ical records, detailed history focusing on historical evidence of congenital disorders of coag- 21 ulation, hemoglobinopathy, and other blood disorders. Additional findings in the history will 22 provide information on the risk of ischemic cardiac disease, any history of use of prescrip- 1 Page 9 of 119 2
  • 10. 1 tion drugs, over-the -counter drugs, or herbal remedies that alter coagulation, and history 2 of prior transfusion. Evidence of prior exposure to drugs (aprotinin) that could precipitate 3 allergic reaction on repeat administration is sought. The patient and family are questioned 4 to document the willingness, or lack of willingness, to accept blood transfusion. Recom- 5 mended laboratory assessments include hemoglobin and hematocrit determinations and a 6 coagulation profile. Management of patients who refuse blood products will be discussed in 7 a later section of the overview. 8 The guidelines note that specific evidence to support use of drugs such as aprotinin, ep- 9 silon-amino caproic acid, and tranexamic acid is lacking except for certain cardiac or or- 10 thopaedic procedures associated with significant risk of bleeding (for example, reoperation 11 for open cardiac surgery and reoperation for joint replacement). They emphasize that anti- 12 fibrinolytic drugs have been implicated in vascular graft thrombosis and severe allergic reac- 13 tions have resulted from aprotinin use. 14 Evidence to document the value of preoperative erythropoietin treatment of anemia is 15 not available although certain patient groups such as patients with renal disease, anemia of 16 chronic disease, and patients who refuse transfusion may benefit. Several weeks of treat- 17 ment are required for correction of anemia using erythropoietin. The guidelines note that 18 preoperative collection of autologous blood has been associated with reduced transfusion 19 risks. They emphasize, however, that severe transfusion reactions (associated with misiden- 20 tification of patients) and bacterial infections have been reported from programs using pre- 21 operative collection of autologous blood. 1 Page 10 of 119 2
  • 11. 1 The guidelines recommend cessation of drugs such as warfarin, aspirin, and clopidogrel 2 before elective operations. Intervals of one to three weeks are required for reversal of the 3 affects of clopidogrel and aspirin on platelets. The method chosen for preoperative restora- 4 tion of clotting function depends on a careful assessment of the type, urgency, and risk of 5 the surgical procedure chosen. The risk of thromboembolic complications that might occur 6 soon after the chronic warfarin dose is decreased or eliminated is also assessed. For exam- 7 ple, patients with cancer are at increased risk for thromboembolic complications. By con- 8 trast, recent data indicate that stroke risk reduction from warfarin treatment in patients 9 with atrial fibrillation is overcome by the risk of bleeding when patients are under 70 years 10 of age and have minimal stroke risk.6 Warfarin cessation can result in restoration of clotting 11 capability as evidenced by an international normalized ratio of 1.5 within several days to 12 one week. Operation is usually safe at this level of INR and re-starting of warfarin when the 13 patient is stable and free of significant bleeding risk usually results in rapid and dependable 14 re-anticoagulation. If reversal of warfarin affects is needed within 48-72 hours, intravenous 15 vitamin K is indicated. More rapid reversal than this will require use of fresh frozen plasma 16 or, occasionally, recombinant activated factor VII. Use of recombinant factor VII is discussed 17 in more detail later in the overview. Reversal of warfarin with vitamin K or fresh frozen plas- 18 ma is associated with more difficult re-anticoagulation postoperatively. 19 The decision to transfuse before, during, and after an operation is based on clinical as- 20 sessments of the volume of blood loss and the physiologic effects of blood loss. Monitoring 21 of ongoing blood loss requires clear and frequent communication between the surgical 22 team and the anesthesiology team. Use of assessments of blood pressure, heart rate, arteri- 1 Page 11 of 119 2
  • 12. 1 al oxygen saturation, central venous pressure, pulmonary artery occlusion pressure, central 2 venous (or mixed venous) oxygen saturation, and lactate levels depends on type of opera- 3 tion and patient risk. For patients with a history of cardiac dysfunction, intraoperative 4 echocardiography may be indicated. The practice guidelines note that assessments of blood 5 pressure, heart rate, and arterial oxygen saturation are routine during surgical procedures, 6 but the literature is unclear about specific contributions these assessments make with re- 7 gard to transfusion. A synthesis of various information points will usually be required to 8 support clinical decisions. Intraoperative measurement of hemoglobin and hematocrit is 9 common but these values may not reflect end-organ perfusion status. The guidelines note 10 that transfusion is not needed in stable patients who do not have cardiac disease until the 11 hemoglobin level is below 6 gm/dL. Transfusion is definitely not needed when the 12 hemoglobin level is above 10 gm/dL. 13 The decision to transfuse patients whose hemoglobin levels are between 6 gm/dL and 14 10 gm/dL is made based on assessment of each patient’s cardiovascular reserve, the risk of 15 ongoing blood loss, and the status of end organ perfusion. The safety of lower hemoglobin 16 levels in stable, critically ill patients was documented in a 1999 report by Hebert and coau- 17 thors.7 An appreciation of the risks of transfusion and an understanding of the limitations of 18 the blood supply has stimulated caution and overall conservatism about use of banked 19 blood and blood products. Benefits of a conservative approach to transfusion are most obvi- 20 ous in patients under the age of 55 who have no clinical evidence of cardiovascular disease. 21 Assessment and monitoring of patients with blood loss and shock are discussed in later sec- 22 tions of the overview. 1 Page 12 of 119 2
  • 13. 1 Coagulopathy from massive transfusion is discussed in a later section. The practice 2 guidelines support the use of fresh frozen plasma for this condition as well as cryoprecipi- 3 tate for the support of fibrinogen levels. Recombinant activated factor VII may be useful as 4 “rescue therapy” for patients with microvascular bleeding. The guidelines note that mea- 5 sures such as normovolemic hemodilution and deliberately lowered venous pressures may 6 be helpful in selected patients undergoing cardiac, hepatic, and orthopedic procedures. 7Techniques of perioperative blood salvage 8 Blood recovery and reinfusion during and/or after an operation is potentially a means of 9 reducing the use of blood and blood products in surgical patients. Collection and reinfusion 10 of blood after tube thoracostomy for traumatic hemothorax has been shown to be safe. Be- 11 cause liver surgeons have recognized the value of low central venous pressure as a means 12 of reducing blood loss during liver parenchymal transection, there is interest in collecting 13 blood before liver transaction, and re-infusing the blood once liver hemostasis has been ob- 14 tained. This topic is addressed in an article by Hashimoto and coauthors8 in Annals of 15 Surgery, 2007. These authors conducted a randomized trial comparing one group of living 16 liver donors who had removal of a volume of blood equal to 0.7% of body weight with a 17 group of patients treated with conventional management of liver resection. The endpoints 18 of interest were the amount of blood loss during liver parenchymal transection and the vol- 19 ume of banked blood infused after parenchymal transection. The patients who had removal 20 and reinfusion of blood had significantly less blood loss and used less banked blood than the 21 patients did in the comparison group. The trend toward smaller blood product use in pa- 22 tients who had intraoperative blood salvage was identified, but this difference was not sta- 1 Page 13 of 119 2
  • 14. 1 tistically significant. Intraoperative blood salvage is used frequently in cardiac surgical pro- 2 cedures. The value of this approach in abdominal operations is debated. Limitations to the 3 use of intraoperative blood salvage in abdominal operations are concerns over depletion of 4 clotting factors in salvaged blood and the potential for bacterial contamination during ab- 5 dominal procedures. 6 Recovery of postoperative blood drainage from the operative site is possible using 7 closed drainage systems that collect blood through a filtration system into a blood adminis- 8 tration bag. This approach is used in Europe and is especially well suited for patients under- 9 going orthopaedic procedures that, predictably, have significant postoperative blood 10 drainage. An article describing the potential value of postoperative blood salvage by Mirza 11 and coauthors9 appeared in the Annals of the Royal College of Surgeons, 2007. The authors 12 report results in 109 patients undergoing total hip replacement. The amount of periopera- 13 tive blood loss (as indicated by the change in hemoglobin level) in these patients was com- 14 pared with a group of historical control patients. Patients who had blood salvage had a 15 smaller perioperative hemoglobin drop. Nine percent of the salvage patients required peri- 16 operative transfusion of banked blood compared with 30 percent of the historical control 17 group. The authors conclude that this approach may reduce use of banked blood in patients 18 undergoing operations associated with predictable postoperative drainage of uncontami- 19 nated blood. 20Management of patients who refuse blood and blood products 21 Surgeons inevitably will encounter patients who decline all or some parts of proposed 22 strategies for care of surgical conditions. Use of blood and blood products is unacceptable 1 Page 14 of 119 2
  • 15. 1 to some patients. Typically, this patient group includes, but is not limited to, Jehovah’s Wit- 2 nesses. A significant body of knowledge has accumulated that has permitted safe surgical 3 care for Jehovah’s Witnesses and this knowledge can be used to optimize the care of any 4 patient who declines the use of blood and blood products. In this section of the overview, 5 we will discuss two articles that focus on the elements of care for Jehovah’s Witnesses. The 6 first article discussed is from Hughes and coauthors10 in the Journal of Trauma, 2008, enti- 7 tled “The contemporary approach to the care of Jehovah’s Witnesses.” This article is sup- 8 plied as a full-text reprint accompanying this issue of SRGS. The authors begin by providing 9 background on the origins and development of the Jehovah’s Witnesses sect. They note 10 that the sect evolved from a Bible study group formed by Charles Taze Russell in Alleghany, 11 Pennsylvania, in 1869. Based on extensive study, the group identified what they perceived 12 as fundamental errors of interpretation of biblical text. The interpretation of the group led 13 to the perception that there were philosophical errors in the practice of Christian doctrine. 14 The literal interpretations of scripture by the group evolved into commands. Obedience to 15 these commands, in the eyes of the adherents to this doctrine, was required for any chance 16 at life after death. In 1879, the group was known as “Bible Students” and the group pro- 17 duced a religious magazine later called The Watchtower. In 1931, the group adopted the 18 name “Jehovah’s Witnesses.” Currently, this is the fastest growing religious sect in the west- 19 ern world with nearly 7 million members. In the United States, more than 1 million mem- 20 bers are enrolled. The sect is based on person-to-person ministry and the group is noted for 21 their work in literacy and disaster relief. Each member must commit a certain amount of 22 time each month to ministry. Fundamental to their beliefs is the recognition that God’s 1 Page 15 of 119 2
  • 16. 1 Kingdom is the only legitimate government. Thus, members of the sect do not join service 2 organizations or serve in the military. They remain neutral politically. 3 The rejection of blood transfusion was codified in the belief system of Jehovah’s Wit- 4 nesses in 1945. The belief is based on the literal interpretation of several Old Testament 5 passages that prohibit the eating of food that contains blood. In 1951, a Watchtower article 6 cited the use of intravenous fluids in hospitals as “intravenous feeding” and declared that 7 the intravenous administration of blood was equivalent to “feeding” of blood and was, 8 therefore, unacceptable based on the interpretation of Old Testament texts. The authors 9 note that the prohibition has been interpreted to extend to the use of banked blood, blood 10 cells, plasma, and platelets. Preoperative autologous blood donation is prohibited because 11 the blood is separated from the body. This interpretation permits the use of intraoperative 12 blood salvage as long as the collection circuit is continuous with the administration device 13 so that separation of the blood from the patient’s body does not occur. In 2000, the Watch- 14 tower Society issued a statement saying that the Jehovah’s Witness sect would no longer 15 excommunicate members who accepted transfusion. Instead, the statement indicated that 16 the member would be judged to have voluntarily given up membership in the sect based on 17 having accepted blood transfusion. It is important to note, as Hughes and colleagues em- 18 phasize, that there is variability among Jehovah’s Witnesses about the acceptability of blood 19 derivatives. Some adherents will accept albumin, immunoglobulins, and factor concen- 20 trates. Recombinant erythropoietin may also be accepted. Some Jehovah’s Witnesses do 21 not believe that they have committed an act requiring that they leave the sect if the agree- 22 ment to accept a transfusion is made privately with the treating physician or surgeon. In 1 Page 16 of 119 2
  • 17. 1 such circumstances, patient confidentiality is obviously critical. Against this approach is the 2 frequent presence of a member of the sect physically in the care area to make certain that 3 the treated member does not receive a transfusion or any unacceptable blood product. 4 It is important that surgeons decide, ahead of time, whether they will be able to accept 5 the fact that the patient may not accept transfusion. The surgeon will need to reconcile the 6 patient’s wishes with the possibility that a “preventable” death may occur if transfusion is 7 withheld. Acceptable arrangements for transfer of the care of the patient to an alternate 8 surgeon may become necessary. Hospital resources are available for patients and treating 9 surgeons. Ethics committees, risk management group, and transfusion medicine specialists 10 are potentially valuable. In many cities, Jehovah’s Witness groups offer consultative advice 11 for patients and treating surgeons. 12 Legal aspects of the care of Jehovah’s Witnesses are grounded in the 1914 legal decision 13 that established the right of patients to refuse treatment. The decision to exercise this right 14 by a patient, particularly a Jehovah’s Witness, should be confirmed in writing by the patient. 15 Many Jehovah’s Witnesses carry an advance directive document with them at all times. 16 Hughes and associates stress the importance that this knowledge is made known to all care- 17 givers. Thus, the medical record should display, predominantly, the wishes of the patient. 18 It is worth noting that many court decisions have determined that parents do not have 19 the right to refuse transfusion for their children. The ability of adolescents, or mature mi- 20 nors, to refuse transfusion is less clear and rulings have varied depending on the jurisdic- 1 Page 17 of 119 2
  • 18. 1 tion. Surgeons will need to consult hospital risk management and counsel for assistance in 2 dealing with these issues. 3 Where time permits full discussion of the risks and benefits of operation, formal in- 4 formed consent will be possible. What the surgeon should do to proceed with treatment 5 when the informed consent discussion has not occurred is challenging. The presence of an 6 advance directive card does not preclude the necessities of obtaining informed consent or 7 proceeding with needed treatment in emergencies where informed consent cannot be ob- 8 tained. This means that the decision to transfuse, or withhold transfusion for a Jehovah’s 9 Witness patient, in an emergency may be viewed, in retrospect, as a basis for legal action 10 against the surgeon and/or hospital. To facilitate management of Jehovah’s Witness pa- 11 tients in emergencies, early knowledge of the religious beliefs of the patient is necessary. 12 This information should be actively sought and made available to all caregivers. Hughes and 13 colleagues cite data from a Level I trauma center that indicated that the necessary knowl- 14 edge was frequently not obtained. In this analysis, 5% of the Jehovah’s Witness patients re- 15 ceived transfusion but in only one case was this reasonably preventable. A discussion of 16 some of the measures available for minimizing blood loss as well as examples of advance di- 17 rective and consent forms are found in an article authored by Gohel and coauthors11 in the 18 Annals of the Royal College of Surgeons of England, 2005. 19 It is important to note that data about outcomes of injured Jehovah’s Witness patients 20 have not shown an increased risk of death from injury in this group. Earlier decision for op- 21 eration has been consistently noted in studies of the management of injured Jehovah’s Wit- 1 Page 18 of 119 2
  • 19. 1 nesses patients. In elective surgery patients, measures to prevent bleeding and improved 2 operative approaches have resulted in improved outcomes for Jehovah’s Witnesses as not- 3 ed in data cited by these authors. Additional data have shown that postoperative anemia 4 (hemoglobin level of 6 gm/dL) did not predict mortality or morbidity. Data indicating an in- 5 creased risk of mortality have been reported for patients with chronic severe anemia but 6 anemia, in this setting, has been interpreted as evidence of increased overall risk for this pa- 7 tient group. 8 Hughes and colleagues note that management of Jehovah’s Witnesses should include 9 measures to minimize iatrogenic blood loss (phlebotomy), minimize intraoperative blood 10 loss (hemodilution, intraoperative blood salvage), enhance red blood cell production, en- 11 sure hemostasis, and maintain blood volume with electrolyte or colloid solutions. Protocols 12 for elective management of Jehovah’s Witness patients have avoided transfusion without 13 increasing operative risk. A report on the effectiveness of a transfusion-free program for the 14 conduct of orthotopic liver transplantation in Jehovah’s Witnesses is the subject of an arti- 15 cle by Jabbour and coauthors12 in Archives of Surgery, 2006. These authors reported on a 16 comparison of patients treated by a formal protocol approach to transfusion avoidance 17 compared with a group of historic controls. The protocol stressed the maintenance of low 18 venous pressure, use of acute normovolemic hemodilution, and intraoperative blood sal- 19 vage. These authors noted that their protocol group was sicker as judged by MELD scores 20 compared with the non-protocol historic controls. Despite this, operative mortality in the 21 transfusion-free patients was not increased. These data indicate that avoidance of transfu- 22 sion in complex elective surgery is safe when a protocol approach is used. 1 Page 19 of 119 2
  • 20. 1Editorial comment 2 From the perspective of the editor, it seems clear that transfusion avoidance is not asso- 3 ciated with increased operative risk in elective operations and that reductions in blood 4 product use are associated with decreased risk for transfusion-related complications. Pre- 5 planned protocols designed to identify Jehovah’s Witness patients (and, in fact, any pa- 6 tients) who are unwilling to accept blood and blood products are helpful. Free and open dis- 7 cussion of risks and benefits with the patient is critically important. Use of institutional and 8 community resources to accomplish these goals is helpful. In an emergency when fully in- 9 formed consent is not obtainable, or when dealing with children of Jehovah’s Witnesses 10 parents, therapeutic choices should be directed toward obtaining the optimum safe out- 11 come for the patient. 12Pathophysiology of shock 13 In this section of the overview, derangements in homeostasis that are unique to various 14 forms of shock will be reviewed. Along with this discussion, we will emphasize the physio- 15 logic alterations that are common to most or all forms of shock. 16Shock due to hemorrhage and trauma 17 Traditionally, shock from hemorrhage and trauma has been thought to proceed sequen- 18 tially through stages of compensation that include a phase of catecholamine mediated vaso- 19 constriction and redistribution of blood volume toward the brain and heart and away from 20 skeletal muscle, kidneys, and splanchnic circulation. During this phase, movement of pro- 21 teins, water, and ions from the extracellular fluid space into the intravascular space pro- 22 vides partial refilling of the volume lost to bleeding. This response, coupled with cate- 23 cholamine-mediated vasoconstriction, serves to support blood pressure. A subsequent 1 Page 20 of 119 2
  • 21. 1 phase of partial compensation where the patient is mildly to moderately hypotensive oc- 2 curs; this is followed, within a variable interval, by a final phase characterized by systemic 3 vasodilation, bradycardia, and death. The duration of this phase is determined mainly by 4 the rate and volume of continuing bleeding. The phase of partial compensation has been 5 envisioned as a phase wherein autoregulation of vascular beds fails and tissue blood flow 6 becomes pressure dependent. During this phase, cellular hypoxia is thought to lead to disor- 7 dered mitochondrial function and a shift to anaerobic metabolism. Accumulation of acid 8 metabolites and lactate are evidences of these phenomena. As partial compensation pro- 9 ceeds to decompensation, cell membrane function fails with movement of water and ions 10 from the extracellular space into the intracellular space. 11 The physiologic construct described above has driven the development of treatment 12 protocols for shock that were based on early identification of bleeding sites and control of 13 hemorrhage, replacement of red blood cells, and replacement of volumes of electrolyte so- 14 lution calculated based on expected losses from the extracellular fluid. Among the major 15 features of understanding of shock and resuscitation that have undergone modification in 16 the past two decades are, first, an understanding that patients with compensated and par- 17 tially compensated shock have expected losses of extracellular fluid smaller than those cal- 18 culated on the basis of experimental evidence from models of severe, decompensated 19 shock. In fact, the most common clinical settings in which large volume electrolyte fluid re- 20 suscitation is required are encountered in patients with massive blood loss from penetrat- 21 ing torso trauma and in combat injuries. Further, it is now clear that restoration of effective 22 tissue perfusion pressure and oxygen delivery are the most important resuscitation targets, 1 Page 21 of 119 2
  • 22. 1 and restoration of arterial pressure to “normal” is not necessary. In fact, overzealous 2 restoration of blood pressure may lead to recurrent bleeding and decompensation. Finally, 3 current understandings hold that splanchnic ischemia leads to movement of substances into 4 intestinal lymph that contribute to creation of a proinflammatory state and progression to 5 multiple systems organ failure in patients who are genetically susceptible to the develop- 6 ment of dysfunctional systemic inflammatory responses. In this section of the overview, we 7 review some of the research and clinical data that have contributed to our current under- 8 standings of shock from hemorrhage and trauma. 9 Experimental evidence demonstrating that tissue blood flow was reduced by microvas- 10 cular occlusion because of cell swelling and depolarization during shock stemmed from 11 work completed by several investigators. One example of this research is found in an older 12 article by Borchelt and coauthors13 in the Journal of Trauma, 1995. These authors earlier 13 demonstrated that cellular dysfunction in shock was mediated by a protein they called “cir- 14 culating shock protein.” This substance was shown to cause cellular depolarization that 15 could lead to sequestration of extracellular fluid in the cells. In this study, they hypothesized 16 that this substance could produce migration of water and ions into cells. They incubated 17 cells with the protein and used a double isotope indicator technique to measure cell water. 18 They were able to demonstrate movement of water into cells in response to exposure of 19 cells to the protein; cells used in this experiment were skeletal muscle cells. This paper was 20 presented during the plenary session of the annual meeting of the American Association for 21 the Surgery of Trauma, September 1994. The discussion that followed the presentation ac- 22 companies the article. The discussants agree that cell swelling is an important phenomenon 1 Page 22 of 119 2
  • 23. 1 in shock but limitations of isotope techniques have made determination of the magnitude 2 of cell swelling and fluid migration into cells difficult. Debate has continued about the loca- 3 tion of cell swelling, the types of cells that swell, and magnitude of the contribution of the 4 fluid migration into cells. 5 Defining one location of cell swelling leading to fluid sequestration, cellular hypoxia, and 6 elaboration of proinflammatory mediators is the topic of an article by Zakaria and coau- 7 thors14 in Surgery, 2007. These authors produced severe hemorrhagic shock in a rodent 8 model and used intravital videomicroscopy and Doppler flow measurements to determine 9 microvascular diameters and flow rates. An index of functional capillary density was calcu- 10 lated to estimate the effective cross-sectional area of perfused microvessels. All measure- 11 ments were made in an isolated segment of rat ileum. The authors investigated the follow- 12 ing hypotheses: 1) that endothelial swelling induced by activation of the sodium/hydrogen 13 ion exchanger during shock would reduce tissue blood flow; 2) that conventional resuscita- 14 tion with blood and electrolyte solution would not prevent cell swelling; and 3) that direct 15 inhibition of the sodium/hydrogen ion exchanger with topical amiloride would prevent cell 16 swelling and preserve microcirculatory flow. The authors were able to document cell 17 swelling that reduced microvascular flow and functional capillary density. Conventional re- 18 suscitation did not restore microcirculatory function even though central hemodynamics 19 was returned to baseline levels. When cell swelling was prevented by blocking the 20 sodium/hydrogen ion exchanger, cell swelling was prevented and microvascular flow was 21 restored by conventional resuscitation. As a final component of this experiment, the au- 22 thors prevented cell swelling by bathing the ileum tissue in peritoneal dialysis fluid and not- 1 Page 23 of 119 2
  • 24. 1 ed that direct peritoneal resuscitation using peritoneal dialysis fluid prevented endothelial 2 cell swelling and preserved microcirculatory capillary density. In this setting as well, conven- 3 tional resuscitation restored microvascular flow and function to near baseline levels. The 4 authors note that activation of the sodium/hydrogen ion exchanger permits the cell to 5 transport hydrogen ions into the extracellular space. Chloride ion is also transported into 6 the extracellular space. Bicarbonate and sodium are transported into the cell along with wa- 7 ter. The flux of water, bicarbonate, and sodium into the cell produce cell swelling. The esti- 8 mated size of the endothelial surface in intestine and skeletal muscle would explain the 9 large fluid shifts observed in experimental preparations of severe shock as well as in injured 10 patients sustaining massive blood loss. Persistence of intracellular acidosis could also ex- 11 plain the observed disorders of cellular energy metabolism and the resultant accumulation 12 of acid metabolites and lactate. Reversing cellular edema with direct peritoneal resuscita- 13 tion maintained microvascular flow in the intestinal bed and could reduce the elaboration 14 of proinflammatory cytokines into intestinal lymph. This group of investigators examined 15 the effects of direct peritoneal resuscitation on the flow and composition of mesenteric 16 lymph is a study of rodent hemorrhagic shock authored by Matheson and coauthors15 in 17 Archives of Surgery, 2009. Earlier work by these authors (one report described above) 18 demonstrated endothelial swelling, leading to reductions in intestinal microvascular flow. 19 Conventional resuscitation did not prevent this phenomenon but reductions of cell swelling 20 with direct peritoneal resuscitation, combined with conventional resuscitation, preserved 21 intestinal flow. In this experiment, the authors hypothesized that preservation of intestinal 22 microvascular flow would alter intestinal lymph flow and composition. They were able to 1 Page 24 of 119 2
  • 25. 1 demonstrate increased mesenteric lymph flow with shock and resuscitation. Increased lev- 2 els of lymph hyaluronic acid and proinflammatory cytokines were noted with shock treated 3 by conventional resuscitation. Direct peritoneal resuscitation added to conventional resusci- 4 tation preserved intestinal microvascular flow and function. Mesenteric lymph flow was re- 5 stored to normal, and cytokine levels were returned to control levels by treating rodent 6 hemorrhagic shock with the combination of conventional and direct peritoneal resuscita- 7 tion. These authors have documented a logical mechanism for cellular dysfunction and re- 8 duced intestinal blood flow. They have explained the mechanisms of cellular swelling, re- 9 duced tissue blood flow, and elaboration of proinflammatory cytokines from the gut. In oth- 10 er experiments, they showed that skeletal muscle cell swelling and fluid sequestration oc- 11 curs. These experiments confirm the existence and the magnitude of fluid shifts in profound 12 shock and the authors propose a plausible link between mesenteric ischemia and postshock 13 inflammation. 14 Clinical evidence of mesenteric ischemia is associated with patient mortality and post- 15 shock multiple organ failure. This topic is reviewed by Malinoski and coauthors16 in the Jour- 16 nal of Trauma, 2009. The authors note that animal studies have documented the movement 17 of pancreatic enzymes from the lumen of the intestine into mesenteric lymph and subse- 18 quently into the general circulation in animal models of shock and multiple organ failure. 19 The observed elevations of amylase and lipase occurred without tissue evidence of pancre- 20 atic inflammation and seemed to result from gut ischemia. These authors hypothesized that 21 patients with shock would have elevated levels of pancreatic enzymes and that the eleva- 22 tions would be predictive of mortality and organ failure. They analyzed data from an institu- 1 Page 25 of 119 2
  • 26. 1 tional trauma registry and identified 481 patients with elevations of amylase and lipase 2 more than twice as high as normal levels. Patients in this group were twice as likely to die, 3 to develop organ failure, and require massive transfusion, as were patients without eleva- 4 tions of these enzymes. In the discussion section of their paper, the authors note that ex- 5 perimental preparations have shown that ischemia to the intestinal mucosa allows move- 6 ment of pancreatic enzymes into the submucosa where these substances can activate in- 7 flammatory mediators. The enzymes and mediators can translocate from the submucosa to 8 the mesenteric lymph channels and enter the general circulation by this route. 9 The gut-lymph hypothesis of the origin of multiple organ failure has been extensively in- 10 vestigated in the laboratory. One example of this research is found in an article by Senthil 11 and coauthors17 in the Journal of Trauma, 2006. In a porcine model of trauma and shock, 12 the authors demonstrated that injury and shock are necessary for production of lymph that 13 would activate neutrophils. Neutrophil activation was used as a marker for the presence of 14 proinflammatory cytokines. The authors further documented that the lymph draining from 15 the gut in animals sustaining shock and trauma was cytoxic to endothelial cells. In the dis- 16 cussion section of the article, the authors note that several studies have shown that mesen- 17 teric lymph from animals sustaining shock and trauma has properties that can produce cel- 18 lular effects similar to those seen in multiple system organ failure. They note that the lymph 19 does not contain bacteria or endotoxin, leading to the conclusion that mediators contained 20 in the lymph, such as tumor necrosis factor alpha and interleukin-6, could lead to cellular 21 changes that might induce multiple organ failure syndrome in susceptible patients. 1 Page 26 of 119 2
  • 27. 1 The question of whether lymph draining from other tissues rendered ischemic during 2 shock would also cause cellular changes consistent with multiple organ failure is the topic of 3 two articles by Diebel and coauthors.18-19 These authors showed that lymph gathered from a 4 skeletal muscle bed two hours after shock produced in a canine model led to acute lung cell 5 injury and neutrophil priming. Taken together with the research described earlier, it seems 6 likely that lymph from tissue rendered ischemic during shock can produce changes consis- 7 tent with multiple organ failure. Whether these mechanisms are active in human shock re- 8 quires further clarification. 9 The role of proinflammatory cytokines in the production of multiple organ failure syn- 10 drome has been emphasized in multiple studies. An article documenting the relationship of 11 elevated cytokine levels and multiple organ failure by Jastrow and coauthors20 appeared in 12 the Journal of the American College of Surgeons, 2009. These authors measured sequential 13 levels of cytokines in severely injured patients treated in a single Level I trauma center. Cy- 14 tokine levels were measured during the first 24 hours after admission. There were no signif- 15 icant clinical differences observed when the group of patients who developed multiple sys- 16 tem organ failure was compared to the group that did not develop multiple system organ 17 failure. The authors were able to identify, however, four cytokines present at significantly 18 higher levels in patients who developed organ failure. These included interleukin-10 and in- 19 terleukin-6 that have been associated with organ failure development in a number of exper- 20 imental and clinical studies. Interestingly, there were some patients who did not develop or- 21 gan failure but who had elevated cytokine levels. This observation suggests that other fac- 1 Page 27 of 119 2
  • 28. 1 tors, perhaps including genetic predisposition, might work in conjunction with the cytokine 2 expression to produce a cellular environment leading to the development of organ failure. 3 One potential factor influencing susceptibility to postshock mortality and the risk of or- 4 gan failure is gender. Males are more likely to be injured and are more likely to have elevat- 5 ed levels of circulating cytokines after injury. Mortality and the frequency of multiple organ 6 failure are more common in males as documented in several experimental and clinical se- 7 ries. This issue is the topic of a report by Sperry and coauthors21 in the Journal of Trauma, 8 2008. These authors documented increased levels of interleukin-6 in severely injured male 9 patients. These levels persisted over time and increased serum levels of interleukin-6 were 10 associated with an 11-fold increase in the risk of multiple systems organ failure. These au- 11 thors note that a causal relationship between increased cytokine levels cannot be inferred 12 from these data but increased cytokine levels could be a marker of increased organ failure 13 risk. This same group of investigators examined the role of female hormone levels in pro- 14 ducing the apparent protection against mortality and multiple organ failure in injured wom- 15 en compared with injured men.22 These authors examined hormone levels in pre- and post- 16 menopausal women who had sustained severe injury and noted no difference in the risk for 17 death or multiple organ failure in postmenopausal women compared with premenopausal 18 women. The risk for mortality and multiple organ failure in both groups was lower than that 19 for men after adjustment for multiple risk factors. The authors note that these findings con- 20 trast sharply with experimental animal data that have linked levels of hormones to the pro- 21 tective effect of female gender after shock and injury. They conclude based on the data, 1 Page 28 of 119 2
  • 29. 1 that there are factors other than hormone levels that contribute to the protective effect of 2 female gender. 3 Microvascular flow abnormalities associated with shock and injury may be produced by 4 alterations in circulating blood cells as well as abnormalities in the small vessels of the mi- 5 crocirculation. This topic is addressed in an article by Machiedo and coauthors23 in the Jour- 6 nal of Trauma, 2009. The authors evaluated the affects of infusion of blood from animals 7 subjected to trauma and shock on organ blood flow in a rodent model. Organ blood flow 8 was measured using radioactive microspheres. The authors were able to document in- 9 creased sequestration of red blood cells from animals subjected to trauma and shock and 10 subsequently infused into normal animals in organs such as the liver and spleen. Organ 11 blood flows were reduced. They concluded that red blood cell changes induced by trauma 12 and shock predispose these cells to lodge in organ microcirculations producing obstruction 13 of blood flow. These data and the studies discussed earlier suggest a diverse group of 14 changes in organ microcirculation resulting from trauma and shock. Detailed studies of the 15 human microcirculation are needed to provide clinical evidence of measures to improve 16 outcomes. 17 Protection against cellular death is another avenue that could improve outcomes in 18 severely injured patients with shock. One measure leading to improved cell survival is inhi- 19 bition of deacetylation of histones. Histone deacetylation is one means of altering cellular 20 DNA leading to cell death. Inhibition of this process is the topic of a report authored by Gon- 21 zales and coauthors24 in the Journal of Trauma, 2008. The authors note that hemorrhagic 1 Page 29 of 119 2
  • 30. 1 shock-induced changes in the liver produce aberrations in gene-regulatory programs; one 2 important pathway for these changes is recruitment of histone deacetylases in liver tissue. 3 Valproic acid, a regularly prescribed antiepileptic drug, was recently shown to produce neu- 4 roprotective effects through inhibition of histone deacetylation. Pretreatment with valproic 5 acid in a rodent model of severe hemorrhagic shock produced favorable changes leading to 6 liver cell survival and these changes were directly related to hyper-acetylation of hepatic hi- 7 stones. 8 The cell protective activity of valproic acid was further evaluated in a porcine model of 9 severe hemorrhage, trauma, and shock and reported in an article authored by Alam and 10 coauthors25 in Surgery, 2009. The authors of this report treated animals with valproic acid 11 after hemorrhage and liver injury in contrast to the pretreatment model examined in the ar- 12 ticle authored by Gonzales.24 Alam and coauthors examined outcomes in animals untreated, 13 animals treated with fresh whole blood, and animals treated with intravenous valproic acid. 14 Survival was 100% and 86% in animals treated with fresh whole blood and valproic acid re- 15 spectively compared with 25% in the control group. The authors examined liver tissue and 16 found that survival was associated with preservation of the Akt cell survival pathway. Nor- 17 mal function of this pathway depends on prevention of histone deacetylation. These two 18 studies indicate that interventions at the cellular level hold promise as therapeutic path- 19 ways for the management of trauma and shock. 20 Restoration of perfusion after a period of ischemia is another potential pathway leading to 21tissue damage. Restoration of blood flow to tissue is essential for survival from shock but reper- 1 Page 30 of 119 2
  • 31. 1fusion injury is a potential pathway for production of cellular injury and postshock complica- 2tions through production of reactive oxygen species as well as other substances. Reperfusion 3injury after hemorrhage and injury is reviewed in an article by Rushing and Britt26 in Annals of 4Surgery, 2008. This article is included as a full-text reprint accompanying this issue of SRGS. 5These authors note that tissue level evidence of reperfusion injury is noted, initially, by neu- 6trophil adhesion to venular endothelium. They stress that adhesion molecules are expressed on 7endothelial cells, platelets, and neutrophils are all active in the adhesion process. Blockade of 8cell adhesion is appealing, although trials of adhesion molecule blockade have not shown bene- 9fit. The authors note that mitochondrial injury is a constant factor in reperfusion injury and cite 10evidence suggesting that cytochrome C oxidase is a mediator of reperfusion damage to mito- 11chondria. In addition, enzymatic mediators such as xanthine oxidase are important in the pro- 12duction of reperfusion injury. Reperfusion injury produces alterations of intracellular signaling 13pathways such as the NF-kappa B pathway that augment production of pro-inflammatory cy- 14tokines such as tumor necrosis factor alpha. Immune cells, such as B-lymphocytes, are impor- 15tant locations of these alterations. Changes within these pathways can lead to cell death via 16apoptotic pathways. The events initiating and perpetuating reperfusion injury are important 17foci of research efforts as pathways to improved patient outcomes are sought. 18Sepsis and septic shock 19 A review of the pathophysiology of sepsis and septic shock is authored by Hotchkiss and 20 Karl27 in the New England Journal of Medicine, 2003. The authors begin by noting that sepsis 21 and septic shock are the leading causes of death among critically ill patients in the United 22 States; 750,000 cases of sepsis are diagnosed annually and 25%-40% of these patients die 1 Page 31 of 119 2
  • 32. 1 depending on risk factors (age, comorbidities), the etiology of sepsis, and the mode of ther- 2 apy. They go on to stress that the major clinical manifestations of sepsis are not infection- 3 specific but represent an inherent pattern of response to infection regardless of the infect- 4 ing organism. Although clinical sepsis is thought to result from dysfunction of the inflamma- 5 tory response, proinflammatory cytokines are variably recovered from septic patients and 6 blockade of cytokines has not shown benefit as a means of improving sepsis outcomes. Re- 7 cent data have described targeted alterations in the innate immune system that may in- 8 crease susceptibility to sepsis. As an example, the authors cite data that alterations in the 9 toll-like receptor 4 gene have been demonstrated in humans who show increased suscepti- 10 bility to sepsis. The authors go on to discuss the shift from a proinflammatory state to a 11 state of immune suppression which occurs during the septic event and this immune sup- 12 pression may predispose to nosocomial infections in patients recovering from sepsis. As im- 13 munosuppression progresses, anergy may occur due to apoptotic cell death in populations 14 of immune cells such as lymphocytes and gastrointestinal mucosal cells. Animal data have 15 shown that anti-apoptotic drugs reduce the impact of this process and in animals, mortality 16 from sepsis is reduced28. Data from surgical patients suggest that restoration of the proin- 17 flammatory state that characterizes the early septic response is associated with restoration 18 of immune function and improved survival. 19 Genetic alterations also may act to perpetuate the immunosuppressed state. The au- 20 thors cite data that alterations in the genes that produce tumor necrosis factors alpha and 21 beta result in low levels of these cytokines in patients who die of infection during the im- 22 mune suppressed phase of sepsis. 1 Page 32 of 119 2
  • 33. 1 Neutrophils have traditionally been thought essential to the successful control of infec- 2 tion. Recent experimental studies have suggested that neutrophils may mediate tissue in- 3 jury (see discussion of Rushing’s review, above). Blockade of neutrophil-mediated injury has 4 not improved sepsis outcomes, however. In contrast, some suggestion of benefit was noted 5 in patients with pneumonia who were treated with granulocyte colony stimulating factor. 6 These patients had neutrophil counts in excess of 70,000 cells/mm3 but there was no sug- 7 gestion of neutrophil-mediated tissue injury. 8 Observations from autopsy data, cited by Hotchkiss and Karl, suggest that the popula- 9 tions of cells dying in patients with sepsis are lymphocytes and gastrointestinal epithelial 10 cells. This cell death is thought to occur because of sepsis-induced acceleration of apoptosis. 11 No specific therapy is available to forestall lymphocyte and gastrointestinal epithelial cell 12 death. These cells are popular foci of research into the basic mechanisms of sepsis and sep- 13 tic shock. 14 Hotchkiss and Karl note that septic shock, though frequent in septic patients, is an un- 15 common cause of death in this patient group. Septic shock is a form of distributive shock 16 characterized by preservation of cardiac output and global indices of oxygenation occurring 17 in the setting of hypotension. Recent studies have shown that microcirculation dysfunction 18 can be observed in the sublingual mucosa, which is anatomically and functionally similar to 19 the intestinal mucosa. Failure to recover microcirculatory function has been associated with 20 mortality from sepsis and septic shock although shock itself was less often a cause of death 21 than the subsequent development of organ failure and/or nosocomial infection. Therapy for 1 Page 33 of 119 2
  • 34. 1 septic shock has been directed toward preserving perfusion and oxygen delivery in an at- 2 tempt to prevent sepsis-associated organ failure that is a more common cause of death in 3 septic patients than septic shock. Therapy for sepsis and septic shock is discussed later. 4Cardiogenic shock 5 Arterial hypotension (systolic blood pressure < 90 mmHg) combined with signs of end- 6 organ hypoperfusion (acidosis, elevated serum creatinine, abnormal sensorium), depressed 7 cardiac index, and signs of elevated left ventricular pressure comprise the clinical features 8 of cardiogenic shock. Cardiogenic shock occurs in 7% of patients after myocardial infarction 9 and this condition is the most common cause of early death after myocardial infarction. 10 Other conditions that complicate myocardial infarction such as papillary muscle rupture 11 with acute mitral insufficiency and ventricular wall rupture with pericardial tamponade are 12 surgical emergencies that also cause cardiogenic shock. 13 The epidemiology of cardiogenic shock is discussed in a review by Topalian and coau- 14 thors29 in Critical Care Medicine, 2008. This article is supplied as a full-text reprint with this 15 issue of SRGS. These authors cite three reports indicating that cardiogenic shock complicat- 16 ing myocardial infarction (defined as ST-segment elevation and/or new left bundle branch 17 block on electrocardiogram) occurred in 7.1%-8.6% of patients after myocardial infarction. 18 Once cardiogenic shock was diagnosed, subsequent mortality rates reported were 60-80%. 19 Mortality rates were higher in patients older than 75 years. Topalian and colleagues stress 20 recent data showing that aggressive attempts to provide complete revascularization of criti- 21 cal coronary stenoses and occlusions in patients with cardiogenic shock has resulted in low- 22 er mortality rates approaching 48%. Patients at increased risk for cardiogenic shock after 1 Page 34 of 119 2
  • 35. 1 myocardial infarction include older patients and patients with a history of hypertension, 2 dyslipidemia, and previous coronary angioplasty. Cardiogenic shock has an average time of 3 onset, after the appearance of clinical evidence of myocardial infarction, of 7 hours. This re- 4 view notes that cardiogenic shock can occur after myocardial infarctions that result in ST- 5 segment elevation and in those patients without ST-segment elevation accompanying the 6 infarction. The etiology of infarction and cardiogenic shock is usually multivessel coronary 7 atherosclerosis. In one report cited by the authors, more than half the patients with cardio- 8 genic shock after myocardial infarction had triple vessel disease, and more than 15% of pa- 9 tients had significant left main coronary artery stenosis. Anterior infarction is common but 10 multiple sites of infarction are diagnosed in more than half the patients who develop car- 11 diogenic shock. Nearly 80% of patients who develop cardiogenic shock have left ventricular 12 failure as the main pathogenesis of the shock event. Acute mitral insufficiency, septal rup- 13 ture, right ventricular infarction, and ventricular wall rupture with pericardial tamponade 14 account for the remaining patients. Ventricular wall rupture is the least frequent etiology of 15 cardiogenic shock, accounting for less than 1.5% of instances. Acute mitral insufficiency ac- 16 counts for 7% of patients developing cardiogenic shock. 17 The pathophysiology of cardiogenic shock is the subject of a review by Aymong and 18 coauthors30 in Medical Clinics of North America, 2007. These authors emphasize the critical 19 importance of reduced coronary blood flow that results in a state of myocardial oxygen de- 20 privation and disordered myocardial energy metabolism. They note that heart muscle is 21 very reliant on aerobic energy metabolism. Oxygen utilization in contracting heart muscle 22 ranges from 8-15 mL of oxygen/100 gm/tissue/min. The noncontracting muscle uses only 1 Page 35 of 119 2
  • 36. 1 1.5 mL/100 gm/tissue/min. The heart, even in its resting state, extracts 2-3 times more oxy- 2 gen than any other single organ. Myocardial oxygen demand is determined by ventricular 3 tension, heart rate, and contractility. Oxygen delivery to the myocardium via the coronary 4 arteries is primarily a diastolic phenomenon. Coronary perfusion pressure can be estimated 5 from the difference in aortic diastolic pressure and mean left ventricular pressure. Coronary 6 vascular resistance interacts with coronary perfusion pressure to determine net coronary 7 flow. Coronary vascular resistance is determined by complicated interactions among various 8 local and systemic mediators. Endothelial dysfunction occurs because of coronary 9 atherosclerosis and produces abnormal coronary responses to endogenous mediators of 10 vasoconstriction and vasodilation. The net result is disordered autoregulation, with coro- 11 nary flow becoming progressively more dependent on coronary perfusion pressure. Dias- 12 tolic coronary perfusion can be reduced during conditions where cardiac output is de- 13 creased and when the diastolic interval is reduced (tachycardia). Myocardial infarction re- 14 sulting from coronary thrombosis directly reduces coronary flow because of obstruction. 15 With extensive involvement of the ventricular wall, cardiac output is reduced. Tachycardia 16 results from the catecholamine response to reduced cardiac output and these factors com- 17 bine to produce a self-perpetuating cycle of myocardial ischemia and infarction. Topalian 18 and associates29 emphasize that “ischemia begets ischemia” during this cycle. 19 Ventricular dysfunction leads to elevated end-diastolic pressures and pulmonary con- 20 gestion. Elevated ventricular filling pressures increase myocardial wall stress. Restricted left 21 ventricular filling was noted in more than 60% of patients evaluated by echocardiography in 22 a series cited by Topalian and coauthors. This pathophysiologic process is complicated by 1 Page 36 of 119 2
  • 37. 1 the elaboration of inflammatory mediators. Clinical evidence of systemic inflammatory re- 2 sponse syndrome was noted in 20% of patients in a report cited by these authors. Aymong 3 and colleagues30 cite data indicating that elevated levels of interleukin-6 have been docu- 4 mented in patients with cardiogenic shock and that these levels are equivalent to the levels 5 recorded in patients with sepsis and septic shock. Topalian and associates and Aymong and 6 colleagues further note that the proinflammatory state observed in some patients with car- 7 diogenic shock is associated with stimulation of inducible nitric oxide. Unfortunately, block- 8 ade of inducible nitric oxide synthesis did not produce a benefit in patients with cardiogenic 9 shock. 10 Aymong and coauthors note that myocardial ischemia can result in myocyte necrosis. 11 Other cells die because of apoptosis (programmed cell death). In addition, myocardial cells 12 may be “stunned” from ischemia. Stunned cells do not recover full contractile function with 13 early restoration of perfusion from revascularization procedures. Thus, normal contractile 14 function might not be restored for several weeks after coronary artery thrombosis followed 15 by revascularization. 16 The extensive multivessel coronary atherosclerosis noted in autopsy reports of patients 17 dying of myocardial infarction and cardiogenic shock usually produces multiple myocardial 18 infarctions of varying age rather than a single massive infarction. Low coronary flow and in- 19 creased coagulation activity because of the presence of unstable coronary plaque can pro- 20 duce progressive coronary thromboses that extend to involve branches of the artery where 21 the thrombosis originated. These authors go on to note that declining myocyte contractility 1 Page 37 of 119 2
  • 38. 1 can occur in areas remote from the infarction and this may be a consequence of production 2 of hypoxia-inducible-factor-1 which is stimulated when cardiac cell mitochondria sense hy- 3 poxia. Reduced cell metabolism and contractility are produced by this factor. The resulting 4 low metabolism state produced in areas remote from the infarction is termed “myocardial 5 hibernation.” One of the benefits of treatment of cardiogenic shock with intra-aortic bal- 6 loon counterpulsation may be restoration of coronary perfusion and myocyte oxygenation 7 that serves to reverse myocyte hibernation and recover contractility. 8Monitoring the patient in shock 9 The clinical hallmark of shock in the critically ill surgery patient is arterial hypotension. 10 The Advanced Trauma Life Support Course offered by the Committee on Trauma of the 11 American College of Surgeons defines shock as an arterial blood pressure < 90 mmHg con- 12 firmed before patient arrival at the hospital and/or present during initial assessment. Addi- 13 tional bits of clinical information available during the initial assessment are used to supple- 14 ment the clinical suspicion raised by the finding of hypotension and provide guidance to the 15 clinician regarding hypoperfusion of critical vascular beds (oliguria, depressed level of con- 16 sciousness, metabolic acidosis) and prognosis (alternating tachycardia and bradycardia, re- 17 sponse to fluid challenge). Clinical experience has shown that significant reductions in car- 18 diac output because of hemorrhage, sepsis, cardiac dysfunction, pericardial tamponade, 19 and massive pulmonary embolus can be present without arterial hypotension. In fact, hy- 20 potension is not a sign of shock but a sign of decompensated shock indicating that the in- 21 trinsic defenses against reductions of cardiac output have failed and, therefore, the hy- 22 potensive patient is literally minutes away from cardiac arrest and death. 1 Page 38 of 119 2
  • 39. 1 Hemodynamic abnormalities resulting from reductions in cardiac output change along a 2 dynamic continuum. The patient who is hypotensive during transport from a crash scene to 3 the trauma center may have a normal arterial pressure in the resuscitation area of the hos- 4 pital because of ongoing adjustments of the blood volume and systemic arteriolar constric- 5 tion induced by catecholamine secretion. Prehospital hypotension can be a marker for pa- 6 tients who have bled massively or who are continuing to bleed. This topic was addressed in 7 an article by Lipsky and coauthors31 in the Journal of Trauma, 2006. These authors reviewed 8 records on more than 1000 injured patients transported to a single trauma center over the 9 course of a 12-month interval. Seven percent of patients were hypotensive during transport 10 as defined by a systolic blood pressure of 90 mmHg or less. Of this group, more than one- 11 third required an operative procedure for hemorrhage control within the first six hours at 12 the trauma center. Underscoring the hazards of clinical classifications based on blood pres- 13 sure readings was the finding that 11% of patients who were normotensive during the pre- 14 hospital interval and who were normotensive during resuscitation also required an opera- 15 tive procedure to control bleeding within the first six hours after arrival at the trauma cen- 16 ter. It is clear that clinical decisions about patients at risk for shock will be based on combi- 17 nations of data and that all of the variables assessed suffer from a lack of sensitivity and 18 specificity. 19 In this section of the overview, a discussion of the capabilities and limitations of moni- 20 toring the patient in shock will be undertaken. 1 Page 39 of 119 2
  • 40. 1Hemodynamic monitoring 2 Basic features of hemodynamic monitoring include intermittent or continuous measure- 3 ments of arterial pressure, heart rate, and arterial oxygen saturation. Arterial pressure can 4 be measured with blood pressure cuffs (automatic or manual) and with indwelling arterial 5 catheters attached to continuous monitoring transducers. Automatic blood pressure cuffs 6 produce blood pressure values consistently higher than actual pressures. This feature is par- 7 ticularly noticeable in lower pressure ranges. Manual blood pressure cuffs require person- 8 nel, and the measurement process is cumbersome in critically ill patients. Placement of ar- 9 terial catheters in peripheral arteries may be challenging in vasoconstricted patients. Arteri- 10 al pressure measurements can be supplemented with serial measurements of central ve- 11 nous pressure. In the intensive care unit or the operating room additional variables such as 12 central venous oxygen saturation, right heart pressures, mixed venous oxygen saturation, 13 and cardiac output can be measured. Transthoracic or transesophageal echocardiography 14 can be used to determine the presence and degree of cardiac dysfunction. Controversy con- 15 tinues about the additional benefit of these assessments. Isolated values derived from 16 hemodynamic measurements are of limited value. Trends are therefore monitored and re- 17 sponses to interventions such as endotracheal intubation and ventilation, decompression of 18 hemo- or pneumothoraces, and intravenous fluid boluses, are recorded. 19 A critical aspect of early resuscitation from shock involves decisions to undertake an in- 20 tervention to correct the underlying cause of the shock state. This might be a procedure to 21 stop bleeding or control the source of sepsis. Interventions may take the form of thrombol- 22 ysis of pulmonary embolus, revascularization of occluded coronary arteries, or insertion of 1 Page 40 of 119 2
  • 41. 1 an intra-aortic balloon pump. The clinician establishes goals of early resuscitation to help 2 guide these decisions. These are termed “endpoints of resuscitation.” The first article dis- 3 cussed in this section addresses this topic. It is by McCunn and Dutton32 and appeared in 4 Current Opinion in Anesthesiology, 2000. The authors begin the discussion by confirming the 5 hazards of depending on specific values for monitoring variables. They stress the consistent 6 observation that more than one-third of injured patients in shock are not tachycardic. Ex- 7 perimental studies of shock from blood loss disclose that pure blood loss most often results 8 in slowing of the heart rate. 9 They go on to emphasize the importance of separating resuscitation from shock into 10 phases. The initial phase takes place before a needed intervention to reverse the underlying 11 cause of shock and the second phase occurs after the intervention has been completed. 12 During the initial phase, goals of resuscitation include identification of the underlying etiolo- 13 gy of shock and expansion of the intravascular space with intravenous electrolyte solution. 14 McCunn and Dutton stress the importance of careful adjustment of the arterial pressure. 15 The initial goal is to raise mean arterial pressure to a level that will support cell survival. At- 16 tempts to normalize the arterial pressure will lead to recurrence or acceleration of bleeding 17 in the acutely injured patient. In addition, McCunn and Dutton note that infusion of a vol- 18 ume of electrolyte solution sufficient to raise arterial pressure to normal will lead to exces- 19 sive volume infusion and complications such as abdominal compartment syndrome. They 20 emphasize the importance of warming intravenous fluids to support core patient tempera- 21 ture. Arterial pressure goals before controlling the cause of shock should be set at mean ar- 22 terial pressure of 60-70 mmHg with adjustments upward for elderly patients, patients with 1 Page 41 of 119 2
  • 42. 1 traumatic brain injury, and patients with known cardiac dysfunction. Supplemental informa- 2 tion can be gleaned from monitoring trends in central venous pressure. In the early phase of 3 resuscitation, risks associated with central venous catheterization include arterial injury and 4 pneumothorax. These risks may be reduced, somewhat, by using ultrasound guidance for 5 central venous catheter insertion. Central venous pressures of 8-12 cm H20 are adequate to 6 support cardiac output in healthy patients. Pressure goals will need to be adjusted upward 7 in patients who are requiring positive pressure ventilation. As in all other global hemody- 8 namic measurements, trends are more important than isolated values. 9 A review of hemodynamic monitoring in the intensive care unit appeared in Chest in 10 2007, by Pinsky.33 The author begins by describing clinical objectives of hemodynamic moni- 11 toring. Clinicians use hemodynamic monitoring to establish cause of shock and to estimate 12 the direction and degree of response to therapy. The first steps are to determine how much 13 cardiac output is likely to increase in response to a first line intervention (usually an intra- 14 venous fluid bolus) and then to determine whether the systemic vasomotor tone is in- 15 creased or decreased. Distributive shock (most commonly septic shock) is the most com- 16 mon shock state encountered by surgeons where vasomotor tone is decreased. Finally, an 17 assessment of the ability of the heart to sustain function when arterial pressure is restored 18 completes the initial characterization of the shock state. Pinsky emphasizes that the re- 19 sponse to intravascular volume expansion (preload responsiveness) cannot be predicted 20 from estimates of ventricular end-diastolic volume. This observation calls into question the 21 clinical value of data that can be obtained from placement of a pulmonary artery catheter. 1 Page 42 of 119 2
  • 43. 1 Whether data obtained from pulmonary artery catheter measurements alters outcomes 2 in patients with shock is controversial. A consensus conference produced recommendations 3 published in 1997.34 The recommendations pertinent to surgical patients suggested that 4 preoperative optimization of hemodynamic status using data derived from the pulmonary 5 artery catheter would probably improve outcomes in high-risk patients undergoing vascular 6 operations. The consensus noted that clinical decisions made using pulmonary artery 7 catheter measurements of filling pressures and cardiac output could be useful in the man- 8 agement of injured patients when standard hemodynamic measurements were deemed in- 9 adequate. This recommendation was based on expert opinion because no high-quality data 10 were available. The recommendation specifically focused on patients with brain injury and 11 postinjury acute respiratory distress syndrome. Overall, the data available do not support 12 the widespread use of the pulmonary artery catheter as a means of improving patient out- 13 comes in shock. In an editorial published in Critical Care Medicine in 2005, Pinsky and Vin- 14 cent35 addressed the lack of data supporting the use of the pulmonary artery catheter and 15 noted that the available studies are insufficient to document lack of efficacy of the pul- 16 monary artery catheter because the studies only compared outcomes in patients treated 17 with and without the device. A valid evaluation would have compared treatment protocols 18 using data derived from the pulmonary artery catheter compared with treatment protocols 19 using other hemodynamic data to support treatment decisions. These authors acknowledge 20 the availability of preload assessments guided by echocardiographic measurements as de- 21 scribed by Voga.36 Pinsky and Vincent reiterate the well-known lack of echocardiographic 22 capability at all times in most intensive care units. 1 Page 43 of 119 2
  • 44. 1 Currently, use of the pulmonary artery catheter to guide therapy in critically ill surgery 2 patients should be selective. Indirect indices of adequacy of blood volume and oxygen 3 transport are available. Trends of variables that are related to ventricular end-diastolic vol- 4 ume such as right atrial pressure and pulmonary artery occlusion pressure do not predict 5 accurately, changes in cardiac output in response to fluid boluses. The author goes on to 6 note that preload responsiveness can be predicted from alterations in arterial pulse pres- 7 sure in response to cycles of positive pressure ventilation. 8 Preload responsiveness can also be predicted from pulse pressure variation measured 9 using echocardiography. Obvious limitations of these assessments relate to the fact that the 10 patient must be on a ventilator and echocardiographic assessment must be readily avail- 11 able. These assessments also lose their predictive ability when heart rate is irregular as in 12 atrial fibrillation. Measurement of the response of aortic flow velocity to a passive leg raise 13 is an assessment that can be performed in patients with any cardiac rhythm. In addition, the 14 patient does not have to be on the ventilator for this assessment to occur. Since flow veloci- 15 ty is measured by trans-esophageal Doppler techniques, special equipment is required. In 16 some critically injured patients, passive leg raising may not be feasible. 17 Because of the limitations of pressure measurements and the lack of universal availabili- 18 ty of other equipment, indirect assessments of the adequacy of oxygen transport have been 19 used and these are discussed in the next section. 20Monitoring oxygenation and perfusion 21 As noted above, continuous measurement of arterial oxygen saturation is a component 22 of the basic hemodynamic assessments performed on all critically ill patients. Arterial oxy- 1 Page 44 of 119 2
  • 45. 1 gen saturation does not provide information relating to oxygen delivery, oxygen consump- 2 tion, or the existence of oxygen debt. Mixed venous oxygen saturation can be measured but 3 this requires placement of a pulmonary artery catheter. Fiberoptic central venous catheters 4 are now available that can provide continuous assessments of central venous oxygen satu- 5 ration. The absolute value for central venous oxygen saturation varies compared with abso- 6 lute values for mixed venous oxygen saturation (obtained using a pulmonary artery 7 catheter). Trends of these measures in response to interventions change, in parallel, howev- 8 er, suggest that trends in central venous oxygen saturation are potentially valuable clinical- 9 ly. Data discussed in later sections of the overview document that a central venous oxygen 10 saturation value of < 70% is a dependable indicator of inadequate global oxygen transport. 11 Currently, this assessment is probably the most useful index of adequacy of oxygen delivery. 12 One obvious limitation of this measurement is in sepsis when values above 70% may be 13 present in the face of inadequate tissue perfusion. As a general statement, combining arte- 14 rial pressure and heart rate with central venous pressure measurements supplemented by 15 continuous measurements of central venous oxygen saturation provide adequate estimates 16 of hemodynamic function to guide the clinician dealing with most forms of shock encoun- 17 tered in surgical patients. 18 A fundamental concept of shock is that inadequacy of the circulation leads to a cellular 19 shift from aerobic to anaerobic metabolism. Anaerobic metabolism leads to the accumula- 20 tion of acid metabolites in tissue. Traditionally, assessments of acid base status have been 21 routine in the management of shock. Assessment of global acid-base status has usually 22 been achieved by calculating base deficit from values for pH, bicarbonate and PC02 obtained 1 Page 45 of 119 2
  • 46. 1 from arterial blood gas analysis or from assessments of bicarbonate levels obtained from 2 venous blood samples. Lactic acid is a metabolite that accumulates in cells that are metabo- 3 lizing energy substrates anaerobically. Serum lactate levels reflect lactic acid accumulation 4 and are relatively easy to measure. Absolute lactate levels and rates of lactate clearance 5 have been used as a means of predicting mortality in patients in shock. For example, the 6 rate of lactate clearance has been shown to be predictive of outcomes in injured patients. 7 Whether lactate levels can be used to guide therapeutic decisions is less clear. 8 We discuss several articles dealing with global assessments of acidosis, lactate 9 metabolism, and the roles measurements of these variables may play in managing patients 10 in shock. 11 The relationship between serum bicarbonate (which can be measured from a venous 12 sample) and base deficit (which requires an arterial blood sample) is the topic of an article 13 by Martin and coauthors37 in Archives of Surgery, 2005. These authors reviewed records 14 from intensive care unit stays for 2291 patients. The patients were critically ill surgery pa- 15 tients; injured patients were excluded. Pairs of samples compared serum bicarbonate levels 16 and calculated base deficit. The authors found that trends of the two measurements 17 changed in parallel. Admission serum bicarbonate predicted mortality and length of stay. 18 Defining significant acidosis as a base deficit > 5, the authors determined that serum bicar- 19 bonate was an accurate measure of acid-base status. The authors concluded that serum bi- 20 carbonate was as accurate as base deficit diagnosing acidosis and that low serum bicarbon- 21 ate was a dependable trigger for treatment of acidosis. This same group of investigators ex- 1 Page 46 of 119 2
  • 47. 1 tended the comparison of serum bicarbonate and base deficit to a group of 3102 injured pa- 2 tients admitted to a trauma intensive care unit. These data are found in a report by Fitzsulli- 3 van and coauthors38 in the American Journal of Surgery, 2005. The authors note that base 4 deficit is a calculated value derived from data gathered from analysis of an arterial blood 5 sample. The value represents the number of milliequivalents of additional base buffer that 6 would have to be added to bring the pH of the blood sample to normal. Serum bicarbonate 7 is measured from a venous sample. Potential advantages of using serum bicarbonate are 8 ease of collection and processing as well as lowered cost. The analysis disclosed that serum 9 bicarbonate was an accurate predictor of acid base status and had equivalent clinical value 10 compared with base deficit. Most, but not all, of the variability of base deficit was paralleled 11 by serum bicarbonate values. The authors concluded that serum bicarbonate was as accu- 12 rate as base deficit in predicting clinically significant acidosis. 13 In a final analysis by this group of investigators, a comparison of base deficit to serum 14 lactate was carried out to determine whether base deficit was as accurate as lactate levels 15 for prediction of outcomes in critically ill surgical patients. They confirmed that serum lac- 16 tate was a superior predictor of outcomes compared with base deficit. They concluded from 17 their analysis that admission base deficit and admission lactate predict mortality but that a 18 normal base deficit does not always predict a normal lactate and that an abnormal lactate 19 level was predictive of mortality and length of stay even when the base deficit was normal. 20 Additional discussion of lactate as a clinical indicator of occult anaerobic metabolism is dis- 21 cussed in the next segment. 1 Page 47 of 119 2
  • 48. 1 A review of lactate metabolism and an assessment of the clinical utility of lactate level 2 measurements are found in an article by Jansen and coauthors39 in Critical Care Medicine, 3 2009. The article is entitled “Blood lactate monitoring in critically ill patients: a systematic 4 health technology assessment.” This article is supplied as a full-text reprint accompanying 5 this issue of SRGS. The objective of this report is to attempt to describe the process of mea- 6 suring blood lactate and to establish whether these measurements have value in the man- 7 agement of the critically ill patient. The authors note that there is wide variability among 8 clinicians and hospitals in the use of blood lactate measurements. Although elevated blood 9 lactate is thought to be evidence of anaerobic metabolism that can result from shock and 10 other conditions, there is evidence that elevations of lactate can occur in the absence of 11 anaerobic metabolism. The authors note that the measurement of blood lactate has been 12 standardized and the test is dependable. They review experimental and clinical studies that 13 have evaluated lactate. Experimental preparations that have reduced oxygen delivery until 14 oxygen consumption was delivery-dependent have consistently shown elevations of blood 15 lactate in the experimental subjects. Studies of patients with septic and cardiogenic shock 16 have shown increased lactate/pyruvate ratios consistent with anaerobic metabolism. 17 Jansen and coauthors cite a study by Rivers40 (discussed later in the overview) that docu- 18 mented a consistent relationship between hyperlactatemia and low central venous oxygen 19 saturation indicating inadequate oxygen delivery and suggesting that a shift to anaerobic 20 metabolism had occurred. They also cite data demonstrating that elevations of lactate con- 21 sistently occurred in patients with low mixed venous oxygen saturation, low cardiac output, 22 and clinical signs of shock. The authors stress that there is wide variability in regional oxy- 1 Page 48 of 119 2
  • 49. 1 gen delivery and demand. This fact means there will be no specific value for oxygen delivery 2 or central venous oxygen saturation associated with lactate accumulation. They describe re- 3 search conducted in patients with septic shock that demonstrate lowering of lactate levels 4 when capillary perfusion is improved, even though systemic hemodynamic variables did not 5 change. This observation suggests that local microcirculatory changes may alter the accu- 6 mulation of lactate. 7 The authors go on to review instances where lactate levels may change in the absence 8 of anaerobic metabolism. Conditions that increase aerobic glycolysis to a point where the 9 ability of pyruvate dehydrogenase is exceeded by over production of pyruvate will result in 10 accumulation of lactate. Mitochondrial dysfunction and liver dysfunction can alter lactate 11 production and clearance with increased lactate levels in the absence of anaerobic 12 metabolism. The lung can also be an important source of lactate when pulmonary produc- 13 tion of lactate is stimulated by inflammatory mediators, even though hypoxia is not present. 14 Finally, alkalosis can increase efflux of lactate from cells and several drugs can stimulate lac- 15 tate production. 16 The article next reviews the prognostic value of lactate and the authors conclude that 17 lactate elevations accurately predict mortality in acutely injured patients in the emergency 18 department and critically ill patients in the intensive care unit. The authors reviewed several 19 studies that confirmed an inconsistent relationship between lactate and other indices of aci- 20 dosis. The bulk of the evidence suggests lactate levels cannot be predicted from other in- 21 dices of acidosis such as base deficit and anion gap. Further, the evidence suggests that ele- 1 Page 49 of 119 2
  • 50. 1 vated lactate, along with evidence of acidosis, strongly suggests a shift to anaerobic 2 metabolism in a large proportion of circulatory beds. The authors conclude that the avail- 3 able evidence suggests that lactate changes can be used to indicate the effectiveness of 4 therapeutic efforts to improve oxygen delivery and tissue blood flow. 5 For surgeons managing critically ill patients, lactate is most useful when the elevated 6 lactate level occurs in the setting of metabolic acidosis; acidosis is independently confirmed 7 by measurements of serum bicarbonate and/or base deficit. The presence of elevated lac- 8 tate with metabolic acidosis is predictive of mortality and resolution of hyperlactatemia sug- 9 gests successful reversal of anaerobic metabolism. 10 The final article reviewed in this section deals with the potential value of laboratory 11 tests in the management of shock by Friese and coauthors41 appeared in the Journal of 12 Trauma, 2007. These authors hypothesized that the transition from adequate resuscitation 13 of shock to over resuscitation would be associated with increased myocardial wall stretch 14 and serum levels of B-type natriuretic peptide might be valuable indicators of this transi- 15 tion. Serum levels of B-type natriuretic peptide were followed in 134 injured patients. Chest 16 radiographs obtained 24 hours after admission were graded for the presence of pulmonary 17 edema, which the authors used as an indicator of over resuscitation. Twenty patients who 18 had increased pulmonary edema scores had mean serum levels of B-type natriuretic pep- 19 tide that were significantly higher than the mean levels observed in patients without pul- 20 monary edema. This paper was presented during the plenary session of the annual meeting 21 of the American Association for the Surgery of Trauma and the discussion that followed the 1 Page 50 of 119 2
  • 51. 1 presentation is included with the article. The discussants note the non-specific nature of sin- 2 gle chest radiograph assessments of pulmonary edema. There was no association between 3 serum levels of B-type natriuretic peptide and any clinically meaningful endpoint. It seems 4 safe to conclude that the search for additional laboratory indicators of resuscitation end- 5 points should continue. 6Monitoring at the tissue level 7 Global markers of inadequate oxygen delivery to tissue such as central venous oxygen 8 saturation, base deficit, and lactate levels represent the resultant vector of all vascular 9 beds. There has been wide recognition that some vascular beds (especially the splanchnic 10 bed) are persistently underperfused and hypoxic even though global indices of oxygen sup- 11 ply and consumption have been corrected to normal levels. Studies in humans and experi- 12 mental animals have demonstrated significant variability in blood flow and recovery of nor- 13 mal cellular metabolism in resuscitated hemorrhagic shock. Accessible microvascular beds 14 evaluated in clinical studies include skin, skeletal muscle, the sublingual bed, and the gastric 15 mucosa. Mucosal pH and PC02, tissue oxygen saturation, and tissue oxygen tension have 16 been studied as possible indices of successful resuscitation. Data from these evaluations are 17 discussed in this segment of the overview. 18 Values for pH and PCO2 can be measured in the gastric and sublingual mucosa using 19 saline-filled latex chambers applied to the mucosal surface. Because the chamber is perme- 20 able to C02, the carbon dioxide tension of the mucosa is equivalent to the carbon dioxide 21 tension of the saline within the chamber after equilibration, and this can be measured in a 22 standard blood gas analyzer. Simultaneous measures of blood bicarbonate permit calcula- 1 Page 51 of 119 2
  • 52. 1 tion of the mucosal pH. An important assumption included in these measurements is that 2 mucosal and blood bicarbonate levels are equivalent. This assumption is controversial. 3 The first article reviewed for this discussion is a classic clinical study by Ivatury and coau- 4 thors42 in the Journal of the American College of Surgeons, 1996, who conducted a random- 5 ized prospective trial in which 57 severely injured patients were resuscitated from shock us- 6 ing global indicators of oxygen delivery and consumption. Consistent with the practice at 7 the time, resuscitation to “supranormal” levels of oxygen delivery and consumption was 8 performed. Gastric mucosal pH was assessed using the tonometry technique described 9 above. Elevation of the gastric mucosal pH to a level > 7.3 was defined as adequate tissue- 10 level resuscitation. Forty-four patients reached target levels of gastric mucosal pH and three 11 of these developed multiple organ failure. Fifty-four percent of the patients who did not 12 reach target levels for gastric mucosal pH developed multiple organ failure. The authors 13 noted that low levels of gastric mucosal pH were observed in the hours before a serious 14 complication such as abdominal compartment syndrome was diagnosed. 15 These authors concluded that patients who reach target levels of gastric mucosal pH are 16 less likely to develop organ failure and the development of low gastric mucosal pH may be a 17 warning signal of an impending serious complication. Unfortunately, this study did not show 18 that resuscitation to a target level of gastric mucosal pH was superior to resuscitation using 19 global indicators of oxygen delivery and consumption. In fact, the frequency of complica- 20 tions such as organ failure and abdominal compartment syndrome were equivalent in the 1 Page 52 of 119 2
  • 53. 1 group resuscitated to a target mucosal pH compared to the group resuscitated using global 2 markers. 3 The evidence for and against the use of gastric mucosal pH as a resuscitation target is 4 reviewed in an article by Hameed and Cohn43 in Chest, 2003. These authors reviewed the 5 technique of gastric tonometry and concluded that the technique was standardized and 6 valid but the controversy concerning equivalency of blood and mucosal bicarbonate had not 7 been resolved. They made note that newer tonometry probes had eliminated the need for 8 equilibration with saline and that this technology had simplified the assessment technique. 9 They then reviewed the evidence supporting the use of gastric tonometry in critically ill pa- 10 tients and concluded that the evidence was conclusive; persistent gastric mucosal pH levels 11 < 7.32 predict mortality and complications. In a review of available evidence from trials 12 evaluating gastric mucosal pH as a resuscitation target, Hameed and Cohn concluded that 13 there was no evidence that resuscitation to a target gastric mucosal pH improved outcomes 14 in critically injured patients or patients with septic shock. Because a clinically definable ben- 15 efit has not been established, the use of gastric tonometry has declined. 16 The sublingual mucosa has a microcirculatory anatomy and physiology similar to the 17 gastric mucosa. An available probe will rapidly measure sublingual mucosal carbon dioxide 18 tension and this may be helpful in establishing prognosis and in defining adequate resuscita- 19 tion. A review of the technical aspects of sublingual capnometry is the topic in an article by 20 Boswell and Scalea44 in AACN Clinical Issues, 2003. A clinical evaluation of this technique was 21 published in the Journal of Trauma, 2007 in a report by Baron and coauthors.45 Baron and 1 Page 53 of 119 2
  • 54. 1 colleagues obtained measurements of sublingual mucosal pC02, base deficit, and lactate se- 2 rially during the first 48 hours after admission of 86 severely injured patients to two Level I 3 trauma centers. Their data indicated that the ability of the three tests to predict mortality 4 was equivalent. All three tests demonstrated sensitivity > 60% and specificity > 87% for pre- 5 diction of mortality. The authors concluded that sublingual capnometry was feasible from a 6 technical standpoint but was not superior to conventional global assessments of oxygen de- 7 livery and consumption as means of predicting outcomes. 8 It is possible to assess tissue oxygen saturation using near infrared spectrophotometry. 9 A study assessing this technology as a method for detecting patients with shock who will re- 10 quire massive transfusion is authored by Moore and coauthors46 in the Journal of Trauma, 11 2008. This study was a multicenter analysis involving seven Level I trauma centers. One hun- 12 dred fourteen patients were categorized as massive transfusion patients. All these patients 13 were monitored with standard measures and subcutaneous near infrared spectrometry 14 measurements of oxygen saturation. The authors found that persistently low tissue oxygen 15 saturation (< 70%) was predictive of outcomes. They found that low admission systolic 16 blood pressure and base deficit > 11 accurately predicted the need for massive transfusion. 17 They concluded from their analysis that monitoring subcutaneous oxygen saturation was 18 potentially helpful for establishing prognosis. Shock associated coagulopathy and massive 19 transfusion are discussed in a later section of this overview. 20 Additional data confirming the predictive value of subcutaneous oxygen saturation lev- 21 els is reported by Leone and coauthors47 in Anesthesiology, 2009. These authors measured 1 Page 54 of 119 2
  • 55. 1 muscle tissue oxygen saturation using near infrared technology in a group of patients who 2 fulfilled diagnostic criteria for septic shock. Initial measurements were obtained after global 3 indices of oxygen delivery and consumption were optimized. Tissue oxygen saturations 4 were lower (mean 73%) in nonsurvivors compared with surviving patients (mean 84%). The 5 authors concluded that these measurements were useful for establishing prognosis. To 6 date, there are not sufficient data to support monitoring of tissue oxygen saturation as a 7 method for gauging adequacy of resuscitation. 8 An experimental study evaluating measurements of muscle tissue oxygen tension and 9 muscle blood flow as indices of successful resuscitation is reported in an article by Wan and 10 coauthors48 in the Journal of Trauma, 2009. This report provides data from a series of exper- 11 iments in a porcine model. Separate groups of animals were instrumented for monitoring of 12 muscle and brain blood flow as well as muscle and brain oxygen tension. Tissue blood flow 13 was measured by thermal dilution and tissue oxygen tension by polarographic probes. Oxy- 14 gen challenges were administered during each experimental phase by increasing inspired 15 oxygen tension to 500 mmHg. Experimental phases included baseline, administration of 16 phenylephrine to raise mean arterial pressure to 150 mmHg, and hemorrhage to an initial 17 mean arterial pressure of 60 mmHg and, finally, further hemorrhage to a mean arterial 18 pressure of 40 mmHg. No resuscitation was carried out. The authors found that muscle oxy- 19 gen tension increased with oxygen challenge at baseline and muscle blood flow did not 20 change. With vasopressor administration, muscle blood flow decreased significantly while 21 brain blood flow increased. Muscle oxygen tension trended downward but the decrease 22 was not statistically significant. With hemorrhage, brain and muscle blood flow and brain 1 Page 55 of 119 2
  • 56. 1 and muscle oxygen declined in parallel. The authors concluded that muscle oxygen tension 2 and brain oxygen tension are governed mainly by blood flow and to a lesser extent by oxy- 3 gen tension in arterial blood. These findings support additional research efforts directed to- 4 ward finding ways to improve microcirculatory flow in all vascular beds. 5 The authors further concluded that muscle oxygen tension has potential as a continuous 6 measure of microcirculatory flow. In the discussion section of their paper, they point out 7 the divergent changes in tissue flow and oxygen levels in brain and muscle with vasopressor 8 infusion. They note that current efforts to increase brain blood flow with vasopressor 9 agents may have negative effects on other body tissues. This work reconfirms multiple ob- 10 servations confirming the heterogeneity of microvascular responses in animals and humans 11 who sustain shock from hemorrhage, sepsis, or other etiologies. 12Editorial comment 13 Additional investigation should clarify the complex interrelationships among vascular 14 beds and permit development of more precise approaches to resuscitation in the future. 15 Routine use of tissue oxygen measurements, though theoretically attractive, is not support- 16 ed by sufficient data at this time. The difficulty in using tissue tonometry as a continuous 17 monitoring methodology has limited its use. Global indices of oxygen delivery and consump- 18 tion such as central venous oxygen saturation, base deficit, and lactate levels are valuable 19 indices when used as supplements to sequential clinical assessments during resuscitation. 20Newer monitoring technologies 21 Recently, technology has become available to measure cardiac output noninvasively. 22 The device uses assessments of aortic blood flow derived from Doppler ultrasound analysis. 1 Page 56 of 119 2
  • 57. 1 The probe is placed in the suprasternal notch and spectral arrays of flow patterns are ana- 2 lyzed with computer assistance. A single-center, prospective observational study comparing 3 noninvasive cardiac output measurements with thermodilution cardiac output measure- 4 ments is by van Lelyveld-Haas and coauthors49 in the European Journal of Anesthesiology, 5 2008. These authors compared 263 measurements obtained sequentially with the noninva- 6 sive device with an identical number of thermodilution cardiac output measurements. The 7 authors found that noninvasive measurements were consistently 12% lower than thermodi- 8 lution measurements. The random error rate was 17% and consisted of a 3% inter-observer 9 variability; an 11% rate of inter-patient variability. The learning curve required to master the 10 technique of noninvasive cardiac output measurement was significant. Despite the variabili- 11 ty, the authors concluded that the technique was acceptable for detection of shock in criti- 12 cally ill patients. 13 An informative comparison of currently available cardiac output devices comes from an 14 article by Compton and Schäfer in Seminars in Cardiothoracic and Vascular Anesthesia, 15 2009. These authors concluded that the only available cardiac output devices with accept- 16 able performance were not noninvasive, in the strictest sense of the term, but minimally in- 17 vasive because each of the two acceptable devices require an indwelling arterial catheter. 18 Lithium indicator dilution and pulse wave analysis are the methods used by these two de- 19 vices. Interested readers are encouraged to review this article. 20Resuscitation strategies 21 The objective of resuscitation from shock is to restore tissue blood flow and oxygen de- 22 livery by manipulating systemic arterial pressure, cardiac preload, intravascular volume, and 1 Page 57 of 119 2
  • 58. 1 blood oxygen carrying capacity. Traditionally, resuscitation from shock because of injury, 2 and hemorrhage, septic shock, and cardiogenic shock have shared several common fea- 3 tures, namely, an initial fluid bolus using electrolyte solutions followed by red blood cell 4 transfusion to improve oxygen carrying capacity. If cardiac dysfunction is present, vasopres- 5 sor and/or inotropic drug therapy are added. It is clear that factors other than fluid and 6 blood therapy make important contributions to the success of resuscitation. For shock from 7 hemorrhage, identification of bleeding sites and rapid control of bleeding is the central fac- 8 tor leading to successful resuscitation. Septic shock patients require identification of the 9 source of infection and control of that source, if possible, to ensure successful resuscitation. 10 Patients with cardiogenic shock may benefit from coronary revascularization and/or intra- 11 aortic balloon pump support. Patients with “obstructive” shock (pulmonary embolus, ten- 12 sion hemothorax or pneumothorax, pericardial tamponade) require relief of the obstruction 13 to circulation in order for resuscitation to be successful. 14 In this section of the overview, we discuss resuscitation strategies. The discussion re- 15 views fundamental understandings of electrolyte solution resuscitation, colloid resuscita- 16 tion, hypertonic resuscitation, and the use of nonblood oxygen carrying solutions. Blood 17 and blood product use are discussed in separate sections of the overview. 18Resuscitation with electrolyte solutions 19 Electrolyte resuscitation from shock has been conceptually based on experimental and 20 clinical studies of hemorrhagic and burn shock begun by Carl Moyer in the early 1960s. 21 Moyer’s hypothesis suggested that shock produced a deficit of sodium and water in the in- 22 terstitial space and if this deficit remained uncorrected, resuscitation would not be success- 1 Page 58 of 119 2
  • 59. 1 ful. Later, Shires and numerous colleagues conducted experiments demonstrating a shift of 2 water and sodium into the intravascular space as the body responded to decreased blood 3 volume by moving fluid along pressure gradients from the interstitium into the intravascular 4 space. These studies also identified a second mechanism of interstitial fluid depletion, a 5 movement of water and salt into cells as the shock insult overcame all compensatory de- 6 fenses and entered the decompensated phase. Clinical recommendations evolved from 7 these data and replacement of blood volume supplemented by a volume of electrolyte solu- 8 tion equal to 20% of the calculated interstitial volume became the norm for managing pa- 9 tients in shock. Protocols for the management of traumatic shock emphasized the use of 10 electrolyte solution as an initial means of restoring blood pressure to normal while typed 11 and crossmatched blood was prepared. For patients undergoing major operative proce- 12 dures formulas were suggested that led to hourly electrolyte infusions of 2-3 liters. 13 Unfortunately, independent investigators could not consistently duplicate Shires’s ex- 14 perimental results, and questions arose about the presence and the magnitude of the inter- 15 stitial deficit. The emergence of acute respiratory distress syndrome as a major complica- 16 tion of trauma and shock led to concern that overzealous infusion of electrolyte solution 17 would lead to pulmonary damage. Previous discussion in the overview has stressed that the 18 volume of electrolyte solution necessary to raise arterial blood pressure to normal will lead 19 to significant tissue edema and, most importantly, to recurrent bleeding if control of hemor- 20 rhage is not achieved. 1 Page 59 of 119 2
  • 60. 1 The importance of targeting lower arterial pressures during the early phases of traumat- 2 ic shock resuscitation in order to prevent recurrent hemorrhage until definitive control of 3 bleeding can be achieved was amply demonstrated in the clinical trial reported by Bickell 4 and coauthors50 in the New England Journal of Medicine, 1994. Recommendations for blood 5 pressure targets in the interval before hemorrhage is controlled have been for volume ex- 6 pansion to achieve mean arterial pressures of 60-70 mmHg. Higher pressures may be neces- 7 sary in elderly patients, patients with cardiac disease, and patients with traumatic brain in- 8 jury where maintenance of cerebral perfusion pressure is important. 9 The foregoing discussion of the pathophysiology of shock has documented that a shift of 10 ions and water into cells (endothelial cells and skeletal muscle cells) does occur but formula- 11 based replacement of ion and water deficits is not as effective as resuscitation based on 12 achieving hemodynamic, oxygenation, and blood flow goals. 13 The first article discussed, by Lucas,51 was presented as the Scudder Oration in Trauma 14 at the annual Clinical Congress of the American College of Surgeons in 2000. The article is 15 entitled “The water of life: a century of confusion.” This article is supplied as a full-text 16 reprint accompanying this issue of SRGS. Lucas reviews his perspective on the dynamics of 17 protein and fluid flux during shock and resuscitation. He notes that albumin and fluid enter 18 and leave the intravascular space and the interstitial space based upon physiologic rules 19 such as Starling’s law of the capillary. He notes that there is sound evidence for a three- 20 phase understanding of shock as it is observed in the severely injured patient. Phase one 21 consists of the interval of shock and active hemorrhage, phase two is a phase of obligatory 1 Page 60 of 119 2
  • 61. 1 sequestration of extracellular fluid that begins when bleeding is controlled. The volumes of 2 blood and electrolyte fluid necessary to maintain life while bleeding is controlled produces 3 the interstitial edema that characterizes this phase. Phase three consists of mobilization of 4 fluid and diuresis. Lucas stresses the importance of lymphatic transport of albumin from the 5 interstitial space to the intravascular space during phase three of trauma and shock. This ex- 6 plains the rise in serum albumin levels frequently observed during this phase. Lucas empha- 7 sizes the critical importance of adequate replacement of blood volume and electrolyte as 8 critical features of successful resuscitation from shock. He notes the lack of evidence of ben- 9 efit of colloid based resuscitation strategies and closes by restating the critical importance 10 of early hemorrhage control. 11 Lucas next reviews data on colloid-rich resuscitation. He notes that studies of albumin 12 resuscitation in hemorrhagic shock have consistently demonstrated higher mortality rates 13 compared with resuscitation strategies using blood and electrolyte solutions. Newer col- 14 loids, such as hydroxyethyl starch and dextran, may adversely affect the coagulation mecha- 15 nism. and these agents have not proven superior to resuscitation strategies based on blood 16 and electrolyte fluid replacement. 17 Evidence that serves to guide the choice of electrolyte solution for shock resuscitation is 18 reported by Todd and coauthors52 in the Journal of Trauma, 2007. These authors compared 19 infusions of lactated Ringer’s solution to normal saline in a porcine model of hemorrhagic 20 shock. They chose to resuscitate the animals to their baseline blood pressure. As mentioned 21 above, this would not be desirable in patients before definitive control of bleeding. They 1 Page 61 of 119 2
  • 62. 1 noted that animals resuscitated with normal saline required significantly larger infusion vol- 2 umes, developed hyperchloremic metabolic acidosis, and had significantly lower levels of 3 coagulation factors at the end of resuscitation. 4 Several recent reports and reviews have emphasized possible complications of aggres- 5 sive electrolyte solution resuscitation including higher postoperative complication rates, im- 6 paired neutrophil function, augmented inflammatory mediator production, and acute lung 7 injury.53-54 Lactated Ringer’s solution is a racemic mixture containing equal amounts of d- 8 and l-lactate. Only l-lactate can be metabolized in the liver. Some have speculated that the 9 d-lactate isomer may be the cause of the effects on immune function associated with exper- 10 imental studies of electrolyte solution resuscitation. In the future, it is possible that a single 11 isomer solution will be available. It is clear that electrolyte resuscitation is most beneficial if 12 used in targeted fashion to restore microcirculatory flow and oxygen transport. Formula- 13 based fluid volume prescriptions clearly increase the risk of complications in patients not in 14 severe shock and in patients where rapid control of bleeding is achieved. Despite observa- 15 tions from animal experiments that potentially harmful changes in immune function result 16 from the use of lactated Ringer’s solution, there currently is not a cost-effective substitute 17 fluid that has a similar proven safety record. 18Resuscitation with hypertonic solutions 19 The most common hypertonic solution used for the management of patients in shock is 20 7.5% saline combined with 6% dextran 70. A comprehensive review of the scientific basis 21 for hypertonic resuscitation of hemorrhage is detailed by Kramer55 in the Journal of Trauma, 22 2003. This author provides an informative review of the animal experiments that served to 1 Page 62 of 119 2
  • 63. 1 support early clinical trials. Hypertonic saline/dextran rapidly raises arterial pressure by 2 moving water from erythrocytes and, possibly, endothelial cells into the intravascular space. 3 Microcirculatory vasodilation occurs, possibly because of movement of water from en- 4 dothelial cells. With fixed dose hypertonic resuscitation, the degree of blood pressure rise is 5 not predictable and a risk of recurrent bleeding exists if blood pressure is raised to the point 6 that clot adherent to injured vessels is displaced. Most studies of hypertonic resuscitation 7 have shown that, over time, an amount of isotonic electrolyte solution is required that is 8 equivalent to the amount that would have been administered had resuscitation been car- 9 ried out with isotonic electrolyte solutions. Hypertonic saline dextran does function well as 10 a means of increasing cerebral perfusion pressure and restoring cerebral blood flow in pa- 11 tients (especially children) with traumatic brain injury and this setting is where the current 12 use of hypertonic resuscitation solutions is common. 13 Design and use of resuscitation strategies to improve cerebral perfusion pressure is the 14 focus of a report by Meybohm and coauthors56 in the Journal of Trauma, 2007. These au- 15 thors used small volume hydroxyethyl starch for resuscitation of porcine hemorrhagic shock 16 and compared the use of vasopressin and norepinephrine to maintain and improve cerebral 17 perfusion pressure. Brain energy metabolism was assessed with microdialysis techniques 18 assaying for glucose, glycerol, lactate and the lactate/pyruvate ratio in brain tissue assessed. 19 These authors showed that cerebral perfusion pressure was maintained with either vaso- 20 pressor agent and that cerebral energy metabolism was protected in the groups treated 21 with either agent. 1 Page 63 of 119 2
  • 64. 1 There is a focus on early aggressive maintenance of cerebral perfusion pressure in pa- 2 tients with traumatic brain injury. This fact, combined with concern over possible adverse 3 consequences of aggressive electrolyte fluid resuscitation, has led to increasing use of vaso- 4 pressor drugs in early shock resuscitation. This approach is the topic of a report authored by 5 Sperry and coauthors57 in the Journal of Trauma, 2008. The authors reviewed data from a 6 large multicenter trial of treatment for injured patients in hemorrhagic shock. They per- 7 formed a Cox proportional hazards analysis to determine the influence on patient out- 8 comes, of the use of norepinephrine, phenylephrine, dopamine, and/or vasopressin within 9 the first 24 hours after injury. Their analysis disclosed an almost 80% increase in the risk of 10 death for patients who were administered these drugs. After adjustment for several con- 11 founding factors, the authors showed that early vasopressor use was an independent driver 12 of the risk of mortality. Interestingly, they showed that aggressive electrolyte solution infu- 13 sion (more than 16 liters in the first 24 hours after injury) was an independent predictor of 14 patient survival. This latter finding suggests that the “adverse” affects of large volumes of 15 electrolyte solutions demonstrated in animal experiments and in patients undergoing elec- 16 tive operation (who were not in shock) are absent in patients sustaining injury and shock. 17 Hypertonic resuscitation may have salutary effects on the proinflammatory state that is 18 documented after traumatic shock in some patients. This is the topic of a randomized 19 prospective trial of hypertonic resuscitation carried out in 27 patients in a single trauma 20 center. This report, by Rizoli and coauthors58 appeared in Annals of Surgery, 2006. In this 21 study, patients sustaining blunt trauma who had a history of at least one blood pressure 22 reading of 90 mmHg or less were randomized to receive a single 250 mL infusion of hyper- 1 Page 64 of 119 2
  • 65. 1 tonic saline/dextran or normal saline. A diverse array of immune variables was assessed 2 during the initial hospitalization. The authors noted that patients who received hypertonic 3 saline/dextran had lower levels of proinflammatory cytokine release and a more “balanced” 4 immune response compared with patients receiving normal saline. 5 Experimental studies have shown that hypertonic resuscitation, combined with a vasodi- 6 lating agent, may attenuate ischemic injury to the gut resulting from shock. This topic is 7 dealt with in a report by Deree and coauthors59 from the Journal of Trauma, 2007. These au- 8 thors showed, in previous studies, that addition of pentoxifylline, a nonspecific phosphodi- 9 esterase inhibitor, to hypertonic saline resuscitation of hemorrhagic shock attenuated histo- 10 logic evidence of injury in the terminal ileum. In this analysis, they explored the hypothesis 11 that this form of resuscitation attenuates gut damage by down regulating the activity of in- 12 ducible nitric oxide synthase. They were able to show, in this experimental model, that in- 13 ducible nitric oxide synthase was, in fact down regulated. 14 One effect of gut ischemia and hypoperfusion seen in experimental simulations of trau- 15 ma and shock is altered function of neutrophils. Abnormal neutrophil function has also been 16 linked to resuscitation with isotonic lactated Ringer’s solution. This same group of investiga- 17 tors60 subjected blood drawn from normal, healthy volunteers to stimulation with endotoxin 18 and examined the actions of two hypertonic solutions (3% and 7.5% NaCl) and pentoxi- 19 fylline on activation of neutrophil by assessing CD14 and CD11b expression and tumor 20 necrosis factor alpha production. They found that hypertonic saline combined with pentoxi- 21 fylline prevented neutrophil activation and tumor necrosis factor production more effec- 1 Page 65 of 119 2
  • 66. 1 tively than hypertonic saline alone. The authors note that these data lend support to the 2 use of pentoxifylline as an adjunct to hypertonic saline in experimental models of traumatic 3 shock. 4 The authors speculate that the mechanism of reduced tumor necrosis factor secretion is 5 from the action of pentoxifylline on intracellular pathways such as the cyclic adenosine 6 monophosphate response element binding (CREB) protein. They further speculate that the 7 action of pentoxifylline leading to reduction of adhesion molecule expression occurs via the 8 reduction of intracellular kinase such as P38 MAPK. These demonstrated antiinflammatory 9 effects, combined with the ability of pentoxifylline to improve microcirculatory function, im- 10 ply that this combination could be potentially beneficial in clinical models of traumatic 11 shock. These findings, taken together with the research studies of Zakaria and Matheson,14 12 discussed earlier, lend support to the search for resuscitation strategies that target normal- 13 ization of distal gut microcirculatory function. 14Resuscitation with non-blood oxygen carrying solutions 15 Recognition of the facts that banked and fresh units of red cells and blood for transfu- 16 sion are scarce resources especially in remote locations and in combat conditions has stimu- 17 lated a search for nonblood oxygen carrying solutions that could be used for resuscitation of 18 injured patients and to substitute for blood transfusion in elective surgery patients. In this 19 segment of the overview, a review of the current experimental and clinical research relating 20 to the ability of oxygen-carrying solutions to reverse the microcirculatory changes leading to 21 the oxygen supply/consumption imbalance associated with various shock states is dis- 22 cussed. The potential usefulness of these solutions as a means of avoiding transfusion in 1 Page 66 of 119 2
  • 67. 1 elective and emergency surgical conditions also is reviewed. The outlook for reducing the 2 risks of allogeneic transfusion and reducing the demand for donated blood will also be de- 3 scribed. 4 The first article reviewed in this section of the overview by Creteur and Vincent61 ap- 5 peared in Critical Care Clinics, 2009. This review is entitled “Potential uses of hemoglobin- 6 based oxygen carriers in critical care medicine.” This article is included as a full-text reprint 7 accompanying this issue of SRGS. The authors open the review by pointing out the main 8 drivers of the effort to develop nonblood oxygen carrying solutions. Concern about poten- 9 tial risks of transfusion, particularly transmission of disease and the possibility that a global 10 shortage of donated blood might occur, have been the main influences stimulating this ef- 11 fort. The characteristics of an acceptable oxygen carrying solution would include a better 12 shelf life than banked red blood cells, universal compatibility, physiologically useful intravas- 13 cular half-life, and absence of infection risk. 14 Of the available solutions, shelf life is one to two years and intravascular half-life for 15 most solutions is in the 12-24 hour range. None requires compatibility testing. Preparation 16 processes have included measures to prevent infection transmission of bacteria, viruses, 17 and prions. The currently available solutions are derived from human, bovine, or recombi- 18 nant hemoglobins. The hemodynamic effects of the solutions derive from their oncotic ef- 19 fects and nitric oxide scavenging actions. The currently available hemoglobin solutions all 20 improve tissue oxygen delivery through a combination of oxygen delivery and blood flow 21 improving actions. The oncotic effects of hemoglobin solutions serve to increase blood vol- 1 Page 67 of 119 2
  • 68. 1 ume. Keeping solution viscosity near that of blood serves to improve microvascular flow. 2 The vasopressor effects that derive from nitric oxide scavenging can be offset by encasing 3 the hemoglobin molecules in liposomes. Vasoconstriction can also occur when the cellular 4 oxygen tension in the resistance arterioles increases as a result of off-loading of oxygen 5 from the hemoglobin molecules. This feature of hemoglobin solutions was confirmed in an 6 experimental study reported by Koehler and coauthors62 who showed that brain arteriolar 7 vasoconstriction correlated with off-loading of oxygen to arteriolar cells. 8 Creteur and Vincent stress that modification of hemoglobin solutions that serve to re- 9 duce the vasoconstrictive affects of the solutions result in more efficient oxygen delivery. 10 Solutions that have high viscosity, high oxygen affinity, and high colloid osmotic pressure re- 11 sult in better tissue oxygenation because both oxygen delivery and microcirculatory flow 12 are facilitated. 13 Creteur and Vincent note that avoidance of red blood cell transfusion has become the 14 main index of efficacy in clinical studies of hemoglobin solutions. They cite clinical studies of 15 hemoglobin solution resuscitation of injured patients in shock that have shown reduced red 16 blood cell transfusion volumes and equivalent mortality in groups treated with hemoglobin 17 solutions compared with conventional red blood cell based resuscitation methods. In stud- 18 ies of elective surgical procedures, most patients treated with hemoglobin solutions have 19 been able to avoid allogeneic blood transfusion. 20 Despite these beneficial effects, there remains concern that the vasopressor and vaso- 21 constrictive effects of hemoglobin solutions lead to an increased risk of stroke and myocar- 1 Page 68 of 119 2
  • 69. 1 dial infarction. This concern has been emphasized in a meta-analysis authored by Natanson 2 and coauthors63 in the Journal of the American Medical Association, 2008. These authors an- 3 alyzed five clinical trials involving nearly 4000 patients; they documented a statistically sig- 4 nificant increase in the risk of myocardial infarction and stroke in patients treated with 5 hemoglobin solutions. This meta-analysis has been criticized because of the variability of ex- 6 perimental situations and hemoglobin solutions studied. A review of the clinical usage of 7 hemoglobin solutions in clinical situations, by Napolitano,64 appeared in Critical Care Clinics, 8 2009. In addition to noting the potential shortcomings in the meta-analysis mentioned pre- 9 viously, she notes that the safety record of hemoglobin solution use in South Africa seems 10 to be satisfactory. Nonetheless, this meta-analysis and other safety concerns have prevent- 11 ed approval of hemoglobin solutions for clinical use in the United States. 12 The most detailed analysis of hemoglobin solution use in trauma patients comes from 13 Moore and coauthors65 in the Journal of the American College of Surgeons, 2008. This report 14 presents data from a randomized trial of hemoglobin solution use in seriously injured pa- 15 tients who sustained, for the most part, blunt force injuries. The authors noted a significant 16 reduction in allogeneic transfusion in the patients randomized to receive the hemoglobin 17 solution. Mortality was equivalent in both treatment groups. Adverse events were, howev- 18 er, more frequent in patients receiving hemoglobin solutions. These authors concluded that 19 hemoglobin solution use would be justified in situations where blood might not be avail- 20 able. It is clear that nearly 50 million Americans live more than one hour from a designated 21 or verified trauma center. These patients are at risk for being injured in a setting where 22 blood will not be readily available. Similarly, combat injuries are likely to occur in settings 1 Page 69 of 119 2
  • 70. 1 where blood is not readily available. Hemoglobin solution risk would probably be less than 2 the documented benefit in both situations. 3 Data in support of this benefit is found in a study from Dudkiewicz and coauthors.66 This 4 study evaluated hemoglobin solution resuscitation in an experimental model of hemor- 5 rhage, thoracic injury, and brain injury. In the initial interval, designed to simulate the pre- 6 hospital phase of care, the animals received either saline or hemoglobin solution. There- 7 after, the animals received care designed to simulate protocols of care recommended for 8 patients with severe traumatic brain injury. Treatment in this phase, designed to simulate 9 the emergency department and in-hospital phases of care, focused on maintaining cerebral 10 perfusion pressure and oxygenation. The authors noted that the saline resuscitated animals 11 had maintenance of systemic oxygenation but did not demonstrate restoration of cerebral 12 oxygenation until the 120-minute time point when mannitol was given. The animals receiv- 13 ing hemoglobin solution had restoration of cerebral blood flow and oxygenation within min- 14 utes of receiving the solution and mortality was lower in animals receiving hemoglobin solu- 15 tion. The authors concluded that hemoglobin solution administration could be beneficial in 16 severely injured patients with traumatic brain injury. 17Shock and resuscitation-related coagulopathy 18 In SRGS, Vol. 35, No. 6, the general principles and effective application of “damage con- 19 trol” techniques for management of critically injured patients were discussed. The develop- 20 ment of these techniques was prompted by the recognition of the lethal triad of acidosis, 21 hypothermia, and coagulopathy leading to death in patients with prolonged bleeding and 22 hypovolemic shock. The critically important contribution of “damage control” leading to im- 1 Page 70 of 119 2
  • 71. 1 proved survival in this patient group was to document methods for rapid control of hemor- 2 rhage followed by restoration of tissue perfusion, body temperature, and coagulation sys- 3 tem function in the controlled environment of the intensive care unit. 4 Experience with combat casualties in Iraq and Afghanistan has shown that persistent mi- 5 crovascular hemorrhage from coagulopathy is a component of severe injury that may have 6 its onset early in the management of the trauma victim. These observations have led to the 7 development of “massive transfusion” protocols that stress the replacement of clotting fac- 8 tors along with blood. Combat resuscitation protocols using fresh whole blood are an out- 9 growth of the understanding that clotting factor replacement along with restoration of vol- 10 ume and oxygen carrying capacity ideally should occur simultaneously with hemorrhage 11 control in the severely injured patient. In this section of the overview, the coagulopathy of 12 severe injury will be discussed. 13Mechanisms of coagulopathy 14 The first article reviewed in this section of the overview is by Hess and coauthors67 from 15 the Journal of Trauma, 2008. The article is furnished as a full-text reprint accompanying this 16 issue of SRGS. The article is entitled “The coagulopathy of trauma: a review of 17 mechanisms.” The authors begin by emphasizing the central role of hemorrhage as a deter- 18 minant of outcomes in injured patients. They note that 40% of all trauma deaths are the re- 19 sult of hemorrhage. Lethal bleeding can occur in the immediate postinjury interval leading 20 to death before the injury victim reaches the hospital. The focus of this report, however, is 21 on that group of patients at risk for lethal bleeding because of persistent microvascular 22 hemorrhage that arises when control of bleeding is delayed or incomplete, leading to mas- 1 Page 71 of 119 2
  • 72. 1 sive infusions of red blood cells and electrolyte solutions. The authors stress that the ad- 2 verse affects of activation of the coagulation mechanism are not confined to persistent mi- 3 crovascular bleeding. 4 Activation of coagulation pathways leads to elaboration of pro-inflammatory mediators, 5 exposing the patient to the development of systemic inflammatory response syndrome and 6 multiple system organ failure. Coagulopathy increases the risk of additional intracranial 7 bleeding and additional secondary tissue injury in patients who sustain traumatic brain in- 8 jury. They stress that traumatic brain injury can, by itself, lead to coagulopathy due to re- 9 lease of brain-specific thromboplastins into the circulation. Acute coagulopathy evidenced 10 by an abnormal international normalized ratio was observed in 25% of severely injured pa- 11 tients according to data cited by these authors; in this patient group, there was a four-fold 12 increase in mortality risk. 13 The authors discuss the combined effects of bleeding and tissue injury on activation of 14 coagulation pathways. They point out that tissue injury leads to the exposure of type II col- 15 lagen and tissue factor that is the mechanism for initiation of platelet binding and activation 16 of the coagulation protein cascade. Massive soft tissue injury, in the absence of bleeding 17 and shock, rarely, if ever, results in demonstrable coagulopathy. They note that coagulopa- 18 thy has been thought to occur in patients with multiple long bone fractures by bleeding be- 19 cause of coagulopathy in patients with long bone fractures essentially never occurs without 20 accompanying hemorrhage and hypovolemia. This consistent clinical observation under- 21 scores the importance of the combined effects of tissue trauma and hemorrhagic shock. 1 Page 72 of 119 2
  • 73. 1 The shock-tissue injury combination leads to a hyperfibrinolytic state because of the re- 2 lease of tissue plasminogen activator from injured tissue and from ischemic endothelial 3 cells. Inhibitors of plasminogen activator are also down-regulated with hemorrhage and 4 trauma. As clotting factor levels decrease, abnormal polymerization of fibrin monomers re- 5 sults in a polymer vulnerable to cleavage by plasmin. 6 The authors then review the effects of shock, hemodilution, hypothermia, and acidemia 7 on coagulopathy. End organ hypoperfusion, as evidenced by a base deficit > 6 is associated 8 with coagulopathy (defined as an abnormal international normalized ratio and prolonged 9 partial thromboplastin time) in 25% of injured patients. Platelet counts are preserved in this 10 setting. A consistent observation is that shock is the driver of coagulopathy and this concept 11 is bolstered by a large number of reports confirming coagulopathy in the presence of shock 12 with minimal tissue injury (vascular injury from penetrating mechanism) and the absence of 13 coagulopathy despite extensive tissue injury when hemorrhagic shock is not present. The 14 mechanism of shock-induced coagulopathy remains unclear. It is known that acidemia will 15 interfere with coagulation but coagulopathy is present with lesser degrees of acidemia than 16 necessary to produce this interference. Shock produces changes in coagulation that lead to 17 a relatively anticoagulant and hyperfibrinolytic state. The authors cite one study that has in- 18 criminated increased thrombomodulin activity leading to combined activation of protein C 19 and hyperfibrinolysis. 20 Traditionally, trauma-related coagulopathy has been interpreted to be a “dilutional co- 21 agulopathy” produced by consumption of coagulation factors at the site of injury and dilu- 1 Page 73 of 119 2
  • 74. 1 tion of the remaining factors due to shifts of fluid from interstitial and intracellular spaces 2 and infusion of large volumes of blood and fluid deficient in coagulation factors. Electrolyte 3 fluids and some colloid fluids may alter coagulation according to in vitro studies. Apprecia- 4 tion of the effects of dilution has provided additional support for efforts to restore coagula- 5 tion proteins early in resuscitation. Hypothermia is commonly observed in injured patients, 6 especially those demonstrating abnormal microvascular bleeding. 7 Studies68 from the early 1990s have documented the effects of hypothermia on platelet 8 function and coagulation proteins. A more recent analysis by Wolberg and coauthors69 from 9 the Journal of Trauma, 2004, analyzed coagulation enzyme function and platelet function at 10 37°C and 33°C. They noted no change in platelet activation and only mild changes in coagu- 11 lation enzyme function with reduced temperature. Platelet aggregation and adhesion were 12 significantly impaired at 33°C and below this level; both platelet function and coagulation 13 enzyme activity were impaired. These observations lead to the conclusion that hypothermia 14 plays a role in producing trauma-related coagulopathy when temperature is reduced below 15 33°C, but does not function as an independent driver of the coagulopathy at body tempera- 16 tures observed in most injured patients (34-36°C). Acidemia can alter coagulation functions. 17 Data cited by Hess and colleagues documents significant impairment of activity of coagula- 18 tion factor complexes on cell surfaces at pH levels < 7.0. Fibrinogen degradation is enhanced 19 in acidic environments. Noteworthy is the fact that restoration of pH with buffer does not 20 ameliorate changes in coagulation indicating that combinations of influences are driving the 21 development and severity of coagulopathy. 1 Page 74 of 119 2
  • 75. 1 These authors note that the proinflammatory state commonly observed in many trauma 2 patients who survive the initial injury and resuscitation leads to altered coagulation. During 3 shock and resuscitation, injured patients are in an anticoagulant-hyperfibrinolytic state that 4 evolves into a hypercoagulable state following resuscitation. The characteristics of this hy- 5 percoagulable state are similar to those observed in patients with sepsis and septic shock 6 with depletion of protein C. 7 Hess and associates conclude by noting that trauma-related coagulopathy differs from 8 disseminated intravascular coagulation seen in some forms of sepsis; the coagulopathy has 9 an early onset with abnormalities of prothrombin time and partial thromboplastin time and 10 preserved platelet numbers and normal fibrinogen levels. 11 The view that trauma-related coagulopathy is distinct from classic disseminated in- 12 travascular coagulation is not held by all surgeons. A contrasting view is offered by Gando70 13 in an editorial comment appearing in the Journal of Trauma, 2009. Gando objects to the cat- 14 egorization of the acute coagulopathy of trauma and shock as a unique form of coagulation 15 abnormality and emphasizes the classification of disseminated intravascular coagulation 16 into two phenotypes, fibrinolytic (or hemorrhagic) and antifibrinolytic (or thrombotic). In his 17 view, these two phenotypes correctly characterize the early hemorrhagic and later pro- 18 thrombotic phases of trauma-related coagulopathy. Gando offers data in support of the 19 presence of the hemorrhagic phenotype of disseminated intravascular coagulation early af- 20 ter injury. He further notes his agreement that hemodilution and hypothermia play permis- 21 sive but not primary roles in trauma-related coagulopathy. He concludes by stating that dis- 1 Page 75 of 119 2
  • 76. 1 seminated intravascular coagulation noted in injured patients, septic patients, and patients 2 with medical diseases is a condition characterized by disordered coagulation that may be 3 hemorrhagic or prothrombotic depending on the stimulus and the pattern of disordered an- 4 ticoagulation. 5Editorial comment 6 From the perspective of the editor, the authors of the two interpretations of trauma-re- 7 lated coagulopathy expressed above appear to be in “violent agreement.” Gando empha- 8 sizes the value of defining coagulopathy according to the criteria promulgated by the 9 Japanese Association for Acute Medicine and the International Society on Thrombosis and 10 Hemostasis. He agrees with the mechanisms and clinical descriptions offered by Hess and 11 coauthors. The main point of contention is not clinical but one of terminology. 12Diagnosis of trauma-related coagulopathy 13 Early trauma-related coagulopathy has typically been identified by documenting abnor- 14 malities of prothrombin time (expressed as the international normalized ratio) and activat- 15 ed partial thromboplastin time. This practice has been driven mainly by the availability of 16 these two assays and the fact that results can generally be obtained during the initial as- 17 sessment and resuscitation phase of trauma management. The facts that these two tests do 18 not provide sufficient characterization of the coagulopathy to predict, accurately, the risk of 19 persistent microvascular bleeding or to guide therapy have been widely recognized. The 20 search for more accurate measures has proceeded and thromboelastography has been one 21 test investigated. The use of this measure as a means of characterizing, accurately, the ex- 22 tent of coagulopathy is the subject of an experimental analysis reported by Martini and 1 Page 76 of 119 2
  • 77. 1 coauthors71 in the Journal of Trauma, 2008. The authors created an experimental situation 2 designed to evaluate the effects of shock, hypothermia, and resuscitation on clotting tests 3 currently used to detect the presence of trauma-related coagulopathy. They then compared 4 the commonly used clotting tests to thromboelastography, a test that assesses, separately, 5 initial clot formation time, rapidity of clot formation, time to maximum clotting, and clot 6 strength. In this set of experiments using porcine subjects, shock was produced by bleeding 7 the animal a volume equivalent to 35% of estimated blood volume. Mean arterial pressure 8 was maintained above 40 mm Hg. Resuscitation was carried out with a volume of lactated 9 Ringer’s solution equivalent to three times the hemorrhage volume. Hypothermia, applied 10 with or without shock and resuscitation, was begun at the time of initiation of bleeding and 11 continued until the core temperature was maintained at 32°C. 12 The authors observed little change in activated partial thromboplastin time or pro- 13 thrombin time in any group except the shock-resuscitation-hypothermia group. Platelet 14 counts were reduced with shock-resuscitation, hypothermia, and combined groups, and fib- 15 rinogen level was diminished significantly in the combined shock-resuscitation-hypothermia 16 group. Thromboelastography analyses disclosed significant reductions in clot strength in the 17 shock-resuscitation and combined groups. Hypothermia caused slowing of clot formation 18 time, time to maximum clotting, and clotting rapidity. Shock-resuscitation and combined 19 shock-resuscitation and hypothermia displayed similar findings. The authors concluded that 20 thromboelastography was a more sensitive measure of disorders of coagulation that accom- 21 pany hypothermia, shock, and resuscitation than conventionally used tests. 1 Page 77 of 119 2
  • 78. 1 This group of investigators conducted a clinical study to ascertain whether thromboelas- 2 tography could detect a hypercoagulable state in injured patients and to determine 3 whether the test could identify patients who developed venous thromboembolism. They 4 conducted serial assessments of the coagulation mechanism in a group of 33 injured pa- 5 tients and 25 burn patients. All studies began within 24 hours of admission and continued 6 for seven days. The control group consisted of 20 healthy volunteers. Thromboelastography 7 detected a hypercoagulable state that was confirmed by documenting depressed levels of 8 protein C and elevations of fibrinogen. Activated partial thromboplastin times and pro- 9 thrombin times were prolonged in all patients, suggesting an anticoagulant state. No test 10 detected the three patients who developed pulmonary emboli. The authors concluded that 11 thromboelastography was able to detect, reliably, a hypercoagulable state in this group of 12 injured patients. The data from this study however, do not permit evaluation of thromboe- 13 lastography as a means of predicting thromboembolic complications. 14Editorial comment 15 It is apparent that thromboelastography is a sensitive test for coagulation system dys- 16 function. The test can be a “point of care” assessment carried out at the bedside or in the 17 operating room. Data confirming the utility of the test as an instantaneous guide for thera- 18 peutic decisions has not been forthcoming and this fact probably contributes to lack of 19 widespread adoption of this assessment in trauma centers. The subjects of diagnosis and 20 management of trauma-related coagulopathy are dealt with in more detail in the next sec- 21 tion. 1 Page 78 of 119 2
  • 79. 1Management of coagulopathy 2 The first article reviewed in this section is by Hoyt and coauthors72 in the Journal of 3 Trauma, 2008. This article reports results of an international survey of trauma surgeons. 4 The survey sought to assess practices pertinent to the management of severely injured pa- 5 tients defined as an injury severity score ≥ 16. Most respondents practiced in trauma cen- 6 ters and the majority of the respondents had more than 20 years of clinical experience. The 7 results indicate significant geographic variability. For example, trauma surgeons were more 8 likely to manage patients in the American region while anesthesiologists and other special- 9 ists were active in the management of injured patients in the Europe-Mediterranean region 10 and the Asian-Middle East region. Pharmacologic agents such as aprotinin and desmo- 11 pressin were more likely to be used in areas outside of the American region. Most practi- 12 tioners used general clinical assessment along with body temperature, activated partial 13 thromboplastin time, and prothrombin time to detect coagulopathy. Most respondents re- 14 placed red blood cells, platelets, and clotting proteins (mostly with fresh frozen plasma). 15 Calcium, vitamin K, and recombinant activated factor VII were the most common adjunctive 16 measures used. Fewer than half the respondents followed a prescribed massive transfusion 17 protocol. Many respondents cited barriers to protocol use including delays in obtaining lab- 18 oratory values and blood products. Although this study is limited because less than one- 19 third of the potential respondents actually responded, the available results emphasize the 20 variability and barriers to effective management of coagulopathy in injured patients. 21 The next series of articles reviewed present evidence of the value of early identification 22 of patients at risk for coagulopathy. The principle diagnostic criterion for such patients has 1 Page 79 of 119 2
  • 80. 1 been the need for transfusion of more than 10 units of packed red blood cells within the 2 first 12-24 hours after injury. Once suspicion of trauma-related coagulopathy is present, ag- 3 gressive efforts to stop bleeding along with institution of replacement of blood, clotting pro- 4 teins (fresh frozen plasma), and platelets are indicated. Since ongoing bleeding and shock 5 are the main conditions leading to coagulopathy, successful identification of bleeding points 6 and control of these are critical. The exact configurations of protocols for administration of 7 fresh frozen plasma and platelets continue to evolve. 8 The first article dealing with the appropriate ratio of blood to plasma and platelets is by 9 Holcomb and coauthors73 in Annals of Surgery, 2008. This article is supplied as a full-text 10 reprint accompanying this issue of SRGS. The authors begin by stressing the lethality of early 11 massive bleeding. They note that death from bleeding usually occurs within the first 2-6 12 hours after injury and that most of these deaths are contributed to, at least partially, the 13 development of coagulopathy. They note that recommended civilian injury plasma and 14 platelet administration protocols focus on a ratio of one unit of plasma to three units of red 15 blood cells with platelets administered when bleeding persists and/or when platelet counts 16 are less than 100,000/cm3. Military experience during the conflicts in Iraq and Afghanistan 17 has emphasized the value of early administration of red blood cells, plasma, and platelets in 18 ratios of 1:1:1. Holcomb and associates note that the association of resuscitation with large 19 volumes of electrolyte solution is associated with the diagnosis of abdominal compartment 20 syndrome and they suggest that reductions of electrolyte solution volumes are desirable, al- 21 though clinical evidence to confirm this assertion is scarce. This report involved data from 22 more than 1500 patients admitted to several Level I trauma centers. They were able to doc- 1 Page 80 of 119 2
  • 81. 1 ument an improvement in overall survival from 41% to 71% with increasing ratios of plasma 2 and platelets to red blood cells. 3 Additional data supporting the use of higher plasma to red blood cell ratios comes from 4 a report by Sperry and coauthors74 in the Journal of Trauma, 2008. These authors analyzed a 5 prospective cohort of injured patients who were admitted with clinical signs of shock. Four 6 hundred fifteen of these patients received eight or more units of red blood cells in the first 7 24 hours after injury and these patients were the focus of this analysis. These authors docu- 8 mented a decreased early mortality but an increased frequency of acute respiratory distress 9 syndrome in patients receiving plasma to red blood cell ratio of ≥ 1.5 to 1. Although there 10 was a higher frequency of acute respiratory distress syndrome in the patients who received 11 larger volumes of plasma, the risk-adjusted frequencies of nosocomial infection and multi- 12 ple organ failure were not increased in this patient group. Additional retrospective analy- 13 ses75-76 have also suggested that mortality benefit is observed with increasing use of plasma 14 in patients who have massive hemorrhage. Although these latter studies are limited by ret- 15 rospective design and cannot account for the influence of improved overall recognition and 16 management of massive bleeding, an association remains between improved short-term 17 outcomes and increasing use of plasma. 18 Other reports do not uniformly support a reduction in mortality when aggressive plasma 19 resuscitation is used. It is useful to examine the data to determine which patients will bene- 20 fit from increasing the ratio of plasma to red blood cell transfusion. The first article re- 21 viewed is by Scalea and coauthors77 from the Annals of Surgery, 2008. This article is supplied 1 Page 81 of 119 2
  • 82. 1 as a full-text reprint accompanying this issue of SRGS. This report analyzed prospectively 2 gathered data from patients admitted to the intensive care unit of a single trauma center. 3 The authors report that a massive transfusion protocol was in place during the interval cov- 4 ered by this study. This protocol called for aggressive plasma replacement after five units of 5 packed red blood cells were administered. More than 800 patients were available for analy- 6 sis and 250 of these received plasma and red blood cells during the first 24 hours after in- 7 jury. Eighty-one patients fulfilled criteria for “massive transfusion” as described in the arti- 8 cles reviewed previously. Using logistic regression analysis, these authors could not identify 9 a mortality benefit for aggressive plasma resuscitation even in the massively transfused sub- 10 group. The authors note, in the discussion section of their report, that their study includes 11 brain-injured patients. This patient group is excluded in most of the reports where benefit 12 from increased plasma to red blood cell ratios has been observed. 13 The authors note that their overall mortality was lower than the mortalities reported 14 from combat injury data and from other reports supporting aggressive plasma resuscitation. 15 Finally, the authors note that defining “massive transfusion” in terms of number of units of 16 red blood cells infused over the first 24 hours after injury actually selects a heterogeneous 17 group of patients. Some of these patients present with rapid blood loss (10 or more units 18 within 6-8 hours) while others have slower, more persistent blood loss (10 units spread over 19 the entire 24-hour interval). The risk for coagulopathy is likely different in these two groups 20 of patients. The patients who will likely benefit from aggressive replacement of fresh frozen 21 plasma and platelets (or the use of fresh whole blood) are most likely found in the group 22 with early evidence of rapid blood loss. 1 Page 82 of 119 2
  • 83. 1 A report describing the potential increased risk of morbidity associated with aggressive 2 plasma resuscitation appeared in the Journal of Trauma, 2009, by Watson and coauthors.78 3 This report analyzes data gathered prospectively for a separate study of patients sustaining 4 blunt injury and admitted with a diagnosis of shock. Patients sustaining traumatic brain in- 5 jury were excluded from the analysis. More than one thousand patients were included and 6 nearly two-thirds of the patients received fresh frozen plasma. This report could not identify 7 a relationship between aggressive plasma resuscitation and mortality except when early 8 deaths (within 48 hours) were included. When this was done, a modest reduction in mortal- 9 ity was associated with increasing use of plasma. The authors confirmed an increased risk 10 for acute respiratory distress syndrome and multiple system organ failure with increasing 11 use of fresh frozen plasma. The authors note that a clear determination of an increased risk 12 of dying from acute respiratory distress syndrome and multiple organ failure could not be 13 identified in their analysis. This report was presented during the plenary session of the an- 14 nual meeting of the American Association for the Surgery of Trauma. In the discussion that 15 followed the presentation (included with the article), several discussants emphasize the 16 possibility that there was increased risk for morbidity because a higher proportion of pa- 17 tients survived the early bleeding event. 18 From the available data, reviewed above, it is logical to accept that a group of patients 19 exists who will benefit from aggressive measures to control hemorrhage combined with a 20 resuscitation approach that emphasizes increased ratios of plasma to red blood cells. This 21 group will most likely have severe torso trauma and major vascular injury. Exsanguination 22 within the first 6-8 hours after injury will be the predominant risk. An extension of this 1 Page 83 of 119 2
  • 84. 1 thought process includes consideration for implementation of institutional protocols stress- 2 ing rapid identification of patients at risk, aggressive efforts to control bleeding, and imme- 3 diate availability of red blood cells and plasma. This topic is reviewed in the next two articles 4 discussed. The first is by Cotton and coauthors79 from the Journal of Trauma, 2009. The arti- 5 cle is entitled “Predefined massive transfusion protocols are associated with a reduction in 6 organ failure and postinjury complications.” The protocol evaluated in this report included a 7 telephone alert to the blood bank from the attending trauma surgeon immediately on 8 recognition of the potential for massive transfusion. A blood sample for type and screen of 9 blood products was delivered to the blood bank simultaneously with the alert telephone 10 call. The blood bank immediately prepared and delivered 10 units of un-crossmatched red 11 blood cells, four units of plasma, and two units of platelets and prepared to maintain sup- 12 plies of these products in the same ratio. One hundred twenty-five patients treated under 13 the protocol were compared with matched historical control patients. The authors noted a 14 significant reduction in the frequency of multiple organ failure and abdominal compartment 15 syndrome compared to historical controls. Even with massive transfusion protocols in place, 16 obtaining completely crossmatched blood and thawed plasma may require an hour. Many 17 trauma centers make use of un-crossmatched type O blood for early red blood cell resusci- 18 tation. Type-specific, un-crossmatched blood is not as desirable as type O blood because of 19 the risk of clerical error during a hurried typing process. Type O positive blood can be used 20 for male injured patients; type O negative blood is used for women during the childbearing 21 years. 1 Page 84 of 119 2
  • 85. 1 A report supporting the safety of un-crossmatched blood by Inaba and coauthors80 ap- 2 peared in the Journal of Trauma, 2008. These authors reviewed transfusion usage in more 3 than 25,000 injured patients admitted to a single trauma center over a six-year interval. The 4 authors noted that use of un-crossmatched blood was closely associated with need for mas- 5 sive transfusion. They documented, as have others, that massive transfusion is required 6 most often in young male patients with penetrating torso trauma. They documented, in this 7 analysis, that the use of un-crossmatched blood independently predicted mortality. They 8 stress the importance of early recognition of the patient requiring massive transfusion and 9 they suggest that the order for un-crossmatched blood may be a valuable clue that could be 10 used as a “trigger” for implementation of an institution’s massive transfusion protocol. 11 Although it is tempting to attribute improved results to implementation of a single sys- 12 tem-wide change, there is always a risk that other factors are influencing outcomes. For ex- 13 ample, a report from by Riskin and coauthors81 in the Journal of the American College of 14 Surgeons, 2009, examined the influence of implementation of a massive transfusion proto- 15 col on outcomes. This study reports data from 77 patients treated over a four-year period. 16 Forty patients were treated before protocol implementation and 37 after implementation. 17 The authors noted a significant reduction in mortality in the group treated after protocol 18 implementation. They also documented significantly decreased intervals from admission to 19 blood and plasma availability. Interestingly, there was no difference in ratios of plasma to 20 red blood cells administered to these selected, massively bleeding patients in the first 24 21 hours of treatment in both intervals; ratios were 1:1.8 in both intervals. The authors con- 1 Page 85 of 119 2
  • 86. 1 cluded that factors separate from, or in addition to, the implementation of the massive 2 transfusion protocol were responsible for the observed reductions in mortality. 3Editorial comment 4 The data reviewed documents that a significant proportion of injured patients admitted 5 to trauma centers (up to 25% of admissions) fulfill diagnostic criteria of hemorrhagic/trau- 6 matic shock. Of these, a small proportion will bleed massively and these patients will proba- 7 bly benefit from resuscitation with increased ratios of plasma to red blood cells. Red blood 8 cells and fresh frozen plasma are the main agents used in the early care of these patients. 9 Platelets and cryoprecipitate are used more selectively, based on the time interval required 10 for control of bleeding to occur, platelet counts, and fibrinogen levels. Blood and blood 11 products are in short supply and are expensive. The intent of massive transfusion protocols 12 is to identify patients who would benefit from resuscitation with increased plasma to red 13 blood cell ratios early and to make the necessary products available rapidly so that im- 14 proved survival can occur. It must be emphasized that this approach is likely to benefit rela- 15 tively few patients but it will probably be life-saving in this group. Coupling the availability 16 of blood and blood products with aggressive efforts to identify bleeding sites and control 17 bleeding is critical. It is clear from the articles reviewed that essentially all of the patients 18 who prompt activation of massive transfusion protocols are in transit to the operating room 19 for hemorrhage control. These patients often have sustained penetrating torso trauma and/ 20 or major vascular injury. The absence of clear benefit of plasma-rich resuscitation in unse- 21 lected groups of patients injured primarily by blunt mechanisms emphasizes that massive 22 transfusion protocols cannot be applied to the majority of patients admitted to trauma cen- 1 Page 86 of 119 2
  • 87. 1 ters. The cost of improved survival in massively transfused patients is an increase in the risk 2 of acute respiratory distress syndrome. The available data does not examine healthcare re- 3 source consumption associated with massive transfusion. It is legitimate to hope that mas- 4 sive transfusion protocols would save resources by identifying patients who would benefit 5 and applying resources to this patient group specifically. 6Use of specific hemostatic agents to control microvascular bleeding 7 Although a number of agents are available to assist in hemorrhage control, few of these 8 are effective in the management of life-threatening diffuse microvascular bleeding. Agents 9 such as fibrin glue and recombinant thrombin saturated gelatin sponges are helpful with 10 small areas of bleeding. Desmopressin and aprotinin are limited; these agents are most suc- 11 cessful when given before the bleeding event. Recent reports have emphasized the poten- 12 tial benefit of recombinant factor VIIa as an adjunctive measure for control of persistent, 13 diffuse microvascular bleeding. 14 The first article reviewed is from Dutton and coauthors82 in the Journal of Trauma, 2004. 15 The authors begin by pointing out that this agent was originally developed for use in the 16 management of hemophilia patients who had developed neutralizing antibodies to factor 17 VIII. Recombinant factor VIIa acts by binding tissue factor at the sight of vascular disruption. 18 Coagulation is initiated and a “thrombin burst” is produced on the surface of platelets. Dut- 19 ton and colleagues note that prospective trials have documented the usefulness of this 20 agent in reducing blood loss during major elective surgery and in the management of coagu- 21 lopathy resulting from warfarin. They go on to note that no standard dose exists for use of 22 this agent in injured patients. They chose to use a dose of 100 mcg/kg in injured patients 1 Page 87 of 119 2
  • 88. 1 with bleeding; a dose of 50 mcg/kg was chosen for patients who were coagulopathic sec- 2 ondary to warfarin use. Repeat dosing was used as needed with up to three total doses ap- 3 plied in their patient group. The data regarding efficacy are reported separately for patients 4 with acute traumatic injury, congenital or pharmacologic coagulopathy, and traumatic brain 5 injury. Patients with bleeding because of acute injuries were more likely to be treated with- 6 in the first 24 hours of injury. The authors noted reductions in bleeding in most instances. 7 Thirteen of the 46 patients with acute traumatic bleeding died within the first 24 hours after 8 admission and all of these received relatively large doses of recombinant factor VIIa, raising 9 the possibility that these patients represented failures of treatment. Overall, the authors 10 deemed the treatment successful in assisting to achieve hemostasis in 75% of patients 11 treated. Most of the treatment failures were deemed unsalvageable because of nonsurviv- 12 able injuries or severe brain damage. 13 Dutton and coauthors note the main advantage of recombinant factor VIIa is the imme- 14 diate nature of the drug effect. The authors stress gaps in our knowledge regarding safety. 15 For example, it is not clear whether the agent will accelerate microvascular thrombosis in 16 injured tissue such as the brain. Whether use of this agent enhances the hypercoagulable 17 state seen in patients surviving shock is also not known. Additional data from case series of 18 combat injuries have supported the use of early recombinant factor VIIa in patients with dif- 19 fuse microvascular bleeding from injury and shock.83-84 Patients identified as “massive trans- 20 fusion” patients were treated with doses of recombinant factor VIIa equivalent to120 21 mcg/kg with the dose being repeated, usually up to three times, as needed. These series 22 have noted reductions in overall mortality with no notable increase in episodes of venous 1 Page 88 of 119 2
  • 89. 1 thromboembolism. Readers should note, however, that a causal relationship between use 2 of recombinant factor VIIa and improved survival cannot be established based on data pro- 3 vided. Similarly, with regard to thromboembolic complications, the approach to throm- 4 boembolism detection and protocols for management of thromboembolism prophylaxis 5 were not provided in these articles. Despite these limitations, the evidence suggests that re- 6 combinant factor VIIa is useful as an adjunctive means of hemorrhage control and that the 7 drug has a satisfactory safety profile. 8 Data about patterns of use of recombinant factor VIIa among trauma surgeons are pre- 9 sented in an article by Horton and coauthors85 in The American Surgeon, 2008. These au- 10 thors surveyed surgeons, trauma program managers, and pharmacists who serve in Level I 11 or Level II trauma centers. The survey had a 36% response rate. The responses disclosed 12 that recombinant factor VIIa was used by nearly 90% of Level I trauma centers and just over 13 half of the Level II centers. There was an association between patient volume and usage 14 with increasing usage in high volume centers. Wide variability of dosing was noted. Few 15 centers used the 200 mcg/kg dose that was reported from the only prospective evaluation 16 of the drug in trauma patients reported by Boffard and coauthors.86 Most centers used dos- 17 es at or near the 90 mcg/kg dose recommended for hemophiliac patients. 18 Thrombotic complications are associated with the use of recombinant factor VIIa. This 19 topic is addressed in an article by Rhys Thomas and coauthors87 from the Journal of Trauma, 20 2007. These authors reviewed data from 285 patients treated with this agent during a five- 21 year interval. The authors begin by reviewing data on thrombotic complications associated 1 Page 89 of 119 2
  • 90. 1 with the use of recombinant factor VIIa in patients without traumatic bleeding. For exam- 2 ple, in a reported trial consisting of patients with acute hemorrhagic stroke, 7% of the treat- 3 ed patients had documented thrombotic complications compared with a frequency of 2% in 4 patients receiving placebo. In reported trials and retrospective series dealing with injured 5 patients, no increase in thrombotic complications has been observed. These authors ob- 6 served an overall incidence of thrombotic complications in 9.4% of the 285 patients ana- 7 lyzed. The most serious complications recorded included eight instances of mesenteric in- 8 farction, three instances of myocardial infarction, and five instances of cerebral infarction. 9 The authors noted that the severity of injury in this patient group prevented definite attri- 10 bution of the thrombotic complications to the use of recombinant factor VIIa but the associ- 11 ation of these events to use of the drug suggests that additional surveillance to document 12 the actual risk is warranted. When planning for use of recombinant factor VIIa in a patient 13 with persistent microvascular bleeding, several clinical considerations are appropriate. 14 These are listed in the accompanying table (see Table 1). 15 The use of recombinant factor VIIa as a means of assisting hemostasis in major elective 16 surgical procedures is the topic of a systematic review by Ranucci and coauthors88 in 17 Archives of Surgery, 2008. The authors report data gleaned from seven randomized con- 18 trolled trials. A consistent finding in all studies was a reduction in the number of allogeneic 19 red cell transfusions in groups where recombinant factor VIIa was used as an adjunct to 20 achieve hemostasis. The authors report apparent variability of effectiveness depending on 21 the dose of the agent used in reported trials. They stress the need for additional research so 22 that the appropriate dose for varying indications can be determined; cost of the drug is an 1 Page 90 of 119 2
  • 91. 1 important factor. Where cost/benefit analyses have been done, cost effectiveness is ob- 2 tained in patients requiring massive transfusion only (more than 10 units of red blood cells 3 in 24 hours). 4 In an editorial comment by Dr. Margaret Knudson accompanying the article, data is cit- 5 ed supporting the use of recombinant factor VIIa in situations where major blood loss can 6 be anticipated. She notes that maximum benefit is obtained when the drug is used relative- 7 ly early and is not relied on as a last resort. Another important point emphasized in the edi- 8 torial is the need for additional assessments of the risk of thrombotic complications. She 9 notes that most reports have documented thrombotic events in 2%-4% of patients. This 10 number is, however, smaller than the frequency reported by Rhys Thomas and coauthors87 11 discussed previously. 12Critical care of the patient with sepsis and septic shock 13 In the earlier discussion of the pathophysiology of sepsis and septic shock, emphasis was 14 placed upon the diversity of physiologic responses to inflammation and infection. The septic 15 state is usually characterized by generalized vasodilation and a hyperdynamic circulation. 16 Arterial pressure may be within the low normal range and cardiac index may be increased. 17 Despite these observations, signs of end organ hypoperfusion manifest by elevated blood 18 lactate levels may be present. In patients with severe sepsis, evidence of end organ hypop- 19 erfusion is clear-cut. Septic shock is present when patients exhibit hypotension resistant to 20 intravascular and extracellular volume expansion. Faced with these combinations of clinical 21 manifestations, surgeons caring for septic patients need to be familiar with available means 22 of assessing circulatory status (see the earlier section on monitoring patients in shock) and 1 Page 91 of 119 2
  • 92. 1 to be familiar with the use of volume expanders, vasopressors, inotropic agents, and ad- 2 junctive drugs such as corticosteroids and recombinant activated protein C. These topics are 3 discussed next. 4Goal-directed early comprehensive management of suspected sepsis and/ 5or septic shock 6 Because sepsis and septic shock are associated with infection-induced inflammation, flu- 7 id exudation frequently occurs into the sites of inflammation. In postoperative patients who 8 become septic, recent or ongoing blood loss may also contribute to hypovolemia. Clear evi- 9 dence of myocardial dysfunction will not become manifest until volume status is optimized. 10 Fluid therapy that is too aggressive contributes to sequestration of edema fluid in inflamed 11 tissues. In the lung, edema may contribute to alveolar instability, ventilation/perfusion mis- 12 matching, and hypoxemia. For these reasons, early, goal-directed, fluid therapy of sepsis 13 and septic shock has become a critical component of all care protocols. 14 Recognition of the importance of shortening the duration between injury and definitive 15 care has stimulated the development of prehospital care systems and trauma centers for 16 the management of acutely injured patients. Similarly, observations of septic patients dis- 17 close increasing mortality and morbidity with increases in the interval between recognition 18 of the septic state and implementation of treatment protocols. A classic article dealing with 19 this topic by Rivers and coauthors40 in the New England Journal of Medicine, 2001, empha- 20 sized that mortality for sepsis and septic shock has remained stable despite advances in the 21 effectiveness of therapeutic agents. They note that most reports evaluating these interven- 1 Page 92 of 119 2
  • 93. 1 tions have enrolled patients up to 72 hours after symptom onset. The lack of progress sug- 2 gests that delay in instituting therapy may contribute to suboptimal outcomes. 3 The treatment protocol described in this article required placement of a central venous 4 catheter capable of monitoring central venous oxygen saturation; an arterial catheter was 5 also inserted in each patient. Specimens were obtained for culture and broad-spectrum an- 6 tibiotic therapy was begun. After these interventions, the authors randomly assigned pa- 7 tients to receive conventional intensive care unit admission and treatment and compared 8 this group with patients assigned to receive protocol-directed treatment for a six-hour in- 9 terval in the emergency department, followed by intensive care unit admission. Patients re- 10 ceived electrolyte fluid boluses in volumes of 500 mL/30 minutes until central venous pres- 11 sure was between 8 and 12 cm H20. If, at this point, arterial pressure was ≤ 65 mmHg, vaso- 12 pressors were given to maintain mean arterial pressure at or above 65 mmHg. If mean arte- 13 rial pressure was above 90 mmHg, vasodilator therapy was begun to maintain arterial pres- 14 sure at or near 90 mmHg. After optimization of vascular pressures, central venous oxygen 15 saturation was assessed. If this variable was less than 70%, red blood cell transfusion was 16 given to raise the hematocrit to 30%. If this intervention did not lead to central venous oxy- 17 gen saturation above 70%, inotropic therapy was begun with dobutamine at 2.5 18 mcg/kg/min and the dose was increased in 2.5 mcg increments until central venous oxygen 19 saturation was above 70% or a maximum dose of 20 mcg/kg/min had been reached. Dobu- 20 tamine dosage was reduced if heart rate exceeded 120 bpm or if mean arterial pressure was 21 less than 65 mmHg. If optimum oxygen saturation could not be obtained, oxygen consump- 22 tion was reduced using adjuvant ventilator therapy and sedation. The authors noted that a 1 Page 93 of 119 2
  • 94. 1 similar number of patients were excluded from each group. A few patients in each group 2 were excluded because of the need for urgent operation. There was no difference in clinical 3 characteristics of excluded patients when the patients excluded from each group were com- 4 pared. The authors documented a significantly reduced mortality at 30, 60, and 90 days in 5 patients who had early optimization of end organ perfusion. The authors note that begin- 6 ning assessment of septic patients in the emergency department identified patients with 7 lower central venous oxygen saturations than is typical for septic patients in the intensive 8 care unit. They speculate that this early identification of insufficient oxygen delivery may 9 have contributed to the improvement in mortality that was observed. 10 Despite ongoing debate on use of electrolyte solutions or colloid solutions for early 11 hemodynamic resuscitation of septic patients, available data confirm that the two types of 12 fluid are equivalent in terms of efficacy and safety. Recommendations for fluid therapy are 13 found in a review from Hollenberg and coauthors89 in Critical Care Medicine, 2004. These 14 authors note that significant intravascular and interstitial volume deficits are common in 15 septic patients and, because of this, volume expansion is an important first step in resuscita- 16 tion of this patient group. Hollenberg and associates note that fluid therapy should be guid- 17 ed by clinical assessment of filling pressures and by monitoring of global indices of tissue 18 oxygen supply such as central venous or mixed venous oxygen saturation (see discussion in 19 previous sections of the overview). They stress that venous oxygen saturation may be ele- 20 vated in septic patients and that this variable needs to be considered in the context of the 21 total hemodynamic picture presented by each individual patient. The report also empha- 22 sizes that a liter of electrolyte solution (normal saline or Ringer’s lactate) will provide ap- 1 Page 94 of 119 2
  • 95. 1 proximately 200 mL of persistent intravascular volume expansion. Expected infusion vol- 2 umes within the first 24 hours of management of sepsis may approach 6-10 liters of elec- 3 trolyte solution or 2-4 liters of colloid. Albumin has been the most common colloid evaluat- 4 ed for use in the critically ill septic patient. 5 A report comparing albumin resuscitation to saline resuscitation for critically ill patients 6 is found in a 2004 report by Finfer and coauthors90 from The New England Journal of 7 Medicine. Nearly 7000 patients were included in this randomized prospective study; the 8 vast majority of both treatment groups consisted of acutely injured patients or patients 9 with sepsis. Although the patients treated with saline had net positive fluid balances signifi- 10 cantly higher than observed in the patients receiving albumin during the first three days of 11 treatment, complication rates were equivalent in the two groups. Adequacy of resuscitation 12 was not different in the two groups. When the subgroup of injured patients was analyzed 13 separately, there was a suggestion that saline resuscitation was superior. The authors con- 14 cluded that hemodynamic resuscitation in the intensive care unit could be safely conducted 15 with either saline or albumin. 16 Additional data confirming the importance of early recognition and treatment of sepsis 17 are found in a report by Kumar and coauthors91 in Critical Care Medicine, 2006. In this analy- 18 sis, medical records of nearly 3000 medical and surgical intensive care patients were re- 19 viewed. For patients with the suspected diagnosis of sepsis or septic shock, groups receiving 20 antimicrobial therapy appropriate for the infecting organism within six hours of the onset of 21 hypotension were compared with a group of patients who received antimicrobial therapy 1 Page 95 of 119 2
  • 96. 1 only after hypotension recurred. A significant survival advantage was noted in patients who 2 received early therapy and there was a linear association between the interval of treatment 3 delay and mortality. The highest survival rate (79.9%) was observed in patients who had ap- 4 propriate antimicrobial therapy begun within one hour of symptom recognition. The au- 5 thors stress, in the discussion section of the report, that data from the report authored by 6 Rivers and coauthors40 (discussed above) have demonstrated the importance of early hemo- 7 dynamic resuscitation as a means of achieving improved survival in septic patients. 8 The data reported in this article support the addition of appropriate antimicrobial thera- 9 py to treatment protocols designed for management of the septic patient. In an editorial ac- 10 companying this article, Dr. Peter Gross emphasizes the strengths of this analysis, which are 11 its large sample size, and the consistent results obtained in multiple intensive care units 12 serving a diverse assortment of patients. The strength of the evidence from this study and 13 that of Rivers supports the addition of early hemodynamic resuscitation and early antimi- 14 crobial therapy as performance measures for the management of patients with suspected 15 sepsis or septic shock. Gross notes that these performance measures are being incorporat- 16 ed into sepsis management protocols (sepsis bundles) that provide evidence-based guid- 17 ance for the management of these patients. 18 Early support for a comprehensive management protocol for sepsis and septic shock is 19 found in a description of the guidelines for management of sepsis promulgated by the Sur- 20 viving Sepsis Campaign. These guidelines are found in an article by Dellinger and coauthors92 21 in Critical Care Medicine, 2004. The guidelines were updated with strengthened evidence in 1 Page 96 of 119 2
  • 97. 1 2008.92 In these two articles, a group of interventions including early fluid therapy, antimi- 2 crobial therapy, source control, glycemic control, and selective use of corticosteroids are in- 3 cluded in a “bundled” approach to the septic patient. Each measure is supported by evi- 4 dence with sufficient strength to justify inclusion of the intervention as a performance mea- 5 sure (supported by evidence stronger than expert opinion). The recommended measures 6 are listed in the accompanying table (see Table 2). 7 The effectiveness of “bundling” multiple interventions into a comprehensive manage- 8 ment protocol for sepsis is examined in an article by Kortgen and coauthors93 in Critical Care 9 Medicine, 2006. The report describes a “before and after” study of patients in a single inten- 10 sive care unit. Thirty patients fulfilling diagnostic criteria for septic shock were treated with 11 a protocol that stressed early goal-directed resuscitation, appropriate antimicrobial therapy, 12 stress dose corticosteroids, glycemic control, and selective use of recombinant activated 13 protein C. Results in these 30 patients were compared with a similar-sized cohort of histori- 14 cal control patients. The authors noted that goals of treatment were achieved earlier in the 15 patients treated with the sepsis protocol. The use of insulin, hydrocortisone, and recombi- 16 nant activated protein C all increased following implementation of the protocol. The au- 17 thors noted a reduction in mortality from 53% to 27% when the two groups of patients 18 were compared. 19 The authors conclude that implementation of an evidence-based protocol for sepsis 20 care is feasible and that uniformity of utilization of the recommended interventions was 21 achieved in their unit. In an editorial by Rivers that accompanied this report, emphasis is 1 Page 97 of 119 2
  • 98. 1 placed on the wide variability noted in the United States when rates of use of evidence- 2 based interventions for sepsis are assessed. Rivers asserts that implementation of evidence- 3 based protocols is appropriate and necessary if improvements in sepsis outcomes are to be 4 achieved. 5 Additional evidence that protocol implementation is feasible as a means of improving 6 the early care of patients with sepsis and septic shock is found in another article in the same 7 issue of Critical Care Medicine, 2006.94 In this report, the authors describe some of the edu- 8 cational and process change measures that eased the protocol implementation process. The 9 objectives of the protocol were to enhance early recognition of septic patients, to institute 10 early evidence-based therapy in the emergency department, and to improve outcomes for 11 septic patients. The authors used the regularly scheduled medical and nursing staffs of a 12 university hospital. They conducted education and provided real-time feedback. Care pro- 13 cesses were made easier by providing “sepsis carts” containing equipment and medications, 14 and written versions of the protocol elements. The 116 protocol patients were compared 15 with historic controls. The results disclose that early usage of resuscitation fluids, antimicro- 16 bials, corticosteroids, and recombinant activated protein C all increased after implementa- 17 tion of the protocol. There was a reduction in overall hospital mortality from 29% to 21% 18 but this reduction was not statistically significant. Readers should note, however, that the 19 historic sepsis mortality in this institution was lower than that reported in other series. In 20 fact, it was already near the 20-25% mortality reported in many of the protocol-treated 21 groups reported in evaluations of early management of sepsis. An additional statistically sig- 22 nificant reduction was, therefore, unlikely. 1 Page 98 of 119 2
  • 99. 1Use of vasopressors 2 A significant proportion of septic patients have mild arterial hypotension. By definition, 3 patients with septic shock are hypotensive. Because of the varying efficiency of autoregula- 4 tion in peripheral vascular beds and the wide distribution of tissue oxygen consumptions, 5 choosing an arterial pressure that will uniformly correct disorders of tissue oxygen dynamics 6 is challenging. Most recommendations for arterial pressure targets for septic patients have 7 selected a mean arterial pressure range of 60-70 mmHg because, for most vascular beds, 8 autoregulation is lost and tissue blood flow becomes pressure dependent at mean pres- 9 sures below 60 mmHg. Although at least one clinical report has noted no improvement in 10 tissue oxygen dynamics when a mean arterial pressure target of 85 mmHg was chosen, oth- 11 er studies have shown increases in urine output with stepwise increases in mean arterial 12 pressure. 13 A study by Jhanji and coauthors95 in Critical Care Medicine reported increases in cuta- 14 neous oxygen tension and microvascular flow with increasing norepinephrine doses in 16 15 patients with septic shock. These authors used transcutaneous oxygen measurements and 16 Doppler laser flowmetry to assess microvascular oxygen availability and blood flow. Sublin- 17 gual microvascular flow was assessed with sidestream darkfield imaging. Dosing of nore- 18 pinephrine was adjusted to achieve mean arterial pressures of 60, 70, 80, and 90 mmHg se- 19 quentially. Global oxygen delivery as well as cutaneous oxygen tension and cutaneous mi- 20 crovascular flow increased in keeping with each increase in mean arterial pressure. Sublin- 21 gual microcirculatory status did not change. Outcome assessments were not obtained in 22 these patients. The authors concluded that additional research is desirable to refine defini- 1 Page 99 of 119 2
  • 100. 1 tions of optimum endpoints for vasopressor therapy in patients with septic shock. These ob- 2 servations serve to confirm data from articles discussed in previous sections of the overview 3 confirming the heterogeneity of oxygen delivery, blood flow, and autoregulation in various 4 vascular beds. Studies of capnometry44 have noted the similarity between the sublingual mi- 5 crocirculation and the intestinal microcirculation. The failure to correct flow and oxygen de- 6 livery in the sublingual area suggests that sepsis-induced reductions in flow to the vital vis- 7 ceral vascular bed may remain impaired despite increasing doses of norepinephrine. 8 When patients remain hypotensive despite correction of intravascular volume, vaso- 9 pressor therapy is indicated. This topic is discussed in a review by Hollenberg96 in Chest, 10 2007. The author notes that several vasoactive agents are available for arterial pressure en- 11 hancement in septic patients. These include isoproterenol, dopexamine (may not be widely 12 available in the United States), dobutamine, dopamine, epinephrine, norepinephrine, and 13 phenylephrine. Isoproterenol, dopamine and dobutamine are predominantly beta-receptor 14 agonists. Alpha-receptor stimulatory effects are progressively more pronounced for 15 epinephrine, norepinephrine, and phenylephrine. Dopamine has been recommended as the 16 first line vasoactive agent for the management of sepsis. At low doses (5 mcg/kg/min), 17 dopamine stimulates dopaminergic receptors and vasodilation results. This property was 18 the basis for using dopamine as a means of improving renal blood flow and preventing renal 19 failure but this approach failed. In the dosage range from 5-10 mcg/kg/min, dopamine is pri- 20 marily a beta-receptor stimulant and improvements in myocardial contractility increase car- 21 diac output because of an increase in stroke volume. A secondary effect of dopamine is to 22 increase heart rate that also aids in increasing cardiac output. At doses above 10 1 Page 100 of 119 2
  • 101. 1 mcg/kg/min, dopamine is an alpha-receptor agonist causing vasoconstriction and increases 2 in arterial pressure result from this action. 3 Hollenberg cautions that there is substantial overlap in the thresholds for these hemo- 4 dynamic actions. He goes on to note that dopamine regularly increases global oxygen deliv- 5 ery but consistent improvements in tissue oxygen delivery have not been observed. 6 Dopamine may predispose to cardiac arrhythmias. Because the drug increases heart rate, 7 myocardial oxygen demand may also increase and this effect may be dangerous in patients 8 with coronary artery disease. It is worth noting that one article, by Sakr and coauthors97, 9 compared 375 patients who were treated for shock with dopamine with 683 patients who 10 were in shock but not treated with dopamine. Mortality was significantly higher in patients 11 who received dopamine. In a multivariate analysis, dopamine treatment was independently 12 associated with mortality. 13 Hollenberg notes that norepinephrine is primarily an alpha-receptor agonist and im- 14 proves blood pressure by producing peripheral vasoconstriction. Norepinephrine may pro- 15 duce modest increases in cardiac output. The dose of norepinephrine required to produce 16 needed increases in mean arterial pressure may vary because of alpha-receptor down regu- 17 lation that occurs in sepsis. The author cites a randomized prospective trial comparing nore- 18 pinephrine to dopamine in hypotensive septic patients. Norepinephrine at doses of 1.5-3 19 mcg/kg/min raised arterial pressure to the target range in more than 90% of patients com- 20 pared with 31% satisfactory response to dopamine. Furthermore, 90% of the patients who 21 failed dopamine therapy responded to norepinephrine. Available evidence cited by Hollen- 1 Page 101 of 119 2
  • 102. 1 berg indicates that norepinephrine increases blood pressure without impairing cardiac func- 2 tion and there are data suggesting improved mortality for septic patients treated with nore- 3 pinephrine. Because of the evidence cited above, norepinephrine is recommended as the 4 first choice drug for managing hypotension in septic patients who remain hypotensive fol- 5 lowing optimization of volume status. 6 Hollenberg notes that phenylephrine is generally used as a second line drug when tach- 7 yarrhythmias complicate therapy with other vasopressor drugs. Epinephrine raises blood 8 pressure but the drug increases lactate levels, produces hypoglycemia, and predisposes to 9 tachyarrhythmias. 10 Arginine vasopressin has been suggested as an adjunct to low-dose norepinephrine for 11 the management of hypotension in septic patients. Hollenberg96 notes that this hormone is 12 synthesized in the hypothalamus and stored in the pituitary gland. The hormone is released 13 in response to decreases in intravascular volume and is an arterial vasoconstrictor, acting 14 via V1 receptors on arterial smooth muscle cells. There is evidence that V1 receptors are up- 15 regulated in sepsis and septic shock and that, with time, there is depletion of vasopressin 16 stores. These factors suggest that replacement of vasopressin to achieve physiologic plasma 17 levels would augment the needed vasoconstrictor response in sepsis. Hollenberg cites data 18 suggesting that a constant infusion of vasopressin (0.03 U/min) improves the blood pres- 19 sure response to low-dose norepinephrine. 20 A recent randomized, prospective, double blind trial compared norepinephrine treat- 21 ment alone with norepinephrine combined with arginine vasopressin infusion at the dosage 1 Page 102 of 119 2
  • 103. 1 level cited above.98 The outcomes of interest were 28 day and 90 day mortality. The authors 2 did not confirm a mortality benefit in the group treated with norepinephrine plus vaso- 3 pressin. In the subset of patients with less severe septic shock, there was a trend toward 4 lowered mortality in the group treated with vasopressin but the study was not designed to 5 analyze patients based on shock severity. The authors of the study note that overall mortali- 6 ty rates for both groups were low compared with prior experience and this may reflect an 7 overall improvement in outcomes for patients with sepsis treated with modern protocol ap- 8 proaches. 9 A recent report suggesting a synergistic effect of vasopressin and corticosteroid therapy 10 in patients with septic shock is from Russell and coauthors99 in Critical Care Medicine, 2009. 11 Nearly 800 patients were diagnosed with septic shock and treated with norepinephrine 12 and/or vasopressin. The vasopressin dose ranged from 0.01 U/min–0.03 U/min. Hydrocorti- 13 sone in “stress” doses (150-200 mg/day) was given according to the judgment of the prima- 14 ry caregiver. The authors noted a significant mortality reduction in patients who received 15 hydrocortisone and vasopressin compared with patients who received norepinephrine and 16 hydrocortisone. The authors speculate that interaction between vasopressin and hydrocor- 17 tisone at the V1b receptor may serve to increase serum cortisol levels and produce a syner- 18 gistic effect on arterial tone. 19 Because vasopressin, in the low doses recommended, has few, if any, adverse side ef- 20 fects, combining norepinephrine, cortisone, and vasopressin in selected patients may be 1 Page 103 of 119 2
  • 104. 1 beneficial. Additional data regarding this association is needed. Review of the use of “stress- 2 dose” hydrocortisone therapy in septic shock will occur in a later section of the overview. 3Use of inotropic drugs 4 Traditional approaches to the management of septic patients have included the use of 5 inotropic agents such as dobutamine to assist in support of cardiac output in patients with 6 persistent low cardiac output despite volume loading and vasopressors. The use of inotropic 7 agents in patients with sepsis-associated myocardial depression producing decreased car- 8 diac output is a topic reviewed by Leone and Martin100 in Advances in Sepsis, 2006. These 9 authors note that some septic patients have myocardial depression evidenced by low cen- 10 tral venous oxygen saturation and echocardiographic evidence of myocardial dysfunction. 11 Such patients could possibly benefit from dobutamine therapy. Leone and Martin note that 12 one study reported increased cardiac output when dobutamine was added to nore- 13 pinephrine therapy in septic shock patients with myocardial dysfunction. Leone and Martin 14 caution, however, that beta-1 stimulation has been shown to lead to cardiac myocyte apop- 15 tosis. Fortunately, the proportion of septic patients with documentable myocardial dysfunc- 16 tion is small. 17Use of “stress-dose” corticosteroids 18 High-dose corticosteroid therapy (30 mg/kg methylprednisolone) was suggested as a 19 means of reducing mortality in patients with septic shock in the 1970s. This approach be- 20 came controversial and a meta-analysis authored by Cronin and coauthors101 in Critical Care 21 Medicine, 1995, concluded that “current evidence provides no support for the use of corti- 22 costeroids in septic shock and suggests that their use may be harmful.” In subsequent years, 1 Page 104 of 119 2
  • 105. 1 the discovery that certain proinflammatory states are associated with relative adrenal insuf- 2 ficiency and/or inflammation induced glucocorticoid receptor resistance led to trials that fo- 3 cused on diagnosis of relative adrenal insufficiency with therapy targeted toward patients 4 with adrenal insufficiency. 5 The first article reviewed in this segment of the overview is from Annane and coau- 6 thors102 in the Journal of the American Medical Association, 2002. The article is entitled “Ef- 7 fect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in pa- 8 tients with septic shock.” The authors open their report by citing data suggesting that rela- 9 tive adrenal insufficiency can be detected in critically ill patients using a short corticotropin 10 test. This assessment is performed as follows: a blood sample for measurement of baseline 11 blood cortisol is obtained and this is followed by a single 250 mcg intravenous dose of tetra- 12 cosactin. Additional samples are drawn for blood cortisol levels 30 and 60 minutes after the 13 injection. An elevation of blood cortisol over baseline of 9 mcg/dL or less is considered evi- 14 dence of relative adrenal insufficiency. All patients in this trial fulfilled usual diagnostic crite- 15 ria for septic shock. All underwent testing for adrenal insufficiency, and all were randomized 16 to receive hydrocortisone (50 mg four times daily for seven days) and oral (or via feeding 17 tube) fludrocortisone 50 mcg daily. The endpoint of interest was overall mortality. 18 Mortality in patients diagnosed with relative adrenal insufficiency was 63% in the place- 19 bo group and 53% in the treatment group. This difference was statistically significant. Mor- 20 tality reductions were observed for ICU, hospital, and one-year mortality time points. An ad- 21 ditional trial appeared in the New England Journal of Medicine in 2008 by Sprung and coau- 1 Page 105 of 119 2
  • 106. 1 thors.103 In this trial, patients were enrolled if they had infection and hypotension requiring 2 volume and vasopressor therapy for at least one hour. Randomization could occur within 3 three days of identification of septic shock. A standard corticotropin test was administered 4 to all enrolled patients. This trial could not identify a mortality benefit for stress dose 5 steroids in patients who fulfilled diagnostic criteria for relative adrenal insufficiency com- 6 pared with those who did not. 7 Several important differences exist between this trial and the trial reported by Annan- 8 ne102 discussed above. First, the patients entered into the 2008 trial were, as a group, not as 9 severely septic or as dependent on vasopressors as the patients in the Annane trial. The ob- 10 served mortality in the 2008 trial was less than 30% compared with a mortality rate of 63% 11 in placebo patients in the earlier trial. This would suggest that the groups are not compara- 12 ble and that there have been overall improvements in the management of septic shock that 13 may serve to reduce the impact of cortisone replacement therapy. The results of these trials 14 have led to recommendations for the diagnosis and management of corticosteroid insuffi- 15 ciency in critically ill adult patients. 16 These recommendations can be found in an article by Marik and coauthors104 in Critical 17 Care Medicine, 2008. This article is supplied as a full-text reprint accompanying this issue of 18 SRGS. The recommendations state that diagnosis of relative adrenal insufficiency be estab- 19 lished using the response to a standard corticotropin test or a random blood cortisol of < 10 20 mcg/dL. The recommendations further state that cortisone replacement therapy be admin- 21 istered in a dose of 50 mg four times daily or a continuous infusion of 240 mg/day. This 1 Page 106 of 119 2
  • 107. 1 therapy should be offered to patients with severe, vasopressor dependent septic shock. 2 Higher dose therapy (methylprednisolone 1 mg/kg/day for 14 days) is appropriate for pa- 3 tients with early, severe, acute respiratory distress syndrome. 4Use of recombinant activated protein C 5 Sepsis and septic shock are known to trigger an inflammatory and procoagulant cascade 6 that predisposes to microvascular thrombosis and this may be the etiology of organ failure 7 leading to death in septic patients. A number of interventions designed to modulate these 8 cascades have been evaluated in an effort to target the underlying pathophysiology of sep- 9 sis. Success has been limited in these trials. An agent targeting the coagulation system is re- 10 combinant activated protein C. This agent has been shown to improve microcirculation in 11 sepsis according to data cited in a review by Fuller and Dellinger.105 Additional data cited by 12 these authors indicate that early improvement (within 12-24 hours of beginning treatment) 13 in tissue oxygen was predictive of survival from severe septic shock. 14 An early trial reported by Bernard and coauthors106 in the New England Journal of 15 Medicine, 2001, documented a 6% absolute mortality reduction in patients with severe sep- 16 sis. This survival advantage was observed in patients who were severely ill only (APACHE 17 score > 25). The main adverse affects of treatment with recombinant activated protein C is 18 bleeding; fatal intracranial hemorrhage has been reported in patients where the drug has 19 been used. Use of this agent in patients with increased bleeding risk (abnormal coagulation 20 parameters, peptic ulcer disease, vascular injury, or solid organ injury) is contraindicated. 1 Page 107 of 119 2
  • 108. 1Management of cardiogenic shock 2 Management of patients with suspected cardiogenic shock begins with a rapid assess- 3 ment to determine adequacy of the airway, oxygenation, and circulation. Patients suspect- 4 ed to be hypovolemic will benefit from a fluid challenge and/or blood transfusion (similar to 5 fluid challenges used in the management of hemorrhagic and septic shock, discussed 6 above). Physical examination assisted by plain chest radiograph can disclose clinical evi- 7 dence of pulmonary congestion. Electrocardiography and echocardiography are useful, ear- 8 ly in patient management, to quantify the extent of ischemia and left ventricular dysfunc- 9 tion. Similarly, pulmonary artery catheter placement can supply sequential data on pul- 10 monary artery pressures and cardiac index. Topalian and coauthors29 supply an algorithm 11 suggesting therapeutic approaches adjusted for the presence of hypotension and/or signs 12 of end-organ hypoperfusion. They stress that signs of hypoperfusion can occur without pro- 13 found hypotension. For patients with arterial pressures consistently above 100 mmHg, in- 14 travenous nitroglycerine in doses of 10-20 mcg/min will produce coronary vasodilation and 15 improve coronary flow. Dobutamine is used for hypotensive patients without signs of end- 16 organ hypoperfusion to elevate arterial pressure. Doses of 2-20 mcg/kg/min are indicated 17 initially. If signs of hypoperfusion are present, the initial dose can be increased to 5-15 mcg/ 18 kg/min. Failure to achieve improved blood pressure is an indication for using intravenous 19 norepinephrine. Norepinephrine doses are titrated in the 0.5-30 mcg/min as a continuous 20 intravenous infusion. 21 Early revascularization using percutaneous coronary angioplasty or coronary artery by- 22 pass grafting has reduced overall long-term mortality for patients with myocardial infarction 1 Page 108 of 119 2
  • 109. 1 complicated by cardiogenic shock. This result is particularly noticeable in patients < 75 years 2 old although, as noted by Topalian and associates, mortality rates for older patients are bet- 3 ter in patients who are revascularized than in patients not revascularized. Thus, older pa- 4 tients with good functional status are candidates for early revascularization. These authors 5 note that despite the improved overall outcomes with early revascularization, such inter- 6 ventions are still underutilized. They cite a report that was published in 2004 indicating that 7 only half of eligible patients had revascularization. 8 Overall results of systemic administration of fibrinolytic agents have been inferior to di- 9 rect revascularization procedures. This lack of efficacy probably results from poor penetra- 10 tion of the thrombus by fibrinolytic drugs and early reocclusion of coronary arteries that 11 have been opened by fibrinolysis. 12 Topalian and colleagues go on to discuss the use of intra-aortic balloon counterpulsa- 13 tion. They note that these devices, which can now be introduced percutaneously, can im- 14 prove coronary flow and reduce left ventricular afterload. Currently, these devices are 15 largely used as “bridges” to revascularization interventions. Nearly one-third of the inser- 16 tions of intra-aortic balloon devices, in a report cited by these authors, were for cardiogenic 17 shock. Intra-aortic balloon counterpulsation is useful, as well, in patients with cardiogenic 18 shock because of acute mitral insufficiency and septal rupture. Patients with right ventricu- 19 lar infarction refractory to fluid therapy may also benefit. Complications of the devices in- 20 clude arterial injury, bleeding, and hemolysis. Intra-aortic balloon pumps may be contraindi- 1 Page 109 of 119 2
  • 110. 1 cated in patients with aortic insufficiency, aortic aneurysm, and severe peripheral arterial 2 atherosclerosis. 3 Ventricular assist devices, which can be placed in the cardiac catheterization laboratory, 4 are useful as a means to “buy time” before cardiac transplantation or placement of an im- 5 planted ventricular assist device. Topalian and coauthors conclude by noting that death 6 from cardiogenic shock occurs more often in patients who experience a delay in diagnosis of 7 myocardial infarction. They encourage public education efforts to inform patients of the im- 8 portance of early medical care at the first sign of developing acute myocardial ischemia. 1 Page 110 of 119 2
  • 111. 1 2 TABLES 1 Page 111 of 119 2
  • 112. 1 Table 1 2 Clinical considerations for use of recombinant factor VIIa. 3 1. Is patient salvage realistically possible? (best results are obtained when 4 recombinant factor VIIa is used before the onset of terminal acidosis, 5 hypothermia, and coagulopathy) 6 2. Has accessible, surgically controllable bleeding been addressed? 7 3. Has patient been resuscitated to pH > 7.25? (Recombinant factor VIIa is less effective in acidic environments) 8 4. Have clotting protein levels been restored with fresh frozen plasma? 9 5. Is patient platelet count > 50,000? (Recombinant factor VIIa requires 10 adequate numbers of functioning platelets? 11 6. Is potential benefit from treatment with recombinant factor VIIa suffi- cient to justify the risk? (serious thrombotic complications occur in ap- 12 proximately 10% of patients who have received recombinant factor VIIa 1 Page 112 of 119 2
  • 113. 1 2 3 Table 2 4 Recommended interventions for the initial management of sepsis and 5 septic shock. 6 1. Early (within 6 hrs or less) goal-directed hemodynamic resuscita- tion guided by central venous pressure (8-12 cmH20 or higher if 7 patient is on positive pressure ventilation), mean arterial pressure (titrate to > 65 mmHg), and central venous oxygen saturation 8 (titrate to > 70%) using electrolyte or colloid fluids. 9 2. Blood and other cultures prior to beginning antimicrobial drugs. 10 3. Imaging studies to confirm origin of sepsis. 4. Administration of broad-spectrum antimicrobial drugs within first hour of clinical suspicion of sepsis. Continue antimicrobial therapy for 7-10 days. Adjust antimicrobial therapy depending upon cul- ture results. 5. Vasopressor therapy using norepinephrine or dopamine to raise mean arterial pressure if fluid therapy is unsuccessful. 6. Consider dobutamine therapy if fluids and vasopressors do not re- store cardiac output. 7. Source control using least invasive procedure that has a high pos- sibility of success. (see discussion in SRGS Vol. 35 No. 7 8. Stress dose corticosteroid therapy for patients with septic shock that is poorly responsive the therapy. 9. Use of lung protective ventilation and weaning protocols includ- ing intermittent cessation of sedation. (see discussion in SRGS Vol. 35 No. 8) 10. Use of preventive measures for ventilator associated pneumonia. 11. Control of hyperglycemia. 12. Accept hemoglobin level of 7 gm/dL if patient is stable and free of clinically evident coronary artery disease. 13. Venous thromboembolism prophylaxis. 1 Page 113 of 119 2
  • 114. 1 2 3 REFERENCES 4 51. Goodnough LT. Risks of blood transfusion. Crit Care Med 2003; 31(12 Suppl):S678-86. 62. Bernard AC, Davenport DL, Chang PK, et al. Intraoperative transfusion of 1 U to 2 U packed red 7 blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and 8 sepsis in general surgery patients. J Am Coll Surg 2009; 208(5):931-7, 937 e1-2; discussion 938-9. 93. Weinberg JA, McGwin G, Jr., Marques MB, et al. Transfusions in the less severely injured: does 10 age of transfused blood affect outcomes? J Trauma 2008; 65(4):794-8. 114. Dunne JR, Lee TH, Burns C, et al. Transfusion-associated microchimerism in combat casualties. J 12 Trauma 2008; 64(2 Suppl):S92-7; discussion S97-8. 135. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated 14 report by the American Society of Anesthesiologists Task Force on Perioperative Blood 15 Transfusion and Adjuvant Therapies. Anesthesiology 2006; 105(1):198-208. 166. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial 17 fibrillation. Ann Intern Med 2009; 151(5):297-305. 187. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of 19 transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, 20 Canadian Critical Care Trials Group. N Engl J Med 1999; 340(6):409-17. 218. Hashimoto T, Kokudo N, Orii R, et al. Intraoperative blood salvage during liver resection: a 22 randomized controlled trial. Ann Surg 2007; 245(5):686-91. 239. Mirza SB, Campion J, Dixon JH, et al. Efficacy and economics of postoperative blood salvage in 24 patients undergoing elective total hip replacement. Ann R Coll Surg Engl 2007; 89(8):777-84. 2510. Hughes DB, Ullery BW, Barie PS. The contemporary approach to the care of Jehovah's witnesses. 26 J Trauma 2008; 65(1):237-47. 2711. Gohel MS, Bulbulia RA, Slim FJ, et al. How to approach major surgery where patients refuse 28 blood transfusion (including Jehovah's Witnesses). Ann R Coll Surg Engl 2005; 87(1):3-14. 2912. Jabbour N, Gagandeep S, Shah H, et al. Impact of a transfusion-free program on non-Jehovah's 30 Witness patients undergoing liver transplantation. Arch Surg 2006; 141(9):913-7. 3113. Borchelt BD, Wright PA, Evans JA, et al. Cell swelling and depolarization in hemorrhagic shock. J 32 Trauma 1995; 39(2):187-92; discussion 192-4. 3314. Zakaria el R, Li N, Matheson PJ, et al. Cellular edema regulates tissue capillary perfusion after 34 hemorrhage resuscitation. Surgery 2007; 142(4):487-96; discussion 496 e1-2. 3515. Matheson PJ, Mays CJ, Hurt RT, et al. Modulation of mesenteric lymph flow and composition by 36 direct peritoneal resuscitation from hemorrhagic shock. Arch Surg 2009; 144(7):625-34. 3716. Malinoski DJ, Hadjizacharia P, Salim A, et al. Elevated serum pancreatic enzyme levels after 38 hemorrhagic shock predict organ failure and death. J Trauma 2009; 67(3):445-9. 3917. Senthil M, Brown M, Xu DZ, et al. Gut-lymph hypothesis of systemic inflammatory response 40 syndrome/multiple-organ dysfunction syndrome: validating studies in a porcine model. J 41 Trauma 2006; 60(5):958-65; discussion 965-7. 4218. Diebel LN, Liberati DM, Ledgerwood AM, et al. Systemic not just mesenteric lymph causes acute 43 lung injury following hemorrhagic shock. Surgery 2008; 144(4):686-93; discussion 693-4. 1 Page 114 of 119 2
  • 115. 119. Diebel LN, Liberati DM, Lucas CE, et al. Systemic not just mesenteric lymph causes neutrophil 2 priming after hemorrhagic shock. J Trauma 2009; 66(6):1625-31. 320. Jastrow KM, 3rd, Gonzalez EA, McGuire MF, et al. Early cytokine production risk stratifies trauma 4 patients for multiple organ failure. J Am Coll Surg 2009; 209(3):320-31. 521. Sperry JL, Friese RS, Frankel HL, et al. Male gender is associated with excessive IL-6 expression 6 following severe injury. J Trauma 2008; 64(3):572-8; discussion 578-9. 722. Sperry JL, Nathens AB, Frankel HL, et al. Characterization of the gender dimorphism after injury 8 and hemorrhagic shock: are hormonal differences responsible? Crit Care Med 2008; 9 36(6):1838-45. 1023. Machiedo GW, Zaets SB, Berezina TL, et al. Trauma-hemorrhagic shock-induced red blood cell 11 damage leads to decreased microcirculatory blood flow. Crit Care Med 2009; 37(3):1000-10. 1224. Gonzales ER, Chen H, Munuve RM, et al. Hepatoprotection and lethality rescue by histone 13 deacetylase inhibitor valproic acid in fatal hemorrhagic shock. J Trauma 2008; 65(3):554-65. 1425. Alam HB, Shuja F, Butt MU, et al. Surviving blood loss without blood transfusion in a swine poly- 15 trauma model. Surgery 2009; 146(2):325-33. 1626. Rushing GD, Britt LD. Reperfusion injury after hemorrhage: a collective review. Ann Surg 2008; 17 247(6):929-37. 1827. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 19 348(2):138-50. 2028. Ayala A, Perl M, Venet F, et al. Apoptosis in sepsis: mechanisms, clinical impact and potential 21 therapeutic targets. Curr Pharm Des 2008; 14(19):1853-9. 2229. Topalian S, Ginsberg F, Parrillo JE. Cardiogenic shock. Crit Care Med 2008; 36(1 Suppl):S66-74. 2330. Aymong ED, Ramanathan K, Buller CE. Pathophysiology of cardiogenic shock complicating acute 24 myocardial infarction. Med Clin North Am 2007; 91(4):701-12; xii. 2531. Lipsky AM, Gausche-Hill M, Henneman PL, et al. Prehospital hypotension is a predictor of the 26 need for an emergent, therapeutic operation in trauma patients with normal systolic blood 27 pressure in the emergency department. J Trauma 2006; 61(5):1228-33. 2832. McCunn M, Dutton R. End-points of resuscitation how much is enough? Curr Opin Anaesthesiol 29 2000; 13(2):147-53. 3033. Pinsky MR. Hemodynamic evaluation and monitoring in the ICU. Chest 2007; 132(6):2020-9. 3134. Taylor RW, Jr., Calvin JE, Matuschak GM. Pulmonary Artery Catheter Consensus Conference: the 32 first step. Crit Care Med 1997; 25(12):2064-5. 3335. Pinsky MR, Vincent JL. Let us use the pulmonary artery catheter correctly and only when we 34 need it. Crit Care Med 2005; 33(5):1119-22. 3536. Voga G. Pulmonary artery occlusion pressure estimation by transesophageal echocardiography: 36 is simpler better? Crit Care 2008; 12(2):127. 3737. Martin MJ, FitzSullivan E, Salim A, et al. Use of serum bicarbonate measurement in place of 38 arterial base deficit in the surgical intensive care unit. Arch Surg 2005; 140(8):745-51. 3938. FitzSullivan E, Salim A, Demetriades D, et al. Serum bicarbonate may replace the arterial base 40 deficit in the trauma intensive care unit. Am J Surg 2005; 190(6):941-6. 4139. Jansen TC, van Bommel J, Bakker J. Blood lactate monitoring in critically ill patients: A systematic 42 health technology assessment*. Crit Care Med 2009. 4340. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis 44 and septic shock. N Engl J Med 2001; 345(19):1368-77. 4541. Friese RS, Dineen S, Jennings A, et al. Serum B-type natriuretic peptide: a marker of fluid 46 resuscitation after injury? J Trauma 2007; 62(6):1346-50; discussion 1350-1. 1 Page 115 of 119 2
  • 116. 142. Ivatury RR, Simon RJ, Islam S, et al. A prospective randomized study of end points of 2 resuscitation after major trauma: global oxygen transport indices versus organ-specific gastric 3 mucosal pH. J Am Coll Surg 1996; 183(2):145-54. 443. Hameed SM, Cohn SM. Gastric tonometry: the role of mucosal pH measurement in the 5 management of trauma. Chest 2003; 123(5 Suppl):475S-81S. 644. Boswell SA, Scalea TM. Sublingual capnometry: an alternative to gastric tonometry for the 7 management of shock resuscitation. AACN Clin Issues 2003; 14(2):176-84. 845. Baron BJ, Dutton RP, Zehtabchi S, et al. Sublingual capnometry for rapid determination of the 9 severity of hemorrhagic shock. J Trauma 2007; 62(1):120-4. 1046. Moore FA, Nelson T, McKinley BA, et al. Massive transfusion in trauma patients: tissue 11 hemoglobin oxygen saturation predicts poor outcome. J Trauma 2008; 64(4):1010-23. 1247. Leone M, Blidi S, Antonini F, et al. Oxygen tissue saturation is lower in nonsurvivors than in 13 survivors after early resuscitation of septic shock. Anesthesiology 2009; 111(2):366-71. 1448. Wan JJ, Cohen MJ, Rosenthal G, et al. Refining resuscitation strategies using tissue oxygen and 15 perfusion monitoring in critical organ beds. J Trauma 2009; 66(2):353-7. 1649. van Lelyveld-Haas LE, van Zanten AR, Borm GF, et al. Clinical validation of the non-invasive 17 cardiac output monitor USCOM-1A in critically ill patients. Eur J Anaesthesiol 2008; 18 25(11):917-24. 1950. Bickell WH, Wall MJ, Jr., Pepe PE, et al. Immediate versus delayed fluid resuscitation for 20 hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331(17):1105-9. 2151. Lucas CE. The water of life: a century of confusion. J Am Coll Surg 2001; 192(1):86-93. 2252. Todd SR, Malinoski D, Muller PJ, et al. Lactated Ringer's is superior to normal saline in the 23 resuscitation of uncontrolled hemorrhagic shock. J Trauma 2007; 62(3):636-9. 2453. Cotton BA, Guy JS, Morris JA, Jr., et al. The cellular, metabolic, and systemic consequences of 25 aggressive fluid resuscitation strategies. Shock 2006; 26(2):115-21. 2654. Koustova E, Stanton K, Gushchin V, et al. Effects of lactated Ringer's solutions on human 27 leukocytes. J Trauma 2002; 52(5):872-8. 2855. Kramer GC. Hypertonic resuscitation: physiologic mechanisms and recommendations for trauma 29 care. J Trauma 2003; 54(5 Suppl):S89-99. 3056. Meybohm P, Cavus E, Bein B, et al. Small volume resuscitation: a randomized controlled trial 31 with either norepinephrine or vasopressin during severe hemorrhage. J Trauma 2007; 32 62(3):640-6. 3357. Sperry JL, Minei JP, Frankel HL, et al. Early use of vasopressors after injury: caution before 34 constriction. J Trauma 2008; 64(1):9-14. 3558. Rizoli SB, Rhind SG, Shek PN, et al. The immunomodulatory effects of hypertonic saline 36 resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized, controlled, 37 double-blinded trial. Ann Surg 2006; 243(1):47-57. 3859. Deree J, de Campos T, Shenvi E, et al. Hypertonic saline and pentoxifylline attenuates gut injury 39 after hemorrhagic shock: the kinder, gentler resuscitation. J Trauma 2007; 62(4):818-27; 40 discussion 827-8. 4160. Coimbra R, Loomis W, Melbostad H, et al. Role of hypertonic saline and pentoxifylline on 42 neutrophil activation and tumor necrosis factor-alpha synthesis: a novel resuscitation strategy. J 43 Trauma 2005; 59(2):257-64; discussion 264-5. 4461. Creteur J, Vincent JL. Potential uses of hemoglobin-based oxygen carriers in critical care 45 medicine. Crit Care Clin 2009; 25(2):311-24, Table of Contents. 4662. Koehler RC, Fronticelli C, Bucci E. Insensitivity of cerebral oxygen transport to oxygen affinity of 47 hemoglobin-based oxygen carriers. Biochim Biophys Acta 2008; 1784(10):1387-94. 1 Page 116 of 119 2
  • 117. 163. Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based blood substitutes and risk of 2 myocardial infarction and death: a meta-analysis. JAMA 2008; 299(19):2304-12. 364. Napolitano LM. Hemoglobin-based oxygen carriers: first, second or third generation? Human or 4 bovine? Where are we now? Crit Care Clin 2009; 25(2):279-301, Table of Contents. 565. Moore EE, Moore FA, Fabian TC, et al. Human polymerized hemoglobin for the treatment of 6 hemorrhagic shock when blood is unavailable: the USA multicenter trial. J Am Coll Surg 2009; 7 208(1):1-13. 866. Dudkiewicz M, Harpaul TA, Proctor KG. Hemoglobin-based oxygen carrying compound-201 as 9 salvage therapy for severe neuro- and polytrauma (Injury Severity Score = 27-41). Crit Care Med 10 2008; 36(10):2838-48. 1167. Hess JR, Brohi K, Dutton RP, et al. The coagulopathy of trauma: a review of mechanisms. J 12 Trauma 2008; 65(4):748-54. 1368. Reed RL, 2nd, Bracey AW, Jr., Hudson JD, et al. Hypothermia and blood coagulation: dissociation 14 between enzyme activity and clotting factor levels. Circ Shock 1990; 32(2):141-52. 1569. Wolberg AS, Meng ZH, Monroe DM, 3rd, et al. A systematic evaluation of the effect of 16 temperature on coagulation enzyme activity and platelet function. J Trauma 2004; 56(6):1221-8. 1770. Gando S. Acute coagulopathy of trauma shock and coagulopathy of trauma: a rebuttal. You are 18 now going down the wrong path. J Trauma 2009; 67(2):381-3. 1971. Martini WZ, Cortez DS, Dubick MA, et al. Thrombelastography is better than PT, aPTT, and 20 activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia, 21 hemorrhagic shock and resuscitation in pigs. J Trauma 2008; 65(3):535-43. 2272. Hoyt DB, Dutton RP, Hauser CJ, et al. Management of coagulopathy in the patients with multiple 23 injuries: results from an international survey of clinical practice. J Trauma 2008; 65(4):755-64; 24 discussion 764-5. 2573. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios 26 improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 27 248(3):447-58. 2874. Sperry JL, Ochoa JB, Gunn SR, et al. An FFP:PRBC transfusion ratio >/=1:1.5 is associated with a 29 lower risk of mortality after massive transfusion. J Trauma 2008; 65(5):986-93. 3075. Teixeira PG, Inaba K, Shulman I, et al. Impact of plasma transfusion in massively transfused 31 trauma patients. J Trauma 2009; 66(3):693-7. 3276. Duchesne JC, Islam TM, Stuke L, et al. Hemostatic resuscitation during surgery improves survival 33 in patients with traumatic-induced coagulopathy. J Trauma 2009; 67(1):33-7; discussion 37-9. 3477. Scalea TM, Bochicchio KM, Lumpkins K, et al. Early aggressive use of fresh frozen plasma does 35 not improve outcome in critically injured trauma patients. Ann Surg 2008; 248(4):578-84. 3678. Watson GA, Sperry JL, Rosengart MR, et al. Fresh frozen plasma is independently associated with 37 a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma 2009; 38 67(2):221-7; discussion 228-30. 3979. Cotton BA, Au BK, Nunez TC, et al. Predefined massive transfusion protocols are associated with 40 a reduction in organ failure and postinjury complications. J Trauma 2009; 66(1):41-8; discussion 41 48-9. 4280. Inaba K, Teixeira PG, Shulman I, et al. The impact of uncross-matched blood transfusion on the 43 need for massive transfusion and mortality: analysis of 5,166 uncross-matched units. J Trauma 44 2008; 65(6):1222-6. 4581. Riskin DJ, Tsai TC, Riskin L, et al. Massive transfusion protocols: the role of aggressive 46 resuscitation versus product ratio in mortality reduction. J Am Coll Surg 2009; 209(2):198-205. 4782. Dutton RP, McCunn M, Hyder M, et al. Factor VIIa for correction of traumatic coagulopathy. J 48 Trauma 2004; 57(4):709-18; discussion 718-9. 1 Page 117 of 119 2
  • 118. 183. Spinella PC, Perkins JG, McLaughlin DF, et al. The effect of recombinant activated factor VII on 2 mortality in combat-related casualties with severe trauma and massive transfusion. J Trauma 3 2008; 64(2):286-93; discussion 293-4. 484. Perkins JG, Schreiber MA, Wade CE, et al. Early versus late recombinant factor VIIa in combat 5 trauma patients requiring massive transfusion. J Trauma 2007; 62(5):1095-9; discussion 6 1099-101. 785. Horton JD, DeZee KJ, Wagner M. Use of rFVIIa in the trauma setting--practice patterns in United 8 States trauma centers. Am Surg 2008; 74(5):413-7. 986. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding 10 control in severely injured trauma patients: two parallel randomized, placebo-controlled, 11 double-blind clinical trials. J Trauma 2005; 59(1):8-15; discussion 15-8. 1287. Thomas GO, Dutton RP, Hemlock B, et al. Thromboembolic complications associated with factor 13 VIIa administration. J Trauma 2007; 62(3):564-9. 1488. Ranucci M, Isgro G, Soro G, et al. Efficacy and safety of recombinant activated factor vii in major 15 surgical procedures: systematic review and meta-analysis of randomized clinical trials. Arch Surg 16 2008; 143(3):296-304; discussion 304. 1789. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of 18 sepsis in adult patients: 2004 update. Crit Care Med 2004; 32(9):1928-48. 1990. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in 20 the intensive care unit. N Engl J Med 2004; 350(22):2247-56. 2191. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective 22 antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 23 2006; 34(6):1589-96. 2492. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for 25 management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34(1):17-60. 2693. Kortgen A, Niederprum P, Bauer M. Implementation of an evidence-based "standard operating 27 procedure" and outcome in septic shock. Crit Care Med 2006; 34(4):943-9. 2894. Shapiro NI, Howell MD, Talmor D, et al. Implementation and outcomes of the Multiple Urgent 29 Sepsis Therapies (MUST) protocol. Crit Care Med 2006; 34(4):1025-32. 3095. Jhanji S, Stirling S, Patel N, et al. The effect of increasing doses of norepinephrine on tissue 31 oxygenation and microvascular flow in patients with septic shock. Crit Care Med 2009; 32 37(6):1961-6. 3396. Hollenberg SM. Vasopressor support in septic shock. Chest 2007; 132(5):1678-87. 3497. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine administration in shock influence outcome? 35 Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med 2006; 36 34(3):589-97. 3798. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with 38 septic shock. N Engl J Med 2008; 358(9):877-87. 3999. Russell JA, Walley KR, Gordon AC, et al. Interaction of vasopressin infusion, corticosteroid 40 treatment, and mortality of septic shock. Crit Care Med 2009; 37(3):811-8. 41100. Leone MM, C. How to use adrenergic support in sepsis. Advances in Sepsis 2006; 5(3):78-87. 42101. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and 43 meta-analysis of the literature. Crit Care Med 1995; 23(8):1430-9. 44102. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone 45 and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288(7):862-71. 46103. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl 47 J Med 2008; 358(2):111-24. 1 Page 118 of 119 2
  • 119. 1104. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management 2 of corticosteroid insufficiency in critically ill adult patients: consensus statements from an 3 international task force by the American College of Critical Care Medicine. Crit Care Med 2008; 4 36(6):1937-49. 5105. Fuller BM, Dellinger RP. Hemodynamic resuscitation in septic shock: cardiovascular support and 6 adjunctive therapy. Curr Infect Dis Rep 2009; 11(5):357-64. 7106. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated 8 protein C for severe sepsis. N Engl J Med 2001; 344(10):699-709. 9 10 1 Page 119 of 119 2