Transfusion and Shock

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Transfusion and Shock

  1. 1. TRANSFUSION AND SHOCK FUNDAMENTALS OF MANAGEMENT IN SURGICAL PATIENTS Page 1 of 120 1 2 1 2
  2. 2. INTRODUCTION Transfusion practices and shock are the topics chosen for this issue of Selected Readings in General Surgery (SRGS). In the section dealing with transfusion practices we focus on risks of transfusion, methods for salvaging blood and reducing transfusion volume, and management of the patient who refuses blood and/or blood products. We then move on to a discussion of shock. Classifications of shock have evolved in the last five decades. Currently shock states are classified as hemorrhagic/traumatic, neurogenic (spinal cord injury), cardiogenic, obstructive (pulmonary embolus, pericardial tamponade), and distributive (septic, inflammatory). In this issue of SRGS, a discussion of shock from hemorrhage and/or injury, and septic shock are offered. Other forms of shock have been discussed in previous issues of SRGS dealing with trauma and venous disease. Transfusion in surgical patients—risks and current practices Blood and blood products are life-saving substances and critically important tools used by surgeons to manage critically ill and injured patients. Risks associated with blood product administration include hemolytic transfusion reactions (which usually result from errors in processing and administration), disease transmission, and transfusion-related lung injury. Stored leucocytes may cause febrile acute transfusion reactions. Leucocytes also mediate the process of alloimmunization to platelets. Furthermore, transfusions are associated with immune modulation related to the duration of storage. Transfusion of older units of banked red blood cells in patients with few risk factors for infection has been associated with an increased risk of infection and mortality. Measures to reduce the number of leucocytes in Page 2 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  3. 3. banked blood have not been universally effective in preventing presumed leucocyte- mediated changes in the immune system. Because blood products are, for the most part, administered after acquisition from unrelated donors and stored for varying periods before administration to patients, functions of transfused red blood cells, platelets, and coagulation proteins are not normal and may not immediately correct abnormalities in oxygen delivery or clot formation. The pathophysiologic effects of continued bleeding, combined with the need for multiple transfusions, lead to a coagulopathic state. In this and following sections of the overview, we discuss these problems. The first article reviewed is by Goodnough1 in Critical Care Medicine, 2003. The article is entitled “Risks of blood transfusion.” The author begins by noting that the rarity of serious transfusion reactions and transfusion-related disease transmission has made estimation of the risks of transfusion difficult. Mathematical models have been developed to predict transfusion risk and these models assume that disease transmission is most likely to occur when blood from infected donors is collected in the “window period” when the donor is infectious but donor-screening tests are not positive. This assumption may lead to underestimation of disease transmission risk. Another potentially hazardous assumption is related to the fact that patients who receive blood have 1- and 10-year mortality rates ranging from 24%-52%. The patients may not survive long enough for the diagnosis of disease transmission to be made. Despite these limitations, Goodnough emphasizes that risks of transmission of viral diseases (mainly hepatitis B and C and human Page 3 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  4. 4. immunodeficiency virus) are lower than at any time in the history of transfusion. He presents a table indicating a risk of hepatitis transmission of 1/220,000 transfusions to 1/800,000 transfusions, and a risk of human immunodeficiency virus transmission of 1/1.4 million transfusions. Available data show that risk continues to decline with improved practices of donor screening, particularly the recently implemented practice of nucleic acid testing. The author moves on to discuss specific aspects of viral disease transmission. He notes that the first documented instance of transmission of human immunodeficiency virus in banked blood occurred in 1982. Before screening blood tests were available, blood banks began screening donors for specific characteristics and allowing donors to self-exclude their blood after donation. This practice resulted in an immediate decline in instances of transmission. With the implementation of antibody testing in March 1985, the rate of reported transmissions of human immunodeficiency virus decreased from more than 700/year to 5/year. Additional small increments of progress occurred after the introduction of screening for p24 antigen. Hepatitis B virus transmission declined markedly after the introduction of third-generation tests for the hepatitis B surface antigen. Hepatitis B currently accounts for only 10% of the instances of hepatitis transmission in transfused blood products. Hepatitis C is an important viral disease that can be transmitted via transfusion. Transfusion-related hepatitis C leads to chronic disease in more than 80% of cases. Twenty percent of infections progress to cirrhosis; one to five percent of infections lead to hepatocellular carcinoma. The mortality risk for hepatitis C over 25-30 years after transfusion-related infection is nearly 15%. Page 4 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  5. 5. Screening for human immunodeficiency and hepatitis viral disease is very effective. Since 1999, worldwide, only two cases of human immune deficiency virus infection and one case of hepatitis C have been reported where all screening tests performed in the donors were negative. Cytomegalovirus infection related to transfusion of blood products is an important cause of mortality and morbidity in patients immunocompromised from treatment for malignant disease. The largest risk is observed in patients undergoing stem cell or bone marrow transplantation. The prevalence of cytomegalovirus infection in these patient groups is 60% and viral disease develops in up to one-half of the infected patients. Viral disease can be reduced but not eliminated by using transfusions of blood cells from donors with negative serum tests of cytomegalovirus infection. The author cites data to show that granulocyte transfusions from serum-negative donors resulted in seroconversion in 1%-4% of patients. Other data indicate that the risk of infection is not different with cells originating from donors who are positive for cytomegalovirus infection compared with negative, but the risk of clinically overt viral disease seems to be less when negative donor cells are used. Cytomegalovirus infection is much less common in patients who undergo autologous stem cell or bone marrow transplantation. This protection is observed despite equivalent rates of serum assay conversion and urinary excretion of viral products in patients undergoing allogeneic or autologous bone marrow transplantation. Goodnough notes that 10%-50% of blood donors test negative for cytomegalovirus infection. Leuco- reduction seems to reduce the risk of cytomegalovirus infection also. Current recommendations state that patients receiving allogeneic or autologous bone marrow Page 5 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  6. 6. transplants should receive blood products donated by serum-negative patients; these products should undergo leuco-reduction. Bacterial infection of banked blood products can cause rare but often fatal sepsis in patients who receive transfusion. Yersinia enterocolitica is the most common pathogen infecting red blood cell units. The contamination rate is less than 1/million donated units but clinical infection may become manifest during the transfusion and the mortality rate for clinical infection is 60%. Platelets carry the greatest risk for bacterial infection because these units are stored, for up to five days, at temperatures of 20-24°C. This means that stored platelets are an excellent culture medium for bacteria. Goodnough cites surveillance data indicating that bacterial contamination occurs in one of every 1000-2000 units. Because four million platelet units are transmitted annually in the United States (25% of these are apheresis platelets), estimates are that 300-1000 cases of bacterial sepsis may be expected each year. Pooled platelets carry a higher risk than apheresis platelet transfusions. Liquid medium culturing of platelets has been implemented in an effort to reduce the risk of infection. Other infectious diseases that can potentially be transmitted by blood products include leukemias caused by human lymphotrophic virus 1 or 2. Only a single case had been reported at the time of publication of Goodnough’s article . Epstein-Barr virus disease, leishmaniasis, babesiosis, toxoplasmosis, brucellosis, malaria, Chagas disease, West Nile virus, and prion disease can be transmitted potentially by blood products, but such instances are extremely rare. Page 6 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  7. 7. Leucocytes in stored blood have been implicated in the production of febrile transfusion reactions, postoperative infection, transfusion-related lung injury (discussed in SRGS, Vol. 35, No. 8), and increased recurrence risk for colon cancer. In an article by Bernard and coauthors2 (reviewed in SRGS, Vol. 35, No. 7), an increased risk for mortality and surgical site infection was noted using an analysis of data from the NSQIP database. Currently universal leuco-reduction programs have not resulted in significant protection against these complications. Another report by Weinberg and coauthors3 presents data on injured patients in a retrospective study. These authors had previously observed an increased risk for mortality and infectious morbidity in injured patients who received large volumes of transfused blood. This association was particularly pronounced in patients who received blood with storage age > 14 days. In this study, the authors focused on patients less severely injured (injury severity score of less than 25) who did not receive early or large volume transfusion. They documented an increased risk for mortality, renal failure, and pneumonia when these less severely injured patients received any transfusion of blood with a storage age of > 14 days. The blood administered to these patients was leuco-reduced. These authors note that transfusion carries a risk of mortality and infection related to the age of stored blood, and this risk is not eliminated by leuco-reduction. Their data confirm a number of other analyses of transfusion risk in injured patients. Goodnough cites additional data that indicate no reduction in the risk of infection after cardiac operations when leuco- reduced blood was used. Another study noted no change in the risk of recurrence of colorectal cancer when a leuco-reduction program was implemented. Page 7 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  8. 8. Additional evidence of immune system alterations occurring in patients transfused with blood and blood products is found in an article by Dunne and coauthors4 in the Journal of Trauma, 2008. These authors note that micro-chimerism, or the persistence of donor cells in the circulation of the recipient, represents additional evidence of immune modulation occurring after transfusion. These authors investigated the role of fresh versus banked blood in producing micro-chimerisms in combat casualties. They studied 26 severely injured soldiers who had received fresh whole blood, banked blood, or blood plus platelets. Blood samples from these patients were compared with blood samples from patients who had received no transfusions. There was no evidence of micro-chimerism in the patients who had not been transfused. Half of the patients who had received fresh whole blood had evidence of micro-chimerism. A similar proportion of patients who had received banked blood or blood plus platelets showed evidence of micro-chimerism. The authors cite data from other studies that confirm the significant occurrence of micro-chimerism. The clinical significance of this finding is unknown currently but micro-chimerism is known to be associated with graft-versus-host disease in patients receiving bone marrow transplants. Most of the morbidity from blood transfusion results from transfusion reactions associated with errors of cross matching or blood product administration. Goodnough1 notes that errors in the blood bank or misidentification of recipients occur at a rate of 1/14,000-18,000 transfusions in the United States and Great Britain. Approximately two- thirds of these events are the result of patient misidentification or failure to recognize a transfusion reaction. One-third of the errors occur during crossmatching and blood labelling processes in the blood bank. Approximately 10% of hemolytic transfusion reactions are Page 8 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  9. 9. fatal. The mortality rate for error-related transfusion complications is roughly twice that for all transfusion-related mortalities from infection. Editorial comment Transfusion of blood and blood products is not without risk. To date, measures to establish the specific mechanism of transfusion-related immune modulation have not clearly identified the factors responsible for these changes. Knowledge of these alterations has led to the development of conservative transfusion protocols. It is now recognized that transfusion can be safely withheld in stable patients with hemoglobin levels ≥ 7gm/dL. Higher hemoglobin targets may be required in the critically ill and unstable, or in patients with severe coronary artery disease. Blood and blood products are best used for specific indications; protocols that identify specific goals of blood product use and document evidence of achievement of carefully chosen outcomes will provide surgeons the best means to achieve effective use of blood and blood products. Current transfusion practices Practice guidelines for the use of blood and blood products in the perioperative period were developed and promulgated by the American Society of Anesthesiologists. A summary of the practice guidelines is found in a report published in Anesthesiology in 2006.5 The guidelines begin with a review of practical measures for detection of patients who might require blood or blood products. The initial evaluation includes, at a minimum, review of medical records, detailed history focusing on historical evidence of congenital disorders of coagulation, hemoglobinopathy, and other blood disorders. Additional findings in the history will provide information on the risk of ischemic cardiac disease, any history of use of Page 9 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  10. 10. prescription drugs, over-the -counter drugs, or herbal remedies that alter coagulation, and history of prior transfusion. Evidence of prior exposure to drugs (aprotinin) that could precipitate allergic reaction on repeat administration is sought. The patient and family are questioned to document the willingness, or lack of willingness, to accept blood transfusion. Recommended laboratory assessments include hemoglobin and hematocrit determinations and a coagulation profile. Management of patients who refuse blood products will be discussed in a later section of the overview. The guidelines note that specific evidence to support use of drugs such as aprotinin, epsilon-amino caproic acid, and tranexamic acid is lacking except for certain cardiac or orthopaedic procedures associated with significant risk of bleeding (for example, reoperation for open cardiac surgery and reoperation for joint replacement). They emphasize that anti-fibrinolytic drugs have been implicated in vascular graft thrombosis and severe allergic reactions have resulted from aprotinin use. Evidence to document the value of preoperative erythropoietin treatment of anemia is not available although certain patient groups such as patients with renal disease, anemia of chronic disease, and patients who refuse transfusion may benefit. Several weeks of treatment are required for correction of anemia using erythropoietin. The guidelines note that preoperative collection of autologous blood has been associated with reduced transfusion risks. They emphasize, however, that severe transfusion reactions (associated with misidentification of patients) and bacterial infections have been reported from programs using preoperative collection of autologous blood. Page 10 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  11. 11. The guidelines recommend cessation of drugs such as warfarin, aspirin, and clopidogrel before elective operations. Intervals of one to three weeks are required for reversal of the affects of clopidogrel and aspirin on platelets. The method chosen for preoperative restoration of clotting function depends on a careful assessment of the type, urgency, and risk of the surgical procedure chosen. The risk of thromboembolic complications that might occur soon after the chronic warfarin dose is decreased or eliminated is also assessed. For example, patients with cancer are at increased risk for thromboembolic complications. By contrast, recent data indicate that stroke risk reduction from warfarin treatment in patients with atrial fibrillation is overcome by the risk of bleeding when patients are under 70 years of age and have minimal stroke risk.6 Warfarin cessation can result in restoration of clotting capability as evidenced by an international normalized ratio of 1.5 within several days to one week. Operation is usually safe at this level of INR and re-starting of warfarin when the patient is stable and free of significant bleeding risk usually results in rapid and dependable re-anticoagulation. If reversal of warfarin affects is needed within 48-72 hours, intravenous vitamin K is indicated. More rapid reversal than this will require use of fresh frozen plasma or, occasionally, recombinant activated factor VII. Use of recombinant factor VII is discussed in more detail later in the overview. Reversal of warfarin with vitamin K or fresh frozen plasma is associated with more difficult re-anticoagulation postoperatively. The decision to transfuse before, during, and after an operation is based on clinical assessments of the volume of blood loss and the physiologic effects of blood loss. Monitoring of ongoing blood loss requires clear and frequent communication between the surgical team and the anesthesiology team. Use of assessments of blood pressure, heart Page 11 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  12. 12. rate, arterial oxygen saturation, central venous pressure, pulmonary artery occlusion pressure, central venous (or mixed venous) oxygen saturation, and lactate levels depends on type of operation and patient risk. For patients with a history of cardiac dysfunction, intraoperative echocardiography may be indicated. The practice guidelines note that assessments of blood pressure, heart rate, and arterial oxygen saturation are routine during surgical procedures, but the literature is unclear about specific contributions these assessments make with regard to transfusion. A synthesis of various information points will usually be required to support clinical decisions. Intraoperative measurement of hemoglobin and hematocrit is common but these values may not reflect end-organ perfusion status. The guidelines note that transfusion is not needed in stable patients who do not have cardiac disease until the hemoglobin level is below 6 gm/dL. Transfusion is definitely not needed when the hemoglobin level is above 10 gm/dL. The decision to transfuse patients whose hemoglobin levels are between 6 gm/dL and 10 gm/dL is made based on assessment of each patient’s cardiovascular reserve, the risk of ongoing blood loss, and the status of end organ perfusion. The safety of lower hemoglobin levels in stable, critically ill patients was documented in a 1999 report by Hebert and coauthors.7 An appreciation of the risks of transfusion and an understanding of the limitations of the blood supply has stimulated caution and overall conservatism about use of banked blood and blood products. Benefits of a conservative approach to transfusion are most obvious in patients under the age of 55 who have no clinical evidence of cardiovascular disease. Assessment and monitoring of patients with blood loss and shock are discussed in later sections of the overview. Page 12 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  13. 13. Coagulopathy from massive transfusion is discussed in a later section. The practice guidelines support the use of fresh frozen plasma for this condition as well as cryoprecipitate for the support of fibrinogen levels. Recombinant activated factor VII may be useful as “rescue therapy” for patients with microvascular bleeding. The guidelines note that measures such as normovolemic hemodilution and deliberately lowered venous pressures may be helpful in selected patients undergoing cardiac, hepatic, and orthopedic procedures. Techniques of perioperative blood salvage Blood recovery and reinfusion during and/or after an operation is potentially a means of reducing the use of blood and blood products in surgical patients. Collection and reinfusion of blood after tube thoracostomy for traumatic hemothorax has been shown to be safe. Because liver surgeons have recognized the value of low central venous pressure as a means of reducing blood loss during liver parenchymal transection, there is interest in collecting blood before liver transaction, and re-infusing the blood once liver hemostasis has been obtained. This topic is addressed in an article by Hashimoto and coauthors8 in Annals of Surgery, 2007. These authors conducted a randomized trial comparing one group of living liver donors who had removal of a volume of blood equal to 0.7% of body weight with a group of patients treated with conventional management of liver resection. The endpoints of interest were the amount of blood loss during liver parenchymal transection and the volume of banked blood infused after parenchymal transection. The patients who had removal and reinfusion of blood had significantly less blood loss and used less banked blood than the patients did in the comparison group. The trend toward smaller blood Page 13 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  14. 14. product use in patients who had intraoperative blood salvage was identified, but this difference was not statistically significant. Intraoperative blood salvage is used frequently in cardiac surgical procedures. The value of this approach in abdominal operations is debated. Limitations to the use of intraoperative blood salvage in abdominal operations are concerns over depletion of clotting factors in salvaged blood and the potential for bacterial contamination during abdominal procedures. Recovery of postoperative blood drainage from the operative site is possible using closed drainage systems that collect blood through a filtration system into a blood administration bag. This approach is used in Europe and is especially well suited for patients undergoing orthopaedic procedures that, predictably, have significant postoperative blood drainage. An article describing the potential value of postoperative blood salvage by Mirza and coauthors9 appeared in the Annals of the Royal College of Surgeons, 2007. The authors report results in 109 patients undergoing total hip replacement. The amount of perioperative blood loss (as indicated by the change in hemoglobin level) in these patients was compared with a group of historical control patients. Patients who had blood salvage had a smaller perioperative hemoglobin drop. Nine percent of the salvage patients required perioperative transfusion of banked blood compared with 30 percent of the historical control group. The authors conclude that this approach may reduce use of banked blood in patients undergoing operations associated with predictable postoperative drainage of uncontaminated blood. Page 14 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1 2
  15. 15. Management of patients who refuse blood and blood products Surgeons inevitably will encounter patients who decline all or some parts of proposed strategies for care of surgical conditions. Use of blood and blood products is unacceptable to some patients. Typically, this patient group includes, but is not limited to, Jehovah’s Witnesses. A significant body of knowledge has accumulated that has permitted safe surgical care for Jehovah’s Witnesses and this knowledge can be used to optimize the care of any patient who declines the use of blood and blood products. In this section of the overview, we will discuss two articles that focus on the elements of care for Jehovah’s Witnesses. The first article discussed is from Hughes and coauthors10 in the Journal of Trauma, 2008, entitled “The contemporary approach to the care of Jehovah’s Witnesses.” This article is supplied as a full-text reprint accompanying this issue of SRGS. The authors begin by providing background on the origins and development of the Jehovah’s Witnesses sect. They note that the sect evolved from a Bible study group formed by Charles Taze Russell in Alleghany, Pennsylvania, in 1869. Based on extensive study, the group identified what they perceived as fundamental errors of interpretation of biblical text. The interpretation of the group led to the perception that there were philosophical errors in the practice of Christian doctrine. The literal interpretations of scripture by the group evolved into commands. Obedience to these commands, in the eyes of the adherents to this doctrine, was required for any chance at life after death. In 1879, the group was known as “Bible Students” and the group produced a religious magazine later called The Watchtower. In 1931, the group adopted the name “Jehovah’s Witnesses.” Currently, this is the fastest growing religious sect in the western world with nearly 7 million members. In the United States, more than 1 million members are enrolled. The sect is based on person-to-person Page 15 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 1 2
  16. 16. ministry and the group is noted for their work in literacy and disaster relief. Each member must commit a certain amount of time each month to ministry. Fundamental to their beliefs is the recognition that God’s Kingdom is the only legitimate government. Thus, members of the sect do not join service organizations or serve in the military. They remain neutral politically. The rejection of blood transfusion was codified in the belief system of Jehovah’s Witnesses in 1945. The belief is based on the literal interpretation of several Old Testament passages that prohibit the eating of food that contains blood. In 1951, a Watchtower article cited the use of intravenous fluids in hospitals as “intravenous feeding” and declared that the intravenous administration of blood was equivalent to “feeding” of blood and was, therefore, unacceptable based on the interpretation of Old Testament texts. The authors note that the prohibition has been interpreted to extend to the use of banked blood, blood cells, plasma, and platelets. Preoperative autologous blood donation is prohibited because the blood is separated from the body. This interpretation permits the use of intraoperative blood salvage as long as the collection circuit is continuous with the administration device so that separation of the blood from the patient’s body does not occur. In 2000, the Watchtower Society issued a statement saying that the Jehovah’s Witness sect would no longer excommunicate members who accepted transfusion. Instead, the statement indicated that the member would be judged to have voluntarily given up membership in the sect based on having accepted blood transfusion. It is important to note, as Hughes and colleagues emphasize, that there is variability among Jehovah’s Witnesses about the acceptability of blood derivatives. Some adherents will accept albumin, immunoglobulins, Page 16 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  17. 17. and factor concentrates. Recombinant erythropoietin may also be accepted. Some Jehovah’s Witnesses do not believe that they have committed an act requiring that they leave the sect if the agreement to accept a transfusion is made privately with the treating physician or surgeon. In such circumstances, patient confidentiality is obviously critical. Against this approach is the frequent presence of a member of the sect physically in the care area to make certain that the treated member does not receive a transfusion or any unacceptable blood product. It is important that surgeons decide, ahead of time, whether they will be able to accept the fact that the patient may not accept transfusion. The surgeon will need to reconcile the patient’s wishes with the possibility that a “preventable” death may occur if transfusion is withheld. Acceptable arrangements for transfer of the care of the patient to an alternate surgeon may become necessary. Hospital resources are available for patients and treating surgeons. Ethics committees, risk management group, and transfusion medicine specialists are potentially valuable. In many cities, Jehovah’s Witness groups offer consultative advice for patients and treating surgeons. Legal aspects of the care of Jehovah’s Witnesses are grounded in the 1914 legal decision that established the right of patients to refuse treatment. The decision to exercise this right by a patient, particularly a Jehovah’s Witness, should be confirmed in writing by the patient. Many Jehovah’s Witnesses carry an advance directive document with them at all times. Hughes and associates stress the importance that this knowledge is made known to all Page 17 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1 2
  18. 18. caregivers. Thus, the medical record should display, predominantly, the wishes of the patient. It is worth noting that many court decisions have determined that parents do not have the right to refuse transfusion for their children. The ability of adolescents, or mature minors, to refuse transfusion is less clear and rulings have varied depending on the jurisdiction. Surgeons will need to consult hospital risk management and counsel for assistance in dealing with these issues. Where time permits full discussion of the risks and benefits of operation, formal informed consent will be possible. What the surgeon should do to proceed with treatment when the informed consent discussion has not occurred is challenging. The presence of an advance directive card does not preclude the necessities of obtaining informed consent or proceeding with needed treatment in emergencies where informed consent cannot be obtained. This means that the decision to transfuse, or withhold transfusion for a Jehovah’s Witness patient, in an emergency may be viewed, in retrospect, as a basis for legal action against the surgeon and/or hospital. To facilitate management of Jehovah’s Witness patients in emergencies, early knowledge of the religious beliefs of the patient is necessary. This information should be actively sought and made available to all caregivers. Hughes and colleagues cite data from a Level I trauma center that indicated that the necessary knowledge was frequently not obtained. In this analysis, 5% of the Jehovah’s Witness patients received transfusion but in only one case was this reasonably preventable. A discussion of some of the measures available for minimizing blood loss as well as examples Page 18 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  19. 19. of advance directive and consent forms are found in an article authored by Gohel and coauthors11 in the Annals of the Royal College of Surgeons of England, 2005. It is important to note that data about outcomes of injured Jehovah’s Witness patients have not shown an increased risk of death from injury in this group. Earlier decision for operation has been consistently noted in studies of the management of injured Jehovah’s Witnesses patients. In elective surgery patients, measures to prevent bleeding and improved operative approaches have resulted in improved outcomes for Jehovah’s Witnesses as noted in data cited by these authors. Additional data have shown that postoperative anemia (hemoglobin level of 6 gm/dL) did not predict mortality or morbidity. Data indicating an increased risk of mortality have been reported for patients with chronic severe anemia but anemia, in this setting, has been interpreted as evidence of increased overall risk for this patient group. Hughes and colleagues note that management of Jehovah’s Witnesses should include measures to minimize iatrogenic blood loss (phlebotomy), minimize intraoperative blood loss (hemodilution, intraoperative blood salvage), enhance red blood cell production, ensure hemostasis, and maintain blood volume with electrolyte or colloid solutions. Protocols for elective management of Jehovah’s Witness patients have avoided transfusion without increasing operative risk. A report on the effectiveness of a transfusion-free program for the conduct of orthotopic liver transplantation in Jehovah’s Witnesses is the subject of an article by Jabbour and coauthors12 in Archives of Surgery, 2006. These authors reported on a comparison of patients treated by a formal protocol approach to transfusion Page 19 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  20. 20. avoidance compared with a group of historic controls. The protocol stressed the maintenance of low venous pressure, use of acute normovolemic hemodilution, and intraoperative blood salvage. These authors noted that their protocol group was sicker as judged by MELD scores compared with the non-protocol historic controls. Despite this, operative mortality in the transfusion-free patients was not increased. These data indicate that avoidance of transfusion in complex elective surgery is safe when a protocol approach is used. Editorial comment From the perspective of the editor, it seems clear that transfusion avoidance is not associated with increased operative risk in elective operations and that reductions in blood product use are associated with decreased risk for transfusion-related complications. Preplanned protocols designed to identify Jehovah’s Witness patients (and, in fact, any patients) who are unwilling to accept blood and blood products are helpful. Free and open discussion of risks and benefits with the patient is critically important. Use of institutional and community resources to accomplish these goals is helpful. In an emergency when fully informed consent is not obtainable, or when dealing with children of Jehovah’s Witnesses parents, therapeutic choices should be directed toward obtaining the optimum safe outcome for the patient. Pathophysiology of shock In this section of the overview, derangements in homeostasis that are unique to various forms of shock will be reviewed. Along with this discussion, we will emphasize the physiologic alterations that are common to most or all forms of shock. Page 20 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  21. 21. Shock due to hemorrhage and trauma Traditionally, shock from hemorrhage and trauma has been thought to proceed sequentially through stages of compensation that include a phase of catecholamine mediated vasoconstriction and redistribution of blood volume toward the brain and heart and away from skeletal muscle, kidneys, and splanchnic circulation. During this phase, movement of proteins, water, and ions from the extracellular fluid space into the intravascular space provides partial refilling of the volume lost to bleeding. This response, coupled with catecholamine-mediated vasoconstriction, serves to support blood pressure. A subsequent phase of partial compensation where the patient is mildly to moderately hypotensive occurs; this is followed, within a variable interval, by a final phase characterized by systemic vasodilation, bradycardia, and death. The duration of this phase is determined mainly by the rate and volume of continuing bleeding. The phase of partial compensation has been envisioned as a phase wherein autoregulation of vascular beds fails and tissue blood flow becomes pressure dependent. During this phase, cellular hypoxia is thought to lead to disordered mitochondrial function and a shift to anaerobic metabolism. Accumulation of acid metabolites and lactate are evidences of these phenomena. As partial compensation proceeds to decompensation, cell membrane function fails with movement of water and ions from the extracellular space into the intracellular space. The physiologic construct described above has driven the development of treatment protocols for shock that were based on early identification of bleeding sites and control of hemorrhage, replacement of red blood cells, and replacement of volumes of electrolyte solution calculated based on expected losses from the extracellular fluid. Among the major Page 21 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  22. 22. features of understanding of shock and resuscitation that have undergone modification in the past two decades are, first, an understanding that patients with compensated and partially compensated shock have expected losses of extracellular fluid smaller than those calculated on the basis of experimental evidence from models of severe, decompensated shock. In fact, the most common clinical settings in which large volume electrolyte fluid resuscitation is required are encountered in patients with massive blood loss from penetrating torso trauma and in combat injuries. Further, it is now clear that restoration of effective tissue perfusion pressure and oxygen delivery are the most important resuscitation targets, and restoration of arterial pressure to “normal” is not necessary. In fact, overzealous restoration of blood pressure may lead to recurrent bleeding and decompensation. Finally, current understandings hold that splanchnic ischemia leads to movement of substances into intestinal lymph that contribute to creation of a proinflammatory state and progression to multiple systems organ failure in patients who are genetically susceptible to the development of dysfunctional systemic inflammatory responses. In this section of the overview, we review some of the research and clinical data that have contributed to our current understandings of shock from hemorrhage and trauma. Experimental evidence demonstrating that tissue blood flow was reduced by microvascular occlusion because of cell swelling and depolarization during shock stemmed from work completed by several investigators. One example of this research is found in an older article by Borchelt and coauthors13 in the Journal of Trauma, 1995. These authors earlier demonstrated that cellular dysfunction in shock was mediated by a protein they Page 22 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  23. 23. called “circulating shock protein.” This substance was shown to cause cellular depolarization that could lead to sequestration of extracellular fluid in the cells. In this study, they hypothesized that this substance could produce migration of water and ions into cells. They incubated cells with the protein and used a double isotope indicator technique to measure cell water. They were able to demonstrate movement of water into cells in response to exposure of cells to the protein; cells used in this experiment were skeletal muscle cells. This paper was presented during the plenary session of the annual meeting of the American Association for the Surgery of Trauma, September 1994. The discussion that followed the presentation accompanies the article. The discussants agree that cell swelling is an important phenomenon in shock but limitations of isotope techniques have made determination of the magnitude of cell swelling and fluid migration into cells difficult. Debate has continued about the location of cell swelling, the types of cells that swell, and magnitude of the contribution of the fluid migration into cells. Defining one location of cell swelling leading to fluid sequestration, cellular hypoxia, and elaboration of proinflammatory mediators is the topic of an article by Zakaria and coauthors14 in Surgery, 2007. These authors produced severe hemorrhagic shock in a rodent model and used intravital videomicroscopy and Doppler flow measurements to determine microvascular diameters and flow rates. An index of functional capillary density was calculated to estimate the effective cross-sectional area of perfused microvessels. All measurements were made in an isolated segment of rat ileum. The authors investigated the following hypotheses: 1) that endothelial swelling induced by activation of the sodium/hydrogen ion exchanger during shock would reduce tissue blood flow; 2) that Page 23 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  24. 24. conventional resuscitation with blood and electrolyte solution would not prevent cell swelling; and 3) that direct inhibition of the sodium/hydrogen ion exchanger with topical amiloride would prevent cell swelling and preserve microcirculatory flow. The authors were able to document cell swelling that reduced microvascular flow and functional capillary density. Conventional resuscitation did not restore microcirculatory function even though central hemodynamics was returned to baseline levels. When cell swelling was prevented by blocking the sodium/hydrogen ion exchanger, cell swelling was prevented and microvascular flow was restored by conventional resuscitation. As a final component of this experiment, the authors prevented cell swelling by bathing the ileum tissue in peritoneal dialysis fluid and noted that direct peritoneal resuscitation using peritoneal dialysis fluid prevented endothelial cell swelling and preserved microcirculatory capillary density. In this setting as well, conventional resuscitation restored microvascular flow and function to near baseline levels. The authors note that activation of the sodium/hydrogen ion exchanger permits the cell to transport hydrogen ions into the extracellular space. Chloride ion is also transported into the extracellular space. Bicarbonate and sodium are transported into the cell along with water. The flux of water, bicarbonate, and sodium into the cell produce cell swelling. The estimated size of the endothelial surface in intestine and skeletal muscle would explain the large fluid shifts observed in experimental preparations of severe shock as well as in injured patients sustaining massive blood loss. Persistence of intracellular acidosis could also explain the observed disorders of cellular energy metabolism and the resultant accumulation of acid metabolites and lactate. Reversing cellular edema with direct peritoneal resuscitation maintained microvascular flow in the intestinal bed and could Page 24 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  25. 25. reduce the elaboration of proinflammatory cytokines into intestinal lymph. This group of investigators examined the effects of direct peritoneal resuscitation on the flow and composition of mesenteric lymph is a study of rodent hemorrhagic shock authored by Matheson and coauthors15 in Archives of Surgery, 2009. Earlier work by these authors (one report described above) demonstrated endothelial swelling, leading to reductions in intestinal microvascular flow. Conventional resuscitation did not prevent this phenomenon but reductions of cell swelling with direct peritoneal resuscitation, combined with conventional resuscitation, preserved intestinal flow. In this experiment, the authors hypothesized that preservation of intestinal microvascular flow would alter intestinal lymph flow and composition. They were able to demonstrate increased mesenteric lymph flow with shock and resuscitation. Increased levels of lymph hyaluronic acid and proinflammatory cytokines were noted with shock treated by conventional resuscitation. Direct peritoneal resuscitation added to conventional resuscitation preserved intestinal microvascular flow and function. Mesenteric lymph flow was restored to normal, and cytokine levels were returned to control levels by treating rodent hemorrhagic shock with the combination of conventional and direct peritoneal resuscitation. These authors have documented a logical mechanism for cellular dysfunction and reduced intestinal blood flow. They have explained the mechanisms of cellular swelling, reduced tissue blood flow, and elaboration of proinflammatory cytokines from the gut. In other experiments, they showed that skeletal muscle cell swelling and fluid sequestration occurs. These experiments confirm the existence and the magnitude of fluid shifts in profound shock and the authors propose a plausible link between mesenteric ischemia and postshock inflammation. Page 25 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  26. 26. Clinical evidence of mesenteric ischemia is associated with patient mortality and postshock multiple organ failure. This topic is reviewed by Malinoski and coauthors16 in the Journal of Trauma, 2009. The authors note that animal studies have documented the movement of pancreatic enzymes from the lumen of the intestine into mesenteric lymph and subsequently into the general circulation in animal models of shock and multiple organ failure. The observed elevations of amylase and lipase occurred without tissue evidence of pancreatic inflammation and seemed to result from gut ischemia. These authors hypothesized that patients with shock would have elevated levels of pancreatic enzymes and that the elevations would be predictive of mortality and organ failure. They analyzed data from an institutional trauma registry and identified 481 patients with elevations of amylase and lipase more than twice as high as normal levels. Patients in this group were twice as likely to die, to develop organ failure, and require massive transfusion, as were patients without elevations of these enzymes. In the discussion section of their paper, the authors note that experimental preparations have shown that ischemia to the intestinal mucosa allows movement of pancreatic enzymes into the submucosa where these substances can activate inflammatory mediators. The enzymes and mediators can translocate from the submucosa to the mesenteric lymph channels and enter the general circulation by this route. The gut-lymph hypothesis of the origin of multiple organ failure has been extensively investigated in the laboratory. One example of this research is found in an article by Senthil and coauthors17 in the Journal of Trauma, 2006. In a porcine model of trauma and shock, the authors demonstrated that injury and shock are necessary for production of lymph that Page 26 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  27. 27. would activate neutrophils. Neutrophil activation was used as a marker for the presence of proinflammatory cytokines. The authors further documented that the lymph draining from the gut in animals sustaining shock and trauma was cytoxic to endothelial cells. In the discussion section of the article, the authors note that several studies have shown that mesenteric lymph from animals sustaining shock and trauma has properties that can produce cellular effects similar to those seen in multiple system organ failure. They note that the lymph does not contain bacteria or endotoxin, leading to the conclusion that mediators contained in the lymph, such as tumor necrosis factor alpha and interleukin-6, could lead to cellular changes that might induce multiple organ failure syndrome in susceptible patients. The question of whether lymph draining from other tissues rendered ischemic during shock would also cause cellular changes consistent with multiple organ failure is the topic of two articles by Diebel and coauthors.18-19 These authors showed that lymph gathered from a skeletal muscle bed two hours after shock produced in a canine model led to acute lung cell injury and neutrophil priming. Taken together with the research described earlier, it seems likely that lymph from tissue rendered ischemic during shock can produce changes consistent with multiple organ failure. Whether these mechanisms are active in human shock requires further clarification. The role of proinflammatory cytokines in the production of multiple organ failure syndrome has been emphasized in multiple studies. An article documenting the relationship of elevated cytokine levels and multiple organ failure by Jastrow and coauthors20 appeared Page 27 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  28. 28. in the Journal of the American College of Surgeons, 2009. These authors measured sequential levels of cytokines in severely injured patients treated in a single Level I trauma center. Cytokine levels were measured during the first 24 hours after admission. There were no significant clinical differences observed when the group of patients who developed multiple system organ failure was compared to the group that did not develop multiple system organ failure. The authors were able to identify, however, four cytokines present at significantly higher levels in patients who developed organ failure. These included interleukin-10 and interleukin-6 that have been associated with organ failure development in a number of experimental and clinical studies. Interestingly, there were some patients who did not develop organ failure but who had elevated cytokine levels. This observation suggests that other factors, perhaps including genetic predisposition, might work in conjunction with the cytokine expression to produce a cellular environment leading to the development of organ failure. One potential factor influencing susceptibility to postshock mortality and the risk of organ failure is gender. Males are more likely to be injured and are more likely to have elevated levels of circulating cytokines after injury. Mortality and the frequency of multiple organ failure are more common in males as documented in several experimental and clinical series. This issue is the topic of a report by Sperry and coauthors21 in the Journal of Trauma, 2008. These authors documented increased levels of interleukin-6 in severely injured male patients. These levels persisted over time and increased serum levels of interleukin-6 were associated with an 11-fold increase in the risk of multiple systems organ failure. These authors note that a causal relationship between increased cytokine levels Page 28 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  29. 29. cannot be inferred from these data but increased cytokine levels could be a marker of increased organ failure risk. This same group of investigators examined the role of female hormone levels in producing the apparent protection against mortality and multiple organ failure in injured women compared with injured men.22 These authors examined hormone levels in pre- and postmenopausal women who had sustained severe injury and noted no difference in the risk for death or multiple organ failure in postmenopausal women compared with premenopausal women. The risk for mortality and multiple organ failure in both groups was lower than that for men after adjustment for multiple risk factors. The authors note that these findings contrast sharply with experimental animal data that have linked levels of hormones to the protective effect of female gender after shock and injury. They conclude based on the data, that there are factors other than hormone levels that contribute to the protective effect of female gender. Microvascular flow abnormalities associated with shock and injury may be produced by alterations in circulating blood cells as well as abnormalities in the small vessels of the microcirculation. This topic is addressed in an article by Machiedo and coauthors23 in the Journal of Trauma, 2009. The authors evaluated the affects of infusion of blood from animals subjected to trauma and shock on organ blood flow in a rodent model. Organ blood flow was measured using radioactive microspheres. The authors were able to document increased sequestration of red blood cells from animals subjected to trauma and shock and subsequently infused into normal animals in organs such as the liver and spleen. Organ blood flows were reduced. They concluded that red blood cell changes induced by trauma and shock predispose these cells to lodge in organ microcirculations producing obstruction Page 29 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  30. 30. of blood flow. These data and the studies discussed earlier suggest a diverse group of changes in organ microcirculation resulting from trauma and shock. Detailed studies of the human microcirculation are needed to provide clinical evidence of measures to improve outcomes. Protection against cellular death is another avenue that could improve outcomes in severely injured patients with shock. One measure leading to improved cell survival is inhibition of deacetylation of histones. Histone deacetylation is one means of altering cellular DNA leading to cell death. Inhibition of this process is the topic of a report authored by Gonzales and coauthors24 in the Journal of Trauma, 2008. The authors note that hemorrhagic shock-induced changes in the liver produce aberrations in gene-regulatory programs; one important pathway for these changes is recruitment of histone deacetylases in liver tissue. Valproic acid, a regularly prescribed antiepileptic drug, was recently shown to produce neuroprotective effects through inhibition of histone deacetylation. Pretreatment with valproic acid in a rodent model of severe hemorrhagic shock produced favorable changes leading to liver cell survival and these changes were directly related to hyper- acetylation of hepatic histones. The cell protective activity of valproic acid was further evaluated in a porcine model of severe hemorrhage, trauma, and shock and reported in an article authored by Alam and coauthors25 in Surgery, 2009. The authors of this report treated animals with valproic acid after hemorrhage and liver injury in contrast to the pretreatment model examined in the article authored by Gonzales.24 Alam and coauthors examined outcomes in animals Page 30 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  31. 31. untreated, animals treated with fresh whole blood, and animals treated with intravenous valproic acid. Survival was 100% and 86% in animals treated with fresh whole blood and valproic acid respectively compared with 25% in the control group. The authors examined liver tissue and found that survival was associated with preservation of the Akt cell survival pathway. Normal function of this pathway depends on prevention of histone deacetylation. These two studies indicate that interventions at the cellular level hold promise as therapeutic pathways for the management of trauma and shock. Restoration of perfusion after a period of ischemia is another potential pathway leading to tissue damage. Restoration of blood flow to tissue is essential for survival from shock but reperfusion injury is a potential pathway for production of cellular injury and postshock complications through production of reactive oxygen species as well as other substances. Reperfusion injury after hemorrhage and injury is reviewed in an article by Rushing and Britt26 in Annals of Surgery, 2008. This article is included as a full-text reprint accompanying this issue of SRGS. These authors note that tissue level evidence of reperfusion injury is noted, initially, by neutrophil adhesion to venular endothelium. They stress that adhesion molecules are expressed on endothelial cells, platelets, and neutrophils are all active in the adhesion process. Blockade of cell adhesion is appealing, although trials of adhesion molecule blockade have not shown benefit. The authors note that mitochondrial injury is a constant factor in reperfusion injury and cite evidence suggesting that cytochrome C oxidase is a mediator of reperfusion damage to mitochondria. In addition, enzymatic mediators such as xanthine oxidase are important in the production of reperfusion injury. Reperfusion injury produces alterations of intracellular signaling pathways such as the NF-kappa B pathway that augment production of Page 31 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  32. 32. pro-inflammatory cytokines such as tumor necrosis factor alpha. Immune cells, such as B- lymphocytes, are important locations of these alterations. Changes within these pathways can lead to cell death via apoptotic pathways. The events initiating and perpetuating reperfusion injury are important foci of research efforts as pathways to improved patient outcomes are sought. Sepsis and septic shock A review of the pathophysiology of sepsis and septic shock is authored by Hotchkiss and Karl27 in the New England Journal of Medicine, 2003. The authors begin by noting that sepsis and septic shock are the leading causes of death among critically ill patients in the United States; 750,000 cases of sepsis are diagnosed annually and 25%-40% of these patients die depending on risk factors (age, comorbidities), the etiology of sepsis, and the mode of therapy. They go on to stress that the major clinical manifestations of sepsis are not infection-specific but represent an inherent pattern of response to infection regardless of the infecting organism. Although clinical sepsis is thought to result from dysfunction of the inflammatory response, proinflammatory cytokines are variably recovered from septic patients and blockade of cytokines has not shown benefit as a means of improving sepsis outcomes. Recent data have described targeted alterations in the innate immune system that may increase susceptibility to sepsis. As an example, the authors cite data that alterations in the toll-like receptor 4 gene have been demonstrated in humans who show increased susceptibility to sepsis. The authors go on to discuss the shift from a proinflammatory state to a state of immune suppression which occurs during the septic event and this immune suppression may predispose to nosocomial infections in patients Page 32 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  33. 33. recovering from sepsis. As immunosuppression progresses, anergy may occur due to apoptotic cell death in populations of immune cells such as lymphocytes and gastrointestinal mucosal cells. Animal data have shown that anti-apoptotic drugs reduce the impact of this process and in animals, mortality from sepsis is reduced28 . Data from surgical patients suggest that restoration of the proinflammatory state that characterizes the early septic response is associated with restoration of immune function and improved survival. Genetic alterations also may act to perpetuate the immunosuppressed state. The authors cite data that alterations in the genes that produce tumor necrosis factors alpha and beta result in low levels of these cytokines in patients who die of infection during the immune suppressed phase of sepsis. Neutrophils have traditionally been thought essential to the successful control of infection. Recent experimental studies have suggested that neutrophils may mediate tissue injury (see discussion of Rushing’s review, above). Blockade of neutrophil-mediated injury has not improved sepsis outcomes, however. In contrast, some suggestion of benefit was noted in patients with pneumonia who were treated with granulocyte colony stimulating factor. These patients had neutrophil counts in excess of 70,000 cells/mm3 but there was no suggestion of neutrophil-mediated tissue injury. Observations from autopsy data, cited by Hotchkiss and Karl, suggest that the populations of cells dying in patients with sepsis are lymphocytes and gastrointestinal epithelial cells. This cell death is thought to occur because of sepsis-induced acceleration of apoptosis. No specific therapy is available to forestall lymphocyte and gastrointestinal Page 33 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  34. 34. epithelial cell death. These cells are popular foci of research into the basic mechanisms of sepsis and septic shock. Hotchkiss and Karl note that septic shock, though frequent in septic patients, is an uncommon cause of death in this patient group. Septic shock is a form of distributive shock characterized by preservation of cardiac output and global indices of oxygenation occurring in the setting of hypotension. Recent studies have shown that microcirculation dysfunction can be observed in the sublingual mucosa, which is anatomically and functionally similar to the intestinal mucosa. Failure to recover microcirculatory function has been associated with mortality from sepsis and septic shock although shock itself was less often a cause of death than the subsequent development of organ failure and/or nosocomial infection. Therapy for septic shock has been directed toward preserving perfusion and oxygen delivery in an attempt to prevent sepsis-associated organ failure that is a more common cause of death in septic patients than septic shock. Therapy for sepsis and septic shock is discussed later. Cardiogenic shock Arterial hypotension (systolic blood pressure < 90 mmHg) combined with signs of end- organ hypoperfusion (acidosis, elevated serum creatinine, abnormal sensorium), depressed cardiac index, and signs of elevated left ventricular pressure comprise the clinical features of cardiogenic shock. Cardiogenic shock occurs in 7% of patients after myocardial infarction and this condition is the most common cause of early death after myocardial infarction. Other conditions that complicate myocardial infarction such as papillary muscle rupture with acute mitral insufficiency and ventricular wall rupture with pericardial tamponade are surgical emergencies that also cause cardiogenic shock. Page 34 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  35. 35. The epidemiology of cardiogenic shock is discussed in a review by Topalian and coauthors29 in Critical Care Medicine, 2008. This article is supplied as a full-text reprint with this issue of SRGS. These authors cite three reports indicating that cardiogenic shock complicating myocardial infarction (defined as ST-segment elevation and/or new left bundle branch block on electrocardiogram) occurred in 7.1%-8.6% of patients after myocardial infarction. Once cardiogenic shock was diagnosed, subsequent mortality rates reported were 60-80%. Mortality rates were higher in patients older than 75 years. Topalian and colleagues stress recent data showing that aggressive attempts to provide complete revascularization of critical coronary stenoses and occlusions in patients with cardiogenic shock has resulted in lower mortality rates approaching 48%. Patients at increased risk for cardiogenic shock after myocardial infarction include older patients and patients with a history of hypertension, dyslipidemia, and previous coronary angioplasty. Cardiogenic shock has an average time of onset, after the appearance of clinical evidence of myocardial infarction, of 7 hours. This review notes that cardiogenic shock can occur after myocardial infarctions that result in ST-segment elevation and in those patients without ST-segment elevation accompanying the infarction. The etiology of infarction and cardiogenic shock is usually multivessel coronary atherosclerosis. In one report cited by the authors, more than half the patients with cardiogenic shock after myocardial infarction had triple vessel disease, and more than 15% of patients had significant left main coronary artery stenosis. Anterior infarction is common but multiple sites of infarction are diagnosed in more than half the patients who develop cardiogenic shock. Nearly 80% of patients who develop cardiogenic shock have left ventricular failure as the main pathogenesis of the shock event. Page 35 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  36. 36. Acute mitral insufficiency, septal rupture, right ventricular infarction, and ventricular wall rupture with pericardial tamponade account for the remaining patients. Ventricular wall rupture is the least frequent etiology of cardiogenic shock, accounting for less than 1.5% of instances. Acute mitral insufficiency accounts for 7% of patients developing cardiogenic shock. The pathophysiology of cardiogenic shock is the subject of a review by Aymong and coauthors30 in Medical Clinics of North America, 2007. These authors emphasize the critical importance of reduced coronary blood flow that results in a state of myocardial oxygen deprivation and disordered myocardial energy metabolism. They note that heart muscle is very reliant on aerobic energy metabolism. Oxygen utilization in contracting heart muscle ranges from 8-15 mL of oxygen/100 gm/tissue/min. The noncontracting muscle uses only 1.5 mL/100 gm/tissue/min. The heart, even in its resting state, extracts 2-3 times more oxygen than any other single organ. Myocardial oxygen demand is determined by ventricular tension, heart rate, and contractility. Oxygen delivery to the myocardium via the coronary arteries is primarily a diastolic phenomenon. Coronary perfusion pressure can be estimated from the difference in aortic diastolic pressure and mean left ventricular pressure. Coronary vascular resistance interacts with coronary perfusion pressure to determine net coronary flow. Coronary vascular resistance is determined by complicated interactions among various local and systemic mediators. Endothelial dysfunction occurs because of coronary atherosclerosis and produces abnormal coronary responses to endogenous mediators of vasoconstriction and vasodilation. The net result is disordered autoregulation, with coronary flow becoming progressively more dependent on coronary Page 36 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  37. 37. perfusion pressure. Diastolic coronary perfusion can be reduced during conditions where cardiac output is decreased and when the diastolic interval is reduced (tachycardia). Myocardial infarction resulting from coronary thrombosis directly reduces coronary flow because of obstruction. With extensive involvement of the ventricular wall, cardiac output is reduced. Tachycardia results from the catecholamine response to reduced cardiac output and these factors combine to produce a self-perpetuating cycle of myocardial ischemia and infarction. Topalian and associates29 emphasize that “ischemia begets ischemia” during this cycle. Ventricular dysfunction leads to elevated end-diastolic pressures and pulmonary congestion. Elevated ventricular filling pressures increase myocardial wall stress. Restricted left ventricular filling was noted in more than 60% of patients evaluated by echocardiography in a series cited by Topalian and coauthors. This pathophysiologic process is complicated by the elaboration of inflammatory mediators. Clinical evidence of systemic inflammatory response syndrome was noted in 20% of patients in a report cited by these authors. Aymong and colleagues30 cite data indicating that elevated levels of interleukin-6 have been documented in patients with cardiogenic shock and that these levels are equivalent to the levels recorded in patients with sepsis and septic shock. Topalian and associates and Aymong and colleagues further note that the proinflammatory state observed in some patients with cardiogenic shock is associated with stimulation of inducible nitric oxide. Unfortunately, blockade of inducible nitric oxide synthesis did not produce a benefit in patients with cardiogenic shock. Page 37 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  38. 38. Aymong and coauthors note that myocardial ischemia can result in myocyte necrosis. Other cells die because of apoptosis (programmed cell death). In addition, myocardial cells may be “stunned” from ischemia. Stunned cells do not recover full contractile function with early restoration of perfusion from revascularization procedures. Thus, normal contractile function might not be restored for several weeks after coronary artery thrombosis followed by revascularization. The extensive multivessel coronary atherosclerosis noted in autopsy reports of patients dying of myocardial infarction and cardiogenic shock usually produces multiple myocardial infarctions of varying age rather than a single massive infarction. Low coronary flow and increased coagulation activity because of the presence of unstable coronary plaque can produce progressive coronary thromboses that extend to involve branches of the artery where the thrombosis originated. These authors go on to note that declining myocyte contractility can occur in areas remote from the infarction and this may be a consequence of production of hypoxia-inducible-factor-1 which is stimulated when cardiac cell mitochondria sense hypoxia. Reduced cell metabolism and contractility are produced by this factor. The resulting low metabolism state produced in areas remote from the infarction is termed “myocardial hibernation.” One of the benefits of treatment of cardiogenic shock with intra-aortic balloon counterpulsation may be restoration of coronary perfusion and myocyte oxygenation that serves to reverse myocyte hibernation and recover contractility. Page 38 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1 2
  39. 39. Monitoring the patient in shock The clinical hallmark of shock in the critically ill surgery patient is arterial hypotension. The Advanced Trauma Life Support Course offered by the Committee on Trauma of the American College of Surgeons defines shock as an arterial blood pressure < 90 mmHg confirmed before patient arrival at the hospital and/or present during initial assessment. Additional bits of clinical information available during the initial assessment are used to supplement the clinical suspicion raised by the finding of hypotension and provide guidance to the clinician regarding hypoperfusion of critical vascular beds (oliguria, depressed level of consciousness, metabolic acidosis) and prognosis (alternating tachycardia and bradycardia, response to fluid challenge). Clinical experience has shown that significant reductions in cardiac output because of hemorrhage, sepsis, cardiac dysfunction, pericardial tamponade, and massive pulmonary embolus can be present without arterial hypotension. In fact, hypotension is not a sign of shock but a sign of decompensated shock indicating that the intrinsic defenses against reductions of cardiac output have failed and, therefore, the hypotensive patient is literally minutes away from cardiac arrest and death. Hemodynamic abnormalities resulting from reductions in cardiac output change along a dynamic continuum. The patient who is hypotensive during transport from a crash scene to the trauma center may have a normal arterial pressure in the resuscitation area of the hospital because of ongoing adjustments of the blood volume and systemic arteriolar constriction induced by catecholamine secretion. Prehospital hypotension can be a marker for patients who have bled massively or who are continuing to bleed. This topic was addressed in an article by Lipsky and coauthors31 in the Journal of Trauma, 2006. These Page 39 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  40. 40. authors reviewed records on more than 1000 injured patients transported to a single trauma center over the course of a 12-month interval. Seven percent of patients were hypotensive during transport as defined by a systolic blood pressure of 90 mmHg or less. Of this group, more than one-third required an operative procedure for hemorrhage control within the first six hours at the trauma center. Underscoring the hazards of clinical classifications based on blood pressure readings was the finding that 11% of patients who were normotensive during the prehospital interval and who were normotensive during resuscitation also required an operative procedure to control bleeding within the first six hours after arrival at the trauma center. It is clear that clinical decisions about patients at risk for shock will be based on combinations of data and that all of the variables assessed suffer from a lack of sensitivity and specificity. In this section of the overview, a discussion of the capabilities and limitations of monitoring the patient in shock will be undertaken. Hemodynamic monitoring Basic features of hemodynamic monitoring include intermittent or continuous measurements of arterial pressure, heart rate, and arterial oxygen saturation. Arterial pressure can be measured with blood pressure cuffs (automatic or manual) and with indwelling arterial catheters attached to continuous monitoring transducers. Automatic blood pressure cuffs produce blood pressure values consistently higher than actual pressures. This feature is particularly noticeable in lower pressure ranges. Manual blood pressure cuffs require personnel, and the measurement process is cumbersome in critically ill patients. Placement of arterial catheters in peripheral arteries may be challenging in Page 40 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  41. 41. vasoconstricted patients. Arterial pressure measurements can be supplemented with serial measurements of central venous pressure. In the intensive care unit or the operating room additional variables such as central venous oxygen saturation, right heart pressures, mixed venous oxygen saturation, and cardiac output can be measured. Transthoracic or transesophageal echocardiography can be used to determine the presence and degree of cardiac dysfunction. Controversy continues about the additional benefit of these assessments. Isolated values derived from hemodynamic measurements are of limited value. Trends are therefore monitored and responses to interventions such as endotracheal intubation and ventilation, decompression of hemo- or pneumothoraces, and intravenous fluid boluses, are recorded. A critical aspect of early resuscitation from shock involves decisions to undertake an intervention to correct the underlying cause of the shock state. This might be a procedure to stop bleeding or control the source of sepsis. Interventions may take the form of thrombolysis of pulmonary embolus, revascularization of occluded coronary arteries, or insertion of an intra-aortic balloon pump. The clinician establishes goals of early resuscitation to help guide these decisions. These are termed “endpoints of resuscitation.” The first article discussed in this section addresses this topic. It is by McCunn and Dutton32 and appeared in Current Opinion in Anesthesiology, 2000. The authors begin the discussion by confirming the hazards of depending on specific values for monitoring variables. They stress the consistent observation that more than one-third of injured patients in shock are not tachycardic. Experimental studies of shock from blood loss disclose that pure blood loss most often results in slowing of the heart rate. Page 41 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  42. 42. They go on to emphasize the importance of separating resuscitation from shock into phases. The initial phase takes place before a needed intervention to reverse the underlying cause of shock and the second phase occurs after the intervention has been completed. During the initial phase, goals of resuscitation include identification of the underlying etiology of shock and expansion of the intravascular space with intravenous electrolyte solution. McCunn and Dutton stress the importance of careful adjustment of the arterial pressure. The initial goal is to raise mean arterial pressure to a level that will support cell survival. Attempts to normalize the arterial pressure will lead to recurrence or acceleration of bleeding in the acutely injured patient. In addition, McCunn and Dutton note that infusion of a volume of electrolyte solution sufficient to raise arterial pressure to normal will lead to excessive volume infusion and complications such as abdominal compartment syndrome. They emphasize the importance of warming intravenous fluids to support core patient temperature. Arterial pressure goals before controlling the cause of shock should be set at mean arterial pressure of 60-70 mmHg with adjustments upward for elderly patients, patients with traumatic brain injury, and patients with known cardiac dysfunction. Supplemental information can be gleaned from monitoring trends in central venous pressure. In the early phase of resuscitation, risks associated with central venous catheterization include arterial injury and pneumothorax. These risks may be reduced, somewhat, by using ultrasound guidance for central venous catheter insertion. Central venous pressures of 8-12 cm H20 are adequate to support cardiac output in healthy patients. Pressure goals will need to be adjusted upward in patients who are requiring Page 42 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  43. 43. positive pressure ventilation. As in all other global hemodynamic measurements, trends are more important than isolated values. A review of hemodynamic monitoring in the intensive care unit appeared in Chest in 2007, by Pinsky.33 The author begins by describing clinical objectives of hemodynamic monitoring. Clinicians use hemodynamic monitoring to establish cause of shock and to estimate the direction and degree of response to therapy. The first steps are to determine how much cardiac output is likely to increase in response to a first line intervention (usually an intravenous fluid bolus) and then to determine whether the systemic vasomotor tone is increased or decreased. Distributive shock (most commonly septic shock) is the most common shock state encountered by surgeons where vasomotor tone is decreased. Finally, an assessment of the ability of the heart to sustain function when arterial pressure is restored completes the initial characterization of the shock state. Pinsky emphasizes that the response to intravascular volume expansion (preload responsiveness) cannot be predicted from estimates of ventricular end-diastolic volume. This observation calls into question the clinical value of data that can be obtained from placement of a pulmonary artery catheter. Whether data obtained from pulmonary artery catheter measurements alters outcomes in patients with shock is controversial. A consensus conference produced recommendations published in 1997.34 The recommendations pertinent to surgical patients suggested that preoperative optimization of hemodynamic status using data derived from the pulmonary artery catheter would probably improve outcomes in high-risk patients undergoing vascular Page 43 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  44. 44. operations. The consensus noted that clinical decisions made using pulmonary artery catheter measurements of filling pressures and cardiac output could be useful in the management of injured patients when standard hemodynamic measurements were deemed inadequate. This recommendation was based on expert opinion because no high- quality data were available. The recommendation specifically focused on patients with brain injury and postinjury acute respiratory distress syndrome. Overall, the data available do not support the widespread use of the pulmonary artery catheter as a means of improving patient outcomes in shock. In an editorial published in Critical Care Medicine in 2005, Pinsky and Vincent35 addressed the lack of data supporting the use of the pulmonary artery catheter and noted that the available studies are insufficient to document lack of efficacy of the pulmonary artery catheter because the studies only compared outcomes in patients treated with and without the device. A valid evaluation would have compared treatment protocols using data derived from the pulmonary artery catheter compared with treatment protocols using other hemodynamic data to support treatment decisions. These authors acknowledge the availability of preload assessments guided by echocardiographic measurements as described by Voga.36 Pinsky and Vincent reiterate the well-known lack of echocardiographic capability at all times in most intensive care units. Currently, use of the pulmonary artery catheter to guide therapy in critically ill surgery patients should be selective. Indirect indices of adequacy of blood volume and oxygen transport are available. Trends of variables that are related to ventricular end-diastolic volume such as right atrial pressure and pulmonary artery occlusion pressure do not predict accurately, changes in cardiac output in response to fluid boluses. The author goes on to Page 44 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  45. 45. note that preload responsiveness can be predicted from alterations in arterial pulse pressure in response to cycles of positive pressure ventilation. Preload responsiveness can also be predicted from pulse pressure variation measured using echocardiography. Obvious limitations of these assessments relate to the fact that the patient must be on a ventilator and echocardiographic assessment must be readily available. These assessments also lose their predictive ability when heart rate is irregular as in atrial fibrillation. Measurement of the response of aortic flow velocity to a passive leg raise is an assessment that can be performed in patients with any cardiac rhythm. In addition, the patient does not have to be on the ventilator for this assessment to occur. Since flow velocity is measured by trans-esophageal Doppler techniques, special equipment is required. In some critically injured patients, passive leg raising may not be feasible. Because of the limitations of pressure measurements and the lack of universal availability of other equipment, indirect assessments of the adequacy of oxygen transport have been used and these are discussed in the next section. Monitoring oxygenation and perfusion As noted above, continuous measurement of arterial oxygen saturation is a component of the basic hemodynamic assessments performed on all critically ill patients. Arterial oxygen saturation does not provide information relating to oxygen delivery, oxygen consumption, or the existence of oxygen debt. Mixed venous oxygen saturation can be measured but this requires placement of a pulmonary artery catheter. Fiberoptic central venous catheters are now available that can provide continuous assessments of central venous oxygen saturation. The absolute value for central venous oxygen saturation varies Page 45 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  46. 46. compared with absolute values for mixed venous oxygen saturation (obtained using a pulmonary artery catheter). Trends of these measures in response to interventions change, in parallel, however, suggest that trends in central venous oxygen saturation are potentially valuable clinically. Data discussed in later sections of the overview document that a central venous oxygen saturation value of < 70% is a dependable indicator of inadequate global oxygen transport. Currently, this assessment is probably the most useful index of adequacy of oxygen delivery. One obvious limitation of this measurement is in sepsis when values above 70% may be present in the face of inadequate tissue perfusion. As a general statement, combining arterial pressure and heart rate with central venous pressure measurements supplemented by continuous measurements of central venous oxygen saturation provide adequate estimates of hemodynamic function to guide the clinician dealing with most forms of shock encountered in surgical patients. A fundamental concept of shock is that inadequacy of the circulation leads to a cellular shift from aerobic to anaerobic metabolism. Anaerobic metabolism leads to the accumulation of acid metabolites in tissue. Traditionally, assessments of acid base status have been routine in the management of shock. Assessment of global acid-base status has usually been achieved by calculating base deficit from values for pH, bicarbonate and PC02 obtained from arterial blood gas analysis or from assessments of bicarbonate levels obtained from venous blood samples. Lactic acid is a metabolite that accumulates in cells that are metabolizing energy substrates anaerobically. Serum lactate levels reflect lactic acid accumulation and are relatively easy to measure. Absolute lactate levels and rates of lactate clearance have been used as a means of predicting mortality in patients in shock. For Page 46 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  47. 47. example, the rate of lactate clearance has been shown to be predictive of outcomes in injured patients. Whether lactate levels can be used to guide therapeutic decisions is less clear. We discuss several articles dealing with global assessments of acidosis, lactate metabolism, and the roles measurements of these variables may play in managing patients in shock. The relationship between serum bicarbonate (which can be measured from a venous sample) and base deficit (which requires an arterial blood sample) is the topic of an article by Martin and coauthors37 in Archives of Surgery, 2005. These authors reviewed records from intensive care unit stays for 2291 patients. The patients were critically ill surgery patients; injured patients were excluded. Pairs of samples compared serum bicarbonate levels and calculated base deficit. The authors found that trends of the two measurements changed in parallel. Admission serum bicarbonate predicted mortality and length of stay. Defining significant acidosis as a base deficit > 5, the authors determined that serum bicarbonate was an accurate measure of acid-base status. The authors concluded that serum bicarbonate was as accurate as base deficit diagnosing acidosis and that low serum bicarbonate was a dependable trigger for treatment of acidosis. This same group of investigators extended the comparison of serum bicarbonate and base deficit to a group of 3102 injured patients admitted to a trauma intensive care unit. These data are found in a report by Fitzsullivan and coauthors38 in the American Journal of Surgery, 2005. The authors note that base deficit is a calculated value derived from data gathered from analysis of an Page 47 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  48. 48. arterial blood sample. The value represents the number of milliequivalents of additional base buffer that would have to be added to bring the pH of the blood sample to normal. Serum bicarbonate is measured from a venous sample. Potential advantages of using serum bicarbonate are ease of collection and processing as well as lowered cost. The analysis disclosed that serum bicarbonate was an accurate predictor of acid base status and had equivalent clinical value compared with base deficit. Most, but not all, of the variability of base deficit was paralleled by serum bicarbonate values. The authors concluded that serum bicarbonate was as accurate as base deficit in predicting clinically significant acidosis. In a final analysis by this group of investigators, a comparison of base deficit to serum lactate was carried out to determine whether base deficit was as accurate as lactate levels for prediction of outcomes in critically ill surgical patients. They confirmed that serum lactate was a superior predictor of outcomes compared with base deficit. They concluded from their analysis that admission base deficit and admission lactate predict mortality but that a normal base deficit does not always predict a normal lactate and that an abnormal lactate level was predictive of mortality and length of stay even when the base deficit was normal. Additional discussion of lactate as a clinical indicator of occult anaerobic metabolism is discussed in the next segment. A review of lactate metabolism and an assessment of the clinical utility of lactate level measurements are found in an article by Jansen and coauthors39 in Critical Care Medicine, 2009. The article is entitled “Blood lactate monitoring in critically ill patients: a systematic health technology assessment.” This article is supplied as a full-text reprint accompanying Page 48 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  49. 49. this issue of SRGS. The objective of this report is to attempt to describe the process of measuring blood lactate and to establish whether these measurements have value in the management of the critically ill patient. The authors note that there is wide variability among clinicians and hospitals in the use of blood lactate measurements. Although elevated blood lactate is thought to be evidence of anaerobic metabolism that can result from shock and other conditions, there is evidence that elevations of lactate can occur in the absence of anaerobic metabolism. The authors note that the measurement of blood lactate has been standardized and the test is dependable. They review experimental and clinical studies that have evaluated lactate. Experimental preparations that have reduced oxygen delivery until oxygen consumption was delivery-dependent have consistently shown elevations of blood lactate in the experimental subjects. Studies of patients with septic and cardiogenic shock have shown increased lactate/pyruvate ratios consistent with anaerobic metabolism. Jansen and coauthors cite a study by Rivers40 (discussed later in the overview) that documented a consistent relationship between hyperlactatemia and low central venous oxygen saturation indicating inadequate oxygen delivery and suggesting that a shift to anaerobic metabolism had occurred. They also cite data demonstrating that elevations of lactate consistently occurred in patients with low mixed venous oxygen saturation, low cardiac output, and clinical signs of shock. The authors stress that there is wide variability in regional oxygen delivery and demand. This fact means there will be no specific value for oxygen delivery or central venous oxygen saturation associated with lactate accumulation. They describe research conducted in patients with septic shock that demonstrate lowering of lactate levels when capillary perfusion is improved, even though systemic hemodynamic Page 49 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  50. 50. variables did not change. This observation suggests that local microcirculatory changes may alter the accumulation of lactate. The authors go on to review instances where lactate levels may change in the absence of anaerobic metabolism. Conditions that increase aerobic glycolysis to a point where the ability of pyruvate dehydrogenase is exceeded by over production of pyruvate will result in accumulation of lactate. Mitochondrial dysfunction and liver dysfunction can alter lactate production and clearance with increased lactate levels in the absence of anaerobic metabolism. The lung can also be an important source of lactate when pulmonary production of lactate is stimulated by inflammatory mediators, even though hypoxia is not present. Finally, alkalosis can increase efflux of lactate from cells and several drugs can stimulate lactate production. The article next reviews the prognostic value of lactate and the authors conclude that lactate elevations accurately predict mortality in acutely injured patients in the emergency department and critically ill patients in the intensive care unit. The authors reviewed several studies that confirmed an inconsistent relationship between lactate and other indices of acidosis. The bulk of the evidence suggests lactate levels cannot be predicted from other indices of acidosis such as base deficit and anion gap. Further, the evidence suggests that elevated lactate, along with evidence of acidosis, strongly suggests a shift to anaerobic metabolism in a large proportion of circulatory beds. The authors conclude that the available evidence suggests that lactate changes can be used to indicate the effectiveness of therapeutic efforts to improve oxygen delivery and tissue blood flow. Page 50 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2
  51. 51. For surgeons managing critically ill patients, lactate is most useful when the elevated lactate level occurs in the setting of metabolic acidosis; acidosis is independently confirmed by measurements of serum bicarbonate and/or base deficit. The presence of elevated lactate with metabolic acidosis is predictive of mortality and resolution of hyperlactatemia suggests successful reversal of anaerobic metabolism. The final article reviewed in this section deals with the potential value of laboratory tests in the management of shock by Friese and coauthors41 appeared in the Journal of Trauma, 2007. These authors hypothesized that the transition from adequate resuscitation of shock to over resuscitation would be associated with increased myocardial wall stretch and serum levels of B-type natriuretic peptide might be valuable indicators of this transition. Serum levels of B-type natriuretic peptide were followed in 134 injured patients. Chest radiographs obtained 24 hours after admission were graded for the presence of pulmonary edema, which the authors used as an indicator of over resuscitation. Twenty patients who had increased pulmonary edema scores had mean serum levels of B-type natriuretic peptide that were significantly higher than the mean levels observed in patients without pulmonary edema. This paper was presented during the plenary session of the annual meeting of the American Association for the Surgery of Trauma and the discussion that followed the presentation is included with the article. The discussants note the non- specific nature of single chest radiograph assessments of pulmonary edema. There was no association between serum levels of B-type natriuretic peptide and any clinically meaningful endpoint. It seems safe to conclude that the search for additional laboratory indicators of resuscitation endpoints should continue. Page 51 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  52. 52. Monitoring at the tissue level Global markers of inadequate oxygen delivery to tissue such as central venous oxygen saturation, base deficit, and lactate levels represent the resultant vector of all vascular beds. There has been wide recognition that some vascular beds (especially the splanchnic bed) are persistently underperfused and hypoxic even though global indices of oxygen supply and consumption have been corrected to normal levels. Studies in humans and experimental animals have demonstrated significant variability in blood flow and recovery of normal cellular metabolism in resuscitated hemorrhagic shock. Accessible microvascular beds evaluated in clinical studies include skin, skeletal muscle, the sublingual bed, and the gastric mucosa. Mucosal pH and PC02, tissue oxygen saturation, and tissue oxygen tension have been studied as possible indices of successful resuscitation. Data from these evaluations are discussed in this segment of the overview. Values for pH and PCO2 can be measured in the gastric and sublingual mucosa using saline-filled latex chambers applied to the mucosal surface. Because the chamber is permeable to C02, the carbon dioxide tension of the mucosa is equivalent to the carbon dioxide tension of the saline within the chamber after equilibration, and this can be measured in a standard blood gas analyzer. Simultaneous measures of blood bicarbonate permit calculation of the mucosal pH. An important assumption included in these measurements is that mucosal and blood bicarbonate levels are equivalent. This assumption is controversial. The first article reviewed for this discussion is a classic clinical study by Ivatury and coauthors42 in the Journal of the American College of Surgeons, 1996, who conducted a Page 52 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 2
  53. 53. randomized prospective trial in which 57 severely injured patients were resuscitated from shock using global indicators of oxygen delivery and consumption. Consistent with the practice at the time, resuscitation to “supranormal” levels of oxygen delivery and consumption was performed. Gastric mucosal pH was assessed using the tonometry technique described above. Elevation of the gastric mucosal pH to a level > 7.3 was defined as adequate tissue-level resuscitation. Forty-four patients reached target levels of gastric mucosal pH and three of these developed multiple organ failure. Fifty-four percent of the patients who did not reach target levels for gastric mucosal pH developed multiple organ failure. The authors noted that low levels of gastric mucosal pH were observed in the hours before a serious complication such as abdominal compartment syndrome was diagnosed. These authors concluded that patients who reach target levels of gastric mucosal pH are less likely to develop organ failure and the development of low gastric mucosal pH may be a warning signal of an impending serious complication. Unfortunately, this study did not show that resuscitation to a target level of gastric mucosal pH was superior to resuscitation using global indicators of oxygen delivery and consumption. In fact, the frequency of complications such as organ failure and abdominal compartment syndrome were equivalent in the group resuscitated to a target mucosal pH compared to the group resuscitated using global markers. The evidence for and against the use of gastric mucosal pH as a resuscitation target is reviewed in an article by Hameed and Cohn43 in Chest, 2003. These authors reviewed the technique of gastric tonometry and concluded that the technique was standardized and Page 53 of 120 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1 2

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