- Email: [email protected]
Current concepts in critical care
Current Concepts in Critical Care Syed Hashmi, MD, Selwyn O Rogers, MD, MPH, FACS Since the turn of the millennium, surgical critical care has undergone dramatic changes. These changes could not have come at a more opportune moment, as our profession grapples with decreasing reimbursements and rising inequality in access to health care. By the nature of their service, ICUs are thought to be responsible for about one-fifth of all hospital costs, and hospital costs are thought to comprise about one-third of US health expenditure.1 In fact, it is thought that in the 1990s, critical care costs consumed about $62 billion, which represented about 1% of the gross national product.2 It has become even more important for us as surgeons to focus on ways that we not only can improve the care of our patients but also contribute to decreasing these costs. Application of novel processes of care in the ICU setting can markedly improve outcomes. We will discuss a number of new processes of care that are potentially improving outcomes of surgical patients in the ICU setting. We have chosen a select group of topics in which we believe there has been a clear paradigm shift and whose application will benefit the care of surgical patients.
200 mg/dL decreased by half the number of sternal wound infections in diabetic patients undergoing cardiac operations. Van den Berghe and associates8 examined whether the control of hyperglycemia in critically ill patients can lead to improved outcomes in a prospective randomized trial.8 Study patients were admitted to the ICU for mechanical ventilation. Patients were randomly assigned to one of two groups: the first group received intensive insulin therapy with the goal of trying to maintain glucose at between 80 and 110 mg/dL (ie, normoglycemia), while in the conventional treatment arm the goal glucose was kept between 180 and 200 mg/dL. As soon as the blood glucose in the intensive treatment arm exceeded 110 mg/dL, an insulin infusion was started to maintain normoglycemia. More than half of the patients had undergone cardiac operation and slightly more than 10% had a history of diabetes on admission. It is noteworthy in their study group that they were able to achieve morning glucose levels of 103 mg/dL as opposed to 153 mg/dL in control patients. This study showed that intensive insulin control lowered mortality by ⬎ 40%. It also showed that there was a decreased requirement for ventilator support. Interestingly, a decreased need for renal replacement therapy was also demonstrated. Control of hyperglycemia also decreased septic episodes in the patients randomized to intensive insulin therapy by ⬎ 40%. A followup study by the same investigators showed that correction of hyperglycemia is the critical factor, not the dose of insulin used per se.9 These findings have also been replicated by another group of investigators who also showed that it is hyperglycemia that is the dominant factor determining outcomes, not lack of insulin.10 Although this study does not offer mechanistic explanations, it may offer insight as to why growth hormone treatment in the critically ill may have led to increased mortality, because growth hormone exacerbates insulin resistance and promotes hyperglycemia.11 In totality, these studies make a compelling case that normoglycemia should be the rule rather than the exception in surgical patients in the ICU. It remains to be evaluated by further studies whether nor-
CONTROL OF HYPERGLYCEMIA Control of blood glucose has been shifting toward progressively tighter glucose control in diabetics, a paradigm shift also reflected in the care of critically ill patients. Tighter glucose control in diabetics has been shown to reduce longterm complications such as diabetic retinopathy, nephropathy, and neuropathy.3,4 This change arose from a steady accumulation of data showing that hyperglycemia leads to adverse outcomes. It is well known from laboratory studies that hyperglycemia affects immune function.5 Clinicians have also observed that elevated glucose promotes dehydration and inflammation.6 In clinical practice, Furnary and colleagues7 found the control of blood glucose to between 150 and No competing interests declared.
Received March 9, 2004; Revised August 24, 2004; Accepted August 25, 2004. From the Department of Surgery, Lincoln County Medical Center, Ruidoso, NM (Hashmi) and the Department of Surgery, Brigham and Women’s Hospital, Boston, MA (Rogers). Correspondence address: Syed Hashmi, MD, 207 Sudderth, Ruidoso, NM 88345.
© 2005 by the American College of Surgeons Published by Elsevier Inc.
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Abbreviations and Acronyms
PAC ⫽ pulmonary artery catheter rHuEpo ⫽ recombinant human erythropoietin SBT ⫽ spontaneous breathing trial
moglycemia can improve outcomes in other populations of surgical patients. ADVANCES IN TREATMENT OF SEPSIS Sepsis is a common syndrome in critical care units and is thought to be responsible for as many deaths as myocardial infarction.12 Sepsis has an estimated incidence of about 750,000 cases per year in the United States, with an annual cost of about $17 billion. Despite advancement in the care of the critically ill, mortality rates secondary to sepsis range between 20% and 50%. Although in-hospital mortality rates may have declined, the incidence of sepsis continues to rise.13 Despite multiple attempts at the use of biologic agents, such as HA-1A and antimonoclonal antibody to tumor necrosis factor, in the treatment of sepsis, to date, these have yielded negative results.14 We now have a novel agent in our armamentarium against sepsis. In 2002, recombinant activated protein C or drotrecogin alpha entered into clinical practice. Activated protein C is an endogenous protein that has important antiinflammatory effects, including inhibiting platelet activation, neutrophil recruitment, and mast cell degranulation.15 It is produced from its inactive form, protein C, by thrombin coupled with thrombomodulin on the surface of endothelial cells. Thrombin, unlike protein C, is a procoagulant and exacerbates the inflammatory cascade.16 The antiinflammatory properties of activated protein C allow it to modulate the local inflammatory response.17 Clinical studies have revealed that patients with reduced levels of protein C and sepsis have an increased likelihood of death.18 The role of recombinant protein C was evaluated by the PROWESS (recombinant human activated protein C worldwide evaluation in severe sepsis study group) investigators.19 In this randomized, double-blind, placebo-controlled trial done in 11 countries, patients with severe sepsis were randomized within 24 hours to receive either an infusion of placebo or a 4-day infusion of activated protein C. Three-fourths of the study population had two or more organ failures. Over half had a
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source of infection in the lung; the next most common sites were the abdomen and the urinary tract. In each arm, about 20% had a history of emergency operation. The study was terminated at the second interim analysis because of the statistically significant difference between the 28-day mortality with the drug (24.7%) versus placebo (30.8%). This translated into an absolute risk reduction of 6.1%. These results were achieved at the approximate cost of $7,000 per dose given.20 There are some caveats to this study. The incidence of bleeding was higher in the study population, 3.5% versus 2.0% in the control group. These episodes of bleeding tended to occur in patients who had already had an identifiable risk factor, such as peptic ulcer, or in those patients with elevated coagulation times or thrombocytopenia. The study did not specifically address the issue of whether these were more likely in patients with recent operation. Predisposition to bleeding is directly related to the anticoagulant effect of the drug. Investigators have also raised serious methodological issues about the study.21 The nature of the trial was changed after the first analysis to exclude patients with organ failure for more than 1 day. Other changes, which were done in a blinded fashion, included shifting the focus of the study to patients with more severe infectious diseases and less underlying comorbidities. The rationale for the change given by the investigators was that by excluding the more chronically ill, there was a chance to evaluate the drug on those most likely to benefit. These changes were done with the consent of the FDA.22 More importantly, a new master cellblock to produce activated protein C was also introduced at this time. An extensive analysis of this change by the FDA revealed no changes in the preparation.23 The cumulative result of these changes was the drug that, in the first half of the study, had no effect on mortality, was by the second half of the trial showing a statistically significant effect.24 It may be because of these changes that the FDA Anti-Infective Drug Advisory Committee was split evenly on whether to approve the drug.25 The FDA did approve the drug for clinical use but only for those patients with the highest quartile APACHE II scores. It also required the manufacturer to perform further trials to assess its efficacy. This labeling by itself has aroused concern, as the APACHE II score was developed as a population tool and not intended for use in the individual patient.26 More importantly, the APACHE II score used in this study was based on data
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obtained in the immediate 24 hours before randomization and not on the first 24 hours in a critical care environment. It is also noteworthy that the APACHE score may vary significantly in the same patient, depending on the time of day it is measured and may also vary by observer.27 More important is the fact that the APACHE II score has not been validated beyond the first day of critical care admission.28 Although we recognize that the use of activated protein C represents an important advance in the treatment of sepsis, serious questions still remain about overall efficacy in surgical patients. Further investigation is ongoing to better define the role of activated protein C in those who are not as acutely ill (ie, APACHE II scores between 20 to 25). EVOLVING USE OF STEROID REPLACEMENT IN SEPSIS One of the first therapies attempted for treatment of sepsis was the use of corticosteroids.29 The rationale for use of corticosteroids in sepsis came from their critical role in the maintenance of homeostasis.30 It was found that the administration of steroids not only increased the incidence of secondary infection, but also contributed to increased mortality.31 In certain subsets of patients, recent research has revealed that there exists a relative adrenal insufficiency.32 Rivers and colleagues33 found that a third of their high-risk surgical patients had relative adrenal insufficiency and appeared to benefit from steroid replacement. This is considerably different from the use of steroids in supraphysiolgical doses in the 1970s and 1980s.34 It has been suggested that the threshold level for insufficiency is a random cortisol level that is ⱕ 15 ug/dL.35 Annane and associates,36 in a randomized control trial that included surgical patients, prospectively studied the role of steroid replacement in patients with severe septic shock. This study found that patients who had relative adrenal insufficiency (a postadrenocorticotropic hormone cortisol increase of ⬍ 9 ug/dL) and were treated with both hydrocortisone and fludrocortisone for 7 days had decreased duration of pressor days and decreased mortality. Importantly, there appeared to be no significant difference in complications between the placebo and the study group. Steroids were ineffective in patients who did respond appropriately to the adrenocorticotropic hormone. It is important to note that this was a highly select group of patients with a high mortality. Mortality in the placebo group was ⬎ 60%, and the
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sample size was small, consisting of 300 patients. Whether these results can be generalized to clinical practice requires further study. The action of steroids in this study may be related not only to their immune modulating effects but they may also act to improve responsiveness of blood vessels to vasoactive agents.37 When faced with a patient with sepsis, unresponsive to resuscitation with standard therapy, it may be worthwhile to obtain a random cortisol level. If it is ⬍ 15 ug/dL, consideration should be given to steroid replacement. If it is in an intermediate range, between 15 and 34 ug/dL, followup with a corticotropin stimulation test is recommended to determine whether steroid replacement is indicated.38 Some have advocated use of dexamethasone, 3 mg every 6 hours, as it does not interfere with cortisol measurement.39 EVOLVING INDICATIONS FOR USE OF THE PULMONARY ARTERY CATHETER In recent years, the role of the pulmonary artery catheter (PAC) has become better defined. Part of this debate was precipitated by publication of a study by Connors and colleagues;40 this study showed that in a mixed population of patients in ICUs, the use of PAC was associated with increased costs, length of stay, and, most importantly, mortality. Although the study was observational in nature, it generated intense interest in objectively assessing the efficacy of the PAC.41 One of the studies to evaluate the use of PACs in a randomized controlled trial in high-risk surgical patients was done by the Canadian Critical Care Clinical Trials Group.42 This group randomized patients over the age of 60 with American Society of Anesthesiologists Class III or IV risk and who were scheduled for elective and emergent abdominal, thoracic, vascular, and orthopaedic operations to standard care or to care directed to defined goals by the use of a PAC. Results showed no statistically significant difference in hospital mortality or mortality at 1 year between the groups randomized to a catheter or to standard care. More intriguing, the study showed that there was a small, but statistically higher incidence of pulmonary embolism in the PAC group, despite the use of SC heparin. Although this study focused on surgical patients and did not include patients with ARDS or septic shock, its results did not support routine use of PACs in the setting of routine intraoperative or postoperative care of high-risk surgical patient. Use of PACs in management of ARDS and shock was
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evaluated by Richard and colleagues43 in a multicenter, randomized trial conducted in France. This study randomized 681 patients with shock and ARDS to receive PACs or not. The study revealed no difference in organ dysfunction, duration on ventilation, need for vasoactive therapy, duration of ICU stay, and 90-day mortality between the patients who received PACs and those who did not. There were several criticisms of the study, among which was the fact that there were no protocols to ensure that the patients were treated appropriately, or which proportion of the patients in each arm received which intervention.44 One persistent concern about use of PACs has been that caregivers are sometimes unable to obtain or interpret data from the device.45 The study also had a smaller size than originally envisioned, but the authors did conclude at the risk of 5% that the difference in mortality between the two groups was not more than 7.8%. On a separate note, these investigators did not observe a higher rate of embolism. We are still awaiting results of the ongoing ARDSnet study 05 trial, which compares use of PACs with use of central venous catheters in the management of ARDS.46 This trial will also evaluate fluid strategy in the management of ARDS. ADVANCES IN MANAGEMENT OF ARDS Acute respiratory failure continues to be the major reason for the institution of mechanical ventilation.47 The most serious manifestation of this is ARDS, which is the end result of various insults to the lung itself. Depending on the study population, the mortality of this syndrome remains anywhere between 40% and 60%.48 Treatment of ARDS has followed essentially two strategies: pharmacological manipulation or respiratory management. As yet, pharmacological therapies have not yielded any “magic bullets.”49 With regard to respiratory management, there has been a gradual evolution of therapy that may yield therapeutic benefit. This new management paradigm is aimed at prevention of ventilator-induced lung injury. Initially, the goal in the management of ARDS was to normalize the blood gas and correct the hypoxemia. Data have accumulated indicating that this strategy leads to overdistention of the lung and resultant ventilator-induced lung injury.50 It is now thought that mechanical ventilation itself leads to lung injury by the release of several proinflammatory mediators.51 Release of these mediators may explain why the majority of pa-
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tients with ARDS die not from worsening hypoxemia but from multiorgan system failure.52 It has become clear that, although prevention of atelectasis and the accompanying ventilation-perfusion mismatch is important, overdistention of alveoli is harmful.53 The conventional goal of trying to correct respiratory abnormalities has given way to a focus on lower tidal volumes and tolerating the resulting hypercapnia, as first reported by Hickling and colleagues.54 It was not evident if this approach would yield any survival benefit.55–57 The Acute Respiratory Distress Syndrome Network put these doubts to rest in their multicenter, randomized prospective trial.58 The study randomized patients with acute lung injury or ARDS to tidal volumes of 6 mL/kg or 12 mL/kg. In the study population, plateau pressures were kept at less than 30 cm of water, and control patients were allowed to have plateau pressures as high as 50 cm of water. Both groups of patients had similar ventilatory modes, primarily volume assist-control, and similar oxygenation goals to keep saturations in the 88% to 95% range. The trial was terminated early when it was found that patients with lower tidal volume ventilation had approximately 22% less mortality. The lower tidal volume group was also more likely to breathe without assistance at Day 28 and to have a lower incidence of organ failure. The focus of management of ARDS should be on achieving lower tidal volumes and attempting to keep plateau pressures less than 30 cm of water. An intriguing speculation remains whether the high mortality associated with the syndrome previously was directly related to the high tidal volumes.59 On a separate note, this study became the center of a controversy about its design and whether its participants were subject to elevated risks.60 At the heart of the debate was whether use of the control group reflected the standard of care, and whether lower tidal volumes should have been used.61 This led to an investigation by the Office for Human Research Protection of the Department of Health and Human Services. This investigation refuted concerns about trial design and ethical appropriateness.62 Chest CT scans have demonstrated that lung involvement by ARDS is patchy and is usually worse in dependent portions of the lung.63 To correct this ventilationperfusion mismatch, investigators have suggested proning patients to improve their oxygenation.64 Outcomes
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of prone position on survival appear to be minimal, as recently demonstrated by Gattinoni and associates65 in a multicenter, randomized trial. Despite the failure of this study to show a survival benefit, it did show that there was an improvement of oxygenation in patients who were prone. Possible limitations of the study included its short duration (ie, 6 hours of pronation) and the small sample size of about 300 patients, which may not have been an adequate number to achieve statistical significance. Last, the patients were kept in the prone position for only 10 days and that might not have been long enough to achieve an effect on mortality. It has been estimated that 40% of the time spent on respiratory support is devoted solely to weaning from it.66 A quarter of patients, after being extubated, require reintubation.67 A failed attempt at spontaneous breathing causes considerable stress on the myocardium.68 Patients who require reintubation also have a sixfold higher mortality.69 A decreased duration of weaning also contributes to reducing incidence of nosocomial infections, which then contributes to a decrease in mortality.70 The current evolving approach to weaning uses a team-based approach and integrates the spontaneous breathing trial (SBT). In this mode of weaning, ventilatory support is removed and the patient is allowed to breathe either through a T-tube or through the ventilator circuit by using a flow trigger. Although a number of parameters have been developed to assess a patient’s readiness for extubation, it appears that a carefully monitored SBT allows for physiologic measurement of a patient’s readiness for extubation.71 It is recommended that patients be monitored closely when an SBT is in progress so that at the first sign of decompensation, respiratory support can be resumed. It is noteworthy that the SBT in and of itself is rarely associated with adverse events.72 The SBT should last from half an hour to no more than 2 hours, and whether pressure support is given or not, little change appears in the outcomes.73 A team approach to ventilatory weaning does matter and does make a difference. Ely and colleagues74 found that by using a protocol that allowed nonphysician providers to identify a patient’s readiness for extubation followed by an SBT, they were able to get patients off the ventilator in 2 less days and with reduced ICU costs.74 The exact approach itself does not appear to matter; more important is following the protocol.75
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CHANGING TRANSFUSION PATTERNS IN CRITICALLY ILL PATIENTS Because of the nature of their illness, a significant proportion of patients admitted to surgical ICUs receive blood transfusions.76 The reason for this transfusion requirement is rarely acute blood losses but appears to be multifactorial. ICU patients tend to have inappropriately low erythropoietin levels, and there is also a daily blood loss associated with phlebotomy.77 Until recently, this was justified because it was thought anemia increased the risk of dying in the critically ill.78 More importantly, liberal use of blood transfusion was justified because a hemoglobin ⬎ 10 mg/dL improves oxygen delivery.79 For several reasons, the practice of treating of a number (hemoglobin) is gradually changing. Separate from the concerns about the passage of infective agents, more serious concerns have been raised about the immunosuppressive effect of transfusions in the critically ill.80 One study showed that the risk of pneumonia increased 1% per day that blood was stored.81 An evolving area of research is the deleterious effect of transfusing stored blood. Investigators using an animal model have shown that when blood is stored for more than 15 days, the red blood cell appears to lose its ability to pass through the microcirculation, and that hemoglobin also loses the capability to transport oxygen.82 It has become apparent that liberal use of transfusion may contribute to decreased survival.83 In a prospective randomized fashion, the Canadian Critical Care Trials Group studied this question. Patients were randomized to a hemoglobin maintained between 7 and 9 mg/dL or between 10 and 12 mg/dL. The majority of patients in this trial had three main diagnoses: respiratory disease, cardiovascular disease, or trauma. At least a third of them had another comorbidity. Over a third in each arm came from the operating room to the ICU. The 30-day mortality in their transfusion-restricted group was 18.7% compared with 23.3% in the liberal transfusion group and was not statistically significant. Mortality during hospitalization was significantly different (22.2% for the restricted group versus 28.1% for the liberal transfusion group, p ⫽ 0.05). There also did not appear to be any differences in the development of cardiac complications between the two groups, demonstrating that a lower transfusion threshold was safe. A subgroup analysis done by the same group showed that in patients with active
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heart disease there was a trend toward improved survival with higher hemoglobins.84 By adopting this policy, the group was able to reduce the number of units transfused by half, without use of any adjunctive medications. Use of a restrictive transfusion policy also was assessed in postcardiac surgical patients in a randomized trial where it was found that there were no differences in endurance between patients who received transfusion to keep their hematocrit in the 32% range and those patients who received transfusions when the hematocrit was ⬍ 25%.85 It may still be worthwhile to transfuse elderly patients with anemia and tachycardia to decrease risk of myocardial ischemia.86 In a retrospective review of 30,000 Medicare patients with acute myocardial infarction, the use of blood transfusion to keep hematocrits ⬎ 30% was associated with decreased complication rate and a reduction in 30-day mortality.87 Among the contributing factors to anemia in the ICU is the lack of appropriate response by the bone marrow to produce more red blood cells. This is thought to be related to a lack of response of the bone marrow to erythropoietin.88 The hypothesis that treatment with erythropoietin could increase the level of hemoglobin was tested in the Epo Critical Care Trials Group.89 This was a prospective, randomized, double-blind, placebocontrolled multicenter trial in which study patients (who were expected to have an ICU stay longer than 2 days) were administered 40,000 U of recombinant human erythropoietin (rHuEpo) on ICU Day 3 and weekly thereafter for three doses (study Days 1, 7, and 14). Patients who still were present in the ICU on Day 21 received another dose. Concomitantly, all patients received at least 150 mg a day of elemental iron. There were no specific levels that were mandated for transfusion. A majority of patients in both arms were either postoperative or trauma patients. Results of this study showed that administration of rHuEpo led to a 19% reduction in the units transfused and also an increase in hemoglobin concentration, although there was no statistically significant difference in survival. Reduction in the units transfused also was less than that achieved by restricted transfusion policy, as we mentioned earlier, without the almost $400 cost for each 40,000 dose of rHuEpo. This sum is approximately the same cost as a transfusion. Whether the practice of using rHuEpo needs to become a part of routine clinical practice requires further evaluation through outcomes studies.
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In conclusion, we have shown how critical care has and is continuing to evolve. Several of the therapies we described represent a significant shift in the care of critically ill patients. We believe that the rational use of these ideas should lead to improved outcomes in the care of critically ill patients in the ensuing years. Author Contributions
Study conception and design: Hashmi Acquisition of data: Hashmi Analysis and interpretation of data: Hashmi, Rogers Drafting of manuscript: Hashmi, Rogers Critical revision: Hashmi, Rogers Supervision: Rogers Acknowledgment: We wish to acknowledge the assistance of Christy Pearson, Keith Green, and the staff of the Presbyterian Medical Library in the preparation of this article.
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tality in patients with adult respiratory distress syndrome. Am Rev Respir Dis 1985;132:485–489. Parker JC, Hernandes CA, Peevy KJ. Mechanisms of ventilatorinduced lung injury. Crit Care Med 1993;21:131–143. Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 1990;16:372–377. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998;338: 355–361. Brouchard L, Roudot-Throval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. Am J Respir Crit Care Med 1998;158:1831–1838. Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome. Crit Care Med 1999;27:1492–1498. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. Slutsky AS. The acute respiratory syndrome, mechanical ventilation, and the prone position. N Engl J Med 2001;345:6110– 6112. Steinbrook R. How to ventilate? Trial design and patient safety in studies of the acute respiratory distress syndrome. N Engl J Med 2003;348:1393–1401. Eichacker PQ, Gerstenberger EP, Banks SM, et al. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 2002;166:1510–1514. Steinbrook R. Trial design and patient safety—the debate continues. N Engl J Med 2003;349:629–630. Gattinoni L, Presenti A, Bombino M, et al. Relationships between lung computed tomographic density, gas exchange and peep in acute respiratory failure. Anesthesiology 1988;69:824– 832. Piehl MA, Brown RS. Use of extreme position changes in acute respiratory failure. Crit Care Med 1976;4:13–14. Gattioni L, Togoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001;345:568–573. Esteban A, Alia I, Iabanez J, et al. Modes of mechanical ventilation and weaning: a national survey of Spanish hospitals; the Spanish Lung Failure Collaborative Group. Chest 1994;106: 1188–1193. Brochard L, Rauss A, Beneito S, et al. Comparison of three methods of gradually withdrawing from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 1994;150:896–903. Lemiere F, Teboul JL, Cinotti L, et al. Acute left ventricular dysfunction during unsuccessful weaning from mechanical ventilation. Anesthesiology 1988;69:171–179. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest 1997;112: 186–192. Ely EW, Babr AM, Evans GW, Halpaik EF. The prognostic
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significance of passing a daily screen of weaning parameters. Intensive Care Med 1999;25:581–587. Cook D, Meade M, Guyatt G, et al. Evidence report on criteria for weaning from mechanical ventilation. Rockville, MD: Agency for Health Care Policy and Research; 1999. Ely EW, Baker AM, Evans GW, et al. The prognostic significance of passing a daily screen of breathing spontaneously. N Engl J Med 1999;25:581–587. Esteban A, Alia I, Tobin MJ, et al. Effects of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation: the Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 1999;159:512–518. Ely EW, Baker AM, Dungan DP, et al. Effect on duration of mechanical ventilation on identifying patients capable of breathing spontaneously. N Engl J Med 1996;335:1864–1869. Kollek MA, Shapiro SD, Silver P, et al. A randomized control trial of protocol–directed versus physician–directed weaning from mechanical ventilation. Crit Care Med 1997;25:567–574. Vincent J, Baron JF, Gattioni L, et al. Anemia and blood transfusions in critically ill patients. JAMA 2002;88:1499–1507. Krafte-Jacobs B, Levetown ML, Bray GL, et al. Erythropoietin response to critical illness. Crit Care Med 1994;22:821–826. Hebert PC, Wells G, Tweedale M, et al. Does transfusion practice affect mortality in critically ill patients? Am J Respir Crit Care Med 1997;155:1618–23. Russell JA, Phang PT. The oxygen delivery-consumption controversy: an approach to management of the critically ill. Am J Respir Crit Care Med 1994;149:533–537. Michkler TA, Longnecker DE. The immunosuppressive aspects of blood transfusion. J Intensive Care Med 1992;7:176–188. Purdy FR, Tweddale MG, Merrick PM. Association of mortality with age of blood transfused in septic ICU patients. Can J Anaesth 1997;44:1256–1261. Fitzgerald RD, Martin CM, Dietz GE, et al. Transfusing red blood cells stored in citrate phosphate dextrose adenine-1 for 28 days fails to improve tissue oxygenation in rats. Crit Care Med 1997;25:726–732. Hebert PC, Wells J, Baljchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409–417. Hebert PC, Yetisir E, Martin L, et al. Is a low transfusion threshold safe in critically ill patients with cardiovascular disease? Crit Care Med 2001;29:227–234. Johnson RG, Thurer RL, Kruskall MS, et al. Comparison of two transfusion strategies after elective operation from myocardial vascularization. J Thoracic Cardiovasc Surg 1992;104:307–314. Hogue W Jr, Goodnough LT, Monk TG. Perioperative myocardial ischemic episodes are related to hematocrit levels in patients undergoing radical prostatectomy. Transfusion 1998;38:924– 931. Wu WC, Rathore SS, Wang Y, et al. Blood transfusions in elderly patients with acute myocardial infarction. N Engl J Med 2001; 345:1230–1236. Rogiers P, Zhang H, Leeman M, et al. Erythropoietin response is blunted in critically ill patients. Intensive Care Med 1997;23: 159–162. Corwin HL, Gettinger A, Pearl RG, et al. Efficacy of recombinant human erythropoietin in critically ill patients; randomized control trial. JAMA 2002;288:2827–2835.
200 mg/dL decreased by half the number of sternal wound infections in diabetic patients undergoing cardiac operations. Van den Berghe and associates8 examined whether the control of hyperglycemia in critically ill patients can lead to improved outcomes in a prospective randomized trial.8 Study patients were admitted to the ICU for mechanical ventilation. Patients were randomly assigned to one of two groups: the first group received intensive insulin therapy with the goal of trying to maintain glucose at between 80 and 110 mg/dL (ie, normoglycemia), while in the conventional treatment arm the goal glucose was kept between 180 and 200 mg/dL. As soon as the blood glucose in the intensive treatment arm exceeded 110 mg/dL, an insulin infusion was started to maintain normoglycemia. More than half of the patients had undergone cardiac operation and slightly more than 10% had a history of diabetes on admission. It is noteworthy in their study group that they were able to achieve morning glucose levels of 103 mg/dL as opposed to 153 mg/dL in control patients. This study showed that intensive insulin control lowered mortality by ⬎ 40%. It also showed that there was a decreased requirement for ventilator support. Interestingly, a decreased need for renal replacement therapy was also demonstrated. Control of hyperglycemia also decreased septic episodes in the patients randomized to intensive insulin therapy by ⬎ 40%. A followup study by the same investigators showed that correction of hyperglycemia is the critical factor, not the dose of insulin used per se.9 These findings have also been replicated by another group of investigators who also showed that it is hyperglycemia that is the dominant factor determining outcomes, not lack of insulin.10 Although this study does not offer mechanistic explanations, it may offer insight as to why growth hormone treatment in the critically ill may have led to increased mortality, because growth hormone exacerbates insulin resistance and promotes hyperglycemia.11 In totality, these studies make a compelling case that normoglycemia should be the rule rather than the exception in surgical patients in the ICU. It remains to be evaluated by further studies whether nor-
CONTROL OF HYPERGLYCEMIA Control of blood glucose has been shifting toward progressively tighter glucose control in diabetics, a paradigm shift also reflected in the care of critically ill patients. Tighter glucose control in diabetics has been shown to reduce longterm complications such as diabetic retinopathy, nephropathy, and neuropathy.3,4 This change arose from a steady accumulation of data showing that hyperglycemia leads to adverse outcomes. It is well known from laboratory studies that hyperglycemia affects immune function.5 Clinicians have also observed that elevated glucose promotes dehydration and inflammation.6 In clinical practice, Furnary and colleagues7 found the control of blood glucose to between 150 and No competing interests declared.
Received March 9, 2004; Revised August 24, 2004; Accepted August 25, 2004. From the Department of Surgery, Lincoln County Medical Center, Ruidoso, NM (Hashmi) and the Department of Surgery, Brigham and Women’s Hospital, Boston, MA (Rogers). Correspondence address: Syed Hashmi, MD, 207 Sudderth, Ruidoso, NM 88345.
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Abbreviations and Acronyms
PAC ⫽ pulmonary artery catheter rHuEpo ⫽ recombinant human erythropoietin SBT ⫽ spontaneous breathing trial
moglycemia can improve outcomes in other populations of surgical patients. ADVANCES IN TREATMENT OF SEPSIS Sepsis is a common syndrome in critical care units and is thought to be responsible for as many deaths as myocardial infarction.12 Sepsis has an estimated incidence of about 750,000 cases per year in the United States, with an annual cost of about $17 billion. Despite advancement in the care of the critically ill, mortality rates secondary to sepsis range between 20% and 50%. Although in-hospital mortality rates may have declined, the incidence of sepsis continues to rise.13 Despite multiple attempts at the use of biologic agents, such as HA-1A and antimonoclonal antibody to tumor necrosis factor, in the treatment of sepsis, to date, these have yielded negative results.14 We now have a novel agent in our armamentarium against sepsis. In 2002, recombinant activated protein C or drotrecogin alpha entered into clinical practice. Activated protein C is an endogenous protein that has important antiinflammatory effects, including inhibiting platelet activation, neutrophil recruitment, and mast cell degranulation.15 It is produced from its inactive form, protein C, by thrombin coupled with thrombomodulin on the surface of endothelial cells. Thrombin, unlike protein C, is a procoagulant and exacerbates the inflammatory cascade.16 The antiinflammatory properties of activated protein C allow it to modulate the local inflammatory response.17 Clinical studies have revealed that patients with reduced levels of protein C and sepsis have an increased likelihood of death.18 The role of recombinant protein C was evaluated by the PROWESS (recombinant human activated protein C worldwide evaluation in severe sepsis study group) investigators.19 In this randomized, double-blind, placebo-controlled trial done in 11 countries, patients with severe sepsis were randomized within 24 hours to receive either an infusion of placebo or a 4-day infusion of activated protein C. Three-fourths of the study population had two or more organ failures. Over half had a
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source of infection in the lung; the next most common sites were the abdomen and the urinary tract. In each arm, about 20% had a history of emergency operation. The study was terminated at the second interim analysis because of the statistically significant difference between the 28-day mortality with the drug (24.7%) versus placebo (30.8%). This translated into an absolute risk reduction of 6.1%. These results were achieved at the approximate cost of $7,000 per dose given.20 There are some caveats to this study. The incidence of bleeding was higher in the study population, 3.5% versus 2.0% in the control group. These episodes of bleeding tended to occur in patients who had already had an identifiable risk factor, such as peptic ulcer, or in those patients with elevated coagulation times or thrombocytopenia. The study did not specifically address the issue of whether these were more likely in patients with recent operation. Predisposition to bleeding is directly related to the anticoagulant effect of the drug. Investigators have also raised serious methodological issues about the study.21 The nature of the trial was changed after the first analysis to exclude patients with organ failure for more than 1 day. Other changes, which were done in a blinded fashion, included shifting the focus of the study to patients with more severe infectious diseases and less underlying comorbidities. The rationale for the change given by the investigators was that by excluding the more chronically ill, there was a chance to evaluate the drug on those most likely to benefit. These changes were done with the consent of the FDA.22 More importantly, a new master cellblock to produce activated protein C was also introduced at this time. An extensive analysis of this change by the FDA revealed no changes in the preparation.23 The cumulative result of these changes was the drug that, in the first half of the study, had no effect on mortality, was by the second half of the trial showing a statistically significant effect.24 It may be because of these changes that the FDA Anti-Infective Drug Advisory Committee was split evenly on whether to approve the drug.25 The FDA did approve the drug for clinical use but only for those patients with the highest quartile APACHE II scores. It also required the manufacturer to perform further trials to assess its efficacy. This labeling by itself has aroused concern, as the APACHE II score was developed as a population tool and not intended for use in the individual patient.26 More importantly, the APACHE II score used in this study was based on data
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obtained in the immediate 24 hours before randomization and not on the first 24 hours in a critical care environment. It is also noteworthy that the APACHE score may vary significantly in the same patient, depending on the time of day it is measured and may also vary by observer.27 More important is the fact that the APACHE II score has not been validated beyond the first day of critical care admission.28 Although we recognize that the use of activated protein C represents an important advance in the treatment of sepsis, serious questions still remain about overall efficacy in surgical patients. Further investigation is ongoing to better define the role of activated protein C in those who are not as acutely ill (ie, APACHE II scores between 20 to 25). EVOLVING USE OF STEROID REPLACEMENT IN SEPSIS One of the first therapies attempted for treatment of sepsis was the use of corticosteroids.29 The rationale for use of corticosteroids in sepsis came from their critical role in the maintenance of homeostasis.30 It was found that the administration of steroids not only increased the incidence of secondary infection, but also contributed to increased mortality.31 In certain subsets of patients, recent research has revealed that there exists a relative adrenal insufficiency.32 Rivers and colleagues33 found that a third of their high-risk surgical patients had relative adrenal insufficiency and appeared to benefit from steroid replacement. This is considerably different from the use of steroids in supraphysiolgical doses in the 1970s and 1980s.34 It has been suggested that the threshold level for insufficiency is a random cortisol level that is ⱕ 15 ug/dL.35 Annane and associates,36 in a randomized control trial that included surgical patients, prospectively studied the role of steroid replacement in patients with severe septic shock. This study found that patients who had relative adrenal insufficiency (a postadrenocorticotropic hormone cortisol increase of ⬍ 9 ug/dL) and were treated with both hydrocortisone and fludrocortisone for 7 days had decreased duration of pressor days and decreased mortality. Importantly, there appeared to be no significant difference in complications between the placebo and the study group. Steroids were ineffective in patients who did respond appropriately to the adrenocorticotropic hormone. It is important to note that this was a highly select group of patients with a high mortality. Mortality in the placebo group was ⬎ 60%, and the
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sample size was small, consisting of 300 patients. Whether these results can be generalized to clinical practice requires further study. The action of steroids in this study may be related not only to their immune modulating effects but they may also act to improve responsiveness of blood vessels to vasoactive agents.37 When faced with a patient with sepsis, unresponsive to resuscitation with standard therapy, it may be worthwhile to obtain a random cortisol level. If it is ⬍ 15 ug/dL, consideration should be given to steroid replacement. If it is in an intermediate range, between 15 and 34 ug/dL, followup with a corticotropin stimulation test is recommended to determine whether steroid replacement is indicated.38 Some have advocated use of dexamethasone, 3 mg every 6 hours, as it does not interfere with cortisol measurement.39 EVOLVING INDICATIONS FOR USE OF THE PULMONARY ARTERY CATHETER In recent years, the role of the pulmonary artery catheter (PAC) has become better defined. Part of this debate was precipitated by publication of a study by Connors and colleagues;40 this study showed that in a mixed population of patients in ICUs, the use of PAC was associated with increased costs, length of stay, and, most importantly, mortality. Although the study was observational in nature, it generated intense interest in objectively assessing the efficacy of the PAC.41 One of the studies to evaluate the use of PACs in a randomized controlled trial in high-risk surgical patients was done by the Canadian Critical Care Clinical Trials Group.42 This group randomized patients over the age of 60 with American Society of Anesthesiologists Class III or IV risk and who were scheduled for elective and emergent abdominal, thoracic, vascular, and orthopaedic operations to standard care or to care directed to defined goals by the use of a PAC. Results showed no statistically significant difference in hospital mortality or mortality at 1 year between the groups randomized to a catheter or to standard care. More intriguing, the study showed that there was a small, but statistically higher incidence of pulmonary embolism in the PAC group, despite the use of SC heparin. Although this study focused on surgical patients and did not include patients with ARDS or septic shock, its results did not support routine use of PACs in the setting of routine intraoperative or postoperative care of high-risk surgical patient. Use of PACs in management of ARDS and shock was
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evaluated by Richard and colleagues43 in a multicenter, randomized trial conducted in France. This study randomized 681 patients with shock and ARDS to receive PACs or not. The study revealed no difference in organ dysfunction, duration on ventilation, need for vasoactive therapy, duration of ICU stay, and 90-day mortality between the patients who received PACs and those who did not. There were several criticisms of the study, among which was the fact that there were no protocols to ensure that the patients were treated appropriately, or which proportion of the patients in each arm received which intervention.44 One persistent concern about use of PACs has been that caregivers are sometimes unable to obtain or interpret data from the device.45 The study also had a smaller size than originally envisioned, but the authors did conclude at the risk of 5% that the difference in mortality between the two groups was not more than 7.8%. On a separate note, these investigators did not observe a higher rate of embolism. We are still awaiting results of the ongoing ARDSnet study 05 trial, which compares use of PACs with use of central venous catheters in the management of ARDS.46 This trial will also evaluate fluid strategy in the management of ARDS. ADVANCES IN MANAGEMENT OF ARDS Acute respiratory failure continues to be the major reason for the institution of mechanical ventilation.47 The most serious manifestation of this is ARDS, which is the end result of various insults to the lung itself. Depending on the study population, the mortality of this syndrome remains anywhere between 40% and 60%.48 Treatment of ARDS has followed essentially two strategies: pharmacological manipulation or respiratory management. As yet, pharmacological therapies have not yielded any “magic bullets.”49 With regard to respiratory management, there has been a gradual evolution of therapy that may yield therapeutic benefit. This new management paradigm is aimed at prevention of ventilator-induced lung injury. Initially, the goal in the management of ARDS was to normalize the blood gas and correct the hypoxemia. Data have accumulated indicating that this strategy leads to overdistention of the lung and resultant ventilator-induced lung injury.50 It is now thought that mechanical ventilation itself leads to lung injury by the release of several proinflammatory mediators.51 Release of these mediators may explain why the majority of pa-
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tients with ARDS die not from worsening hypoxemia but from multiorgan system failure.52 It has become clear that, although prevention of atelectasis and the accompanying ventilation-perfusion mismatch is important, overdistention of alveoli is harmful.53 The conventional goal of trying to correct respiratory abnormalities has given way to a focus on lower tidal volumes and tolerating the resulting hypercapnia, as first reported by Hickling and colleagues.54 It was not evident if this approach would yield any survival benefit.55–57 The Acute Respiratory Distress Syndrome Network put these doubts to rest in their multicenter, randomized prospective trial.58 The study randomized patients with acute lung injury or ARDS to tidal volumes of 6 mL/kg or 12 mL/kg. In the study population, plateau pressures were kept at less than 30 cm of water, and control patients were allowed to have plateau pressures as high as 50 cm of water. Both groups of patients had similar ventilatory modes, primarily volume assist-control, and similar oxygenation goals to keep saturations in the 88% to 95% range. The trial was terminated early when it was found that patients with lower tidal volume ventilation had approximately 22% less mortality. The lower tidal volume group was also more likely to breathe without assistance at Day 28 and to have a lower incidence of organ failure. The focus of management of ARDS should be on achieving lower tidal volumes and attempting to keep plateau pressures less than 30 cm of water. An intriguing speculation remains whether the high mortality associated with the syndrome previously was directly related to the high tidal volumes.59 On a separate note, this study became the center of a controversy about its design and whether its participants were subject to elevated risks.60 At the heart of the debate was whether use of the control group reflected the standard of care, and whether lower tidal volumes should have been used.61 This led to an investigation by the Office for Human Research Protection of the Department of Health and Human Services. This investigation refuted concerns about trial design and ethical appropriateness.62 Chest CT scans have demonstrated that lung involvement by ARDS is patchy and is usually worse in dependent portions of the lung.63 To correct this ventilationperfusion mismatch, investigators have suggested proning patients to improve their oxygenation.64 Outcomes
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of prone position on survival appear to be minimal, as recently demonstrated by Gattinoni and associates65 in a multicenter, randomized trial. Despite the failure of this study to show a survival benefit, it did show that there was an improvement of oxygenation in patients who were prone. Possible limitations of the study included its short duration (ie, 6 hours of pronation) and the small sample size of about 300 patients, which may not have been an adequate number to achieve statistical significance. Last, the patients were kept in the prone position for only 10 days and that might not have been long enough to achieve an effect on mortality. It has been estimated that 40% of the time spent on respiratory support is devoted solely to weaning from it.66 A quarter of patients, after being extubated, require reintubation.67 A failed attempt at spontaneous breathing causes considerable stress on the myocardium.68 Patients who require reintubation also have a sixfold higher mortality.69 A decreased duration of weaning also contributes to reducing incidence of nosocomial infections, which then contributes to a decrease in mortality.70 The current evolving approach to weaning uses a team-based approach and integrates the spontaneous breathing trial (SBT). In this mode of weaning, ventilatory support is removed and the patient is allowed to breathe either through a T-tube or through the ventilator circuit by using a flow trigger. Although a number of parameters have been developed to assess a patient’s readiness for extubation, it appears that a carefully monitored SBT allows for physiologic measurement of a patient’s readiness for extubation.71 It is recommended that patients be monitored closely when an SBT is in progress so that at the first sign of decompensation, respiratory support can be resumed. It is noteworthy that the SBT in and of itself is rarely associated with adverse events.72 The SBT should last from half an hour to no more than 2 hours, and whether pressure support is given or not, little change appears in the outcomes.73 A team approach to ventilatory weaning does matter and does make a difference. Ely and colleagues74 found that by using a protocol that allowed nonphysician providers to identify a patient’s readiness for extubation followed by an SBT, they were able to get patients off the ventilator in 2 less days and with reduced ICU costs.74 The exact approach itself does not appear to matter; more important is following the protocol.75
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CHANGING TRANSFUSION PATTERNS IN CRITICALLY ILL PATIENTS Because of the nature of their illness, a significant proportion of patients admitted to surgical ICUs receive blood transfusions.76 The reason for this transfusion requirement is rarely acute blood losses but appears to be multifactorial. ICU patients tend to have inappropriately low erythropoietin levels, and there is also a daily blood loss associated with phlebotomy.77 Until recently, this was justified because it was thought anemia increased the risk of dying in the critically ill.78 More importantly, liberal use of blood transfusion was justified because a hemoglobin ⬎ 10 mg/dL improves oxygen delivery.79 For several reasons, the practice of treating of a number (hemoglobin) is gradually changing. Separate from the concerns about the passage of infective agents, more serious concerns have been raised about the immunosuppressive effect of transfusions in the critically ill.80 One study showed that the risk of pneumonia increased 1% per day that blood was stored.81 An evolving area of research is the deleterious effect of transfusing stored blood. Investigators using an animal model have shown that when blood is stored for more than 15 days, the red blood cell appears to lose its ability to pass through the microcirculation, and that hemoglobin also loses the capability to transport oxygen.82 It has become apparent that liberal use of transfusion may contribute to decreased survival.83 In a prospective randomized fashion, the Canadian Critical Care Trials Group studied this question. Patients were randomized to a hemoglobin maintained between 7 and 9 mg/dL or between 10 and 12 mg/dL. The majority of patients in this trial had three main diagnoses: respiratory disease, cardiovascular disease, or trauma. At least a third of them had another comorbidity. Over a third in each arm came from the operating room to the ICU. The 30-day mortality in their transfusion-restricted group was 18.7% compared with 23.3% in the liberal transfusion group and was not statistically significant. Mortality during hospitalization was significantly different (22.2% for the restricted group versus 28.1% for the liberal transfusion group, p ⫽ 0.05). There also did not appear to be any differences in the development of cardiac complications between the two groups, demonstrating that a lower transfusion threshold was safe. A subgroup analysis done by the same group showed that in patients with active
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heart disease there was a trend toward improved survival with higher hemoglobins.84 By adopting this policy, the group was able to reduce the number of units transfused by half, without use of any adjunctive medications. Use of a restrictive transfusion policy also was assessed in postcardiac surgical patients in a randomized trial where it was found that there were no differences in endurance between patients who received transfusion to keep their hematocrit in the 32% range and those patients who received transfusions when the hematocrit was ⬍ 25%.85 It may still be worthwhile to transfuse elderly patients with anemia and tachycardia to decrease risk of myocardial ischemia.86 In a retrospective review of 30,000 Medicare patients with acute myocardial infarction, the use of blood transfusion to keep hematocrits ⬎ 30% was associated with decreased complication rate and a reduction in 30-day mortality.87 Among the contributing factors to anemia in the ICU is the lack of appropriate response by the bone marrow to produce more red blood cells. This is thought to be related to a lack of response of the bone marrow to erythropoietin.88 The hypothesis that treatment with erythropoietin could increase the level of hemoglobin was tested in the Epo Critical Care Trials Group.89 This was a prospective, randomized, double-blind, placebocontrolled multicenter trial in which study patients (who were expected to have an ICU stay longer than 2 days) were administered 40,000 U of recombinant human erythropoietin (rHuEpo) on ICU Day 3 and weekly thereafter for three doses (study Days 1, 7, and 14). Patients who still were present in the ICU on Day 21 received another dose. Concomitantly, all patients received at least 150 mg a day of elemental iron. There were no specific levels that were mandated for transfusion. A majority of patients in both arms were either postoperative or trauma patients. Results of this study showed that administration of rHuEpo led to a 19% reduction in the units transfused and also an increase in hemoglobin concentration, although there was no statistically significant difference in survival. Reduction in the units transfused also was less than that achieved by restricted transfusion policy, as we mentioned earlier, without the almost $400 cost for each 40,000 dose of rHuEpo. This sum is approximately the same cost as a transfusion. Whether the practice of using rHuEpo needs to become a part of routine clinical practice requires further evaluation through outcomes studies.
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In conclusion, we have shown how critical care has and is continuing to evolve. Several of the therapies we described represent a significant shift in the care of critically ill patients. We believe that the rational use of these ideas should lead to improved outcomes in the care of critically ill patients in the ensuing years. Author Contributions
Study conception and design: Hashmi Acquisition of data: Hashmi Analysis and interpretation of data: Hashmi, Rogers Drafting of manuscript: Hashmi, Rogers Critical revision: Hashmi, Rogers Supervision: Rogers Acknowledgment: We wish to acknowledge the assistance of Christy Pearson, Keith Green, and the staff of the Presbyterian Medical Library in the preparation of this article.
REFERENCES 1. Fair Allocation of Intensive Care Unit Resources (ATS Board of Directors Position Statement). Crit Care Med 1997;156:1282. 2. Halperin NA, Betts L, Greenstein R. Federal and nationwide intensive care unit and health care costs: 1986–1992. Crit Care Med 1994;22:2001–2007. 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulindependent diabetes mellitus. N Engl J Med 1993;329:977–986. 4. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837–853. 5. McMahon MM, Bistarian BR. Host defense and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clinic North Am 1995;9:1–9. 6. McCowen KC, Malhotra A, Bistrain BR. Stress-induced hyperglycemia. Crit Care Clin 2000;17:107–124. 7. Furnary AP, Zerr KJ, Grunkemeir GL, Starr A. Continuous intravenous insulin infusion reduces incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352–362. 8. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Eng J Med 2001;345:1359– 1367. 9. Van Den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359–366. 10. Finney SJ, Zekueld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA 2003;290:2041–2047. 11. Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785–792. 12. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology
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