Raymond A. Zollo

Association between Intraoperative Blood Transfusion and Mortality and Morbidity in Patients Undergoing Noncardiac Surgery

Background:The impact of intraoperative erythrocyte transfusion on outcomes of anemic patients undergoing noncardiac surgery has not been well characterized. The objective of this study was to examine the association between blood transfusion and mortality and morbidity in patients with severe anemia (hematocrit less than 30%) who are exposed to one or two units of erythrocytes intraoperatively. Methods:This was a retrospective analysis of the association of blood transfusion and 30-day mortality and 30-day morbidity in 10,100 patients undergoing general, vascular, or orthopedic surgery. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. Results:Intraoperative blood transfusion was associated with an increased risk of death (odds ratio [OR], 1.29; 95% CI, 1.03–1.62). Patients receiving an intraoperative transfusion were more likely to have pulmonary, septic, wound, or thromboembolic complications, compared with patients not receiving an intraoperative transfusion. Compared with patients who were not transfused, patients receiving one or two units of erythrocytes were more likely to have pulmonary complications (OR, 1.76; 95% CI, 1.48–2.09), sepsis (OR, 1.43; 95% CI, 1.21–1.68), thromboembolic complications (OR, 1.77; 95% CI, 1.32–2.38), and wound complications (OR, 1.87; 95% CI, 1.47–2.37). Conclusions:Intraoperative blood transfusion is associated with a higher risk of mortality and morbidity in surgical patients with severe anemia. It is unknown whether this association is due to the adverse effects of blood transfusion or is, instead, the result of increased blood loss in the patients receiving blood.

Gene therapy for the management of pain part I: methods and strategies

A RECENT report from the Recombinant DNA Advisory Committee lists 393 approved human gene therapy protocols (www.od.nih.gov/oba/documents.htm). Of these, 33 are for infectious diseases, 49 for monogenic diseases (mostly cystic fibrosis), 237 for cancer, 35 for other disorders, and the remainder for nontherapeutic trials. Despite the serious nature of pain, both in terms of human suffering and economic cost, there are no human gene therapy protocols that target it. Could it be that the biologic basis of pain is too ill defined to apply the state-of-art gene therapy to it? In recent years, significant progress has been made in our fundamental understanding of the neurobiology of pain. In parallel, detailed molecular biologic characterization of many of the receptors and ion channels playing significant roles in nociception have become available. Although in its infancy, gene therapy, or the translational clinical application of the molecular biologic revolution, has fundamentally changed the way we study basic biologic processes and clearly will impact our clinical management of diverse diseases, including pain. This review summarizes recent developments in gene therapy and demonstrates the possibility of gene therapy for the management of pain. This is a broad topic requiring expertise in diverse areas of science and medicine. As such, diverse literature spanning basic molecular biology, viral vectors, antisense oligonucleotide, and pain literature was reviewed. We have strived to create a review with a dual mission of serving as a didactic document and as a document that will serve as a reference for active investigators in this area of science. Most importantly, we hope that this review will stimulate the interest of the readers to further explore the genetic approach to pain management. In Part I, we begin with a discussion of strategies for gene therapy, followed by an introduction of the fundamental methods and technologies (both viral and nonviral) available for gene therapy and transfer. Part II of the review, to be published subsequently, will describe potential nociceptive targets for the methods and strategies of gene therapy described in this review. The pathways of nociception are not summarized; however, there are many excellent reviews summarizing recent developments in our understanding of pain mechanisms. An authoritative review covering neuronal pathways to molecules mediating pain was recently published. Our goal is to minimize overlap with these reviews by focusing on information pertinent for gene therapy considerations. Readers unfamiliar with the basic molecular biologic concepts are referred to an excellent primer on molecular biology recently published in ANESTHESIOLOGY or chapters in standard reference books. Specific protocols for routine molecular biologic techniques can be found in any of the laboratory manuals, and practical methods for creating genetransduction viral vectors can be found in references cited in table 1. Reviews by Eck and Wilson, Andersen, and Kay et al. provide excellent general overviews of gene therapy. Lastly, clinical trials using gene therapeutic agents are subject to full federal regulations, as with any new investigational drug. Moreover, gene therapy protocols are subject to an additional oversight by the federal recombinant DNA advisory committee. Further information and guidelines for developing a human clinical trial protocol, as well as an updated list of active gene therapy trials, can be found at the National Institutes of Health web site referenced above. *Assistant Professor, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital. †Assistant Professor, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center. ‡Senior Instructor, Department of Anesthesiology, §Associate Professor, Departments of Anesthesiology, Pharmacology, and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Preoperative thrombocytopenia and postoperative outcomes after noncardiac surgery.

Background:Most studies examining the prognostic value of preoperative coagulation testing are too small to examine the predictive value of routine preoperative coagulation testing in patients having noncardiac surgery. Methods:Using data from the American College of Surgeons National Surgical Quality Improvement database, the authors performed a retrospective observational study on 316,644 patients having noncardiac surgery who did not have clinical indications for preoperative coagulation testing. The authors used multivariable logistic regression analysis to explore the association between platelet count abnormalities and red cell transfusion, mortality, and major complications. Results:Thrombocytopenia or thrombocytosis occurred in 1 in 14 patients without clinical indications for preoperative platelet testing. Patients with mild thrombocytopenia (101,000–150,000 µl−1), moderate-to-severe thrombocytopenia (<100,000 µl−1), and thrombocytosis (≥450,000 µl−1) were significantly more likely to be transfused (7.3%, 11.8%, 8.9%, 3.1%) and had significantly higher 30-day mortality rates (1.5%, 2.6%, 0.9%, 0.5%) compared with patients with a normal platelet count. In the multivariable analyses, mild thrombocytopenia (adjusted odds ratio [AOR], 1.28; 95% CI, 1.18–1.39) and moderate-to-severe thrombocytopenia (AOR, 1.76; 95% CI, 1.49–2.08), and thrombocytosis (AOR, 1.44; 95% CI, 1.30–1.60) were associated with increased risk of blood transfusion. Mild thrombocytopenia (AOR, 1.31; 95% CI, 1.11–1.56) and moderate-to-severe thrombocytopenia (AOR, 1.93; 95% CI, 1.43–2.61) were also associated with increased risk of 30-day mortality, whereas thrombocytosis was not (AOR, 0.94; 95% CI, 0.72–1.22). Conclusion:Platelet count abnormalities found in the course of routine preoperative screening are associated with a higher risk of blood transfusion and death.

Gene therapy for the management of pain: Part II: Molecular targets

TREATMENT of chronic pain, particularly of neuropathic etiology, is extremely difficult and resistant to many available pharmacologic therapies. Current analgesic agents may be limited with regard to analgesic efficacy or side effects. Newer and experimental pharmacologic agents may also have significant limitations. By targeting a specific receptor or other specific protein targets, a gene therapy approach to the treatment of pain may provide greater analgesic efficacy without the limitations associated with current pharmacotherapy. Advances in the field of gene therapy, along with significant increases in our understanding of the neurobiology of nociception and knowledge of the fundamental genetic structure of many nociceptive targets, have made gene therapy for the management of pain a conceivable reality. In part I of this review, we introduced the basic concepts of gene therapy with an emphasis on the available tools (e.g., viral vectors and antisense oligonucleotides) and strategies for upregulating antinociceptive or downregulating pronociceptive targets. In part II, we summarize current knowledge regarding the nociceptive role, molecular biology, and antisense and knockout data of several novel nociceptive targets for gene therapy. We base our selection of the targets included in this review on the three aforementioned criteria. The targets selected are the best characterized and, in our opinion, most likely amenable to the gene therapeutic approach. A simple but feasible strategy and potential gene therapy targets for the management of pain are summarized in figure 1. However, the list is admittedly incomplete, and the readers are referred to other recent reviews cited in part I of this review for a broader perspective on potential targets for the management of pain.

Blood transfusion in the perioperative period

Anemia is associated with perioperative mortality and morbidity. Since the presence of anemia and blood transfusion often go hand in hand, it can be difficult to separate the effects of anemia from the effects of perioperative transfusion. The role for blood transfusion in mitigating the mortality and morbidity associated with anemia is unclear. A restrictive transfusion strategy has been advocated for hemodynamically stable patients, as blood transfusion exposes the patient to both infectious and non-infectious complications. Further research is warranted in patients with the acute coronary syndrome, as there is insufficient evidence to make recommendations for this patient population. Additional multi-center randomized controlled trials need to be conducted in perioperative and critically ill patients with large enough sample sizes to examine differences in mortality and major complications between liberal and restrictive transfusion strategies. Further trials need to incorporate current practices in improved blood storage and leukoreduction techniques.

Patterns of Communication during the Preanesthesia Visit

Background:Effective communication in the preanesthesia clinic is important in patient-centered care. Although patient-physician communication has been studied by recordings in other contexts, there have been no observational studies of the communication patterns of anesthesiologists and patients during the preanesthesia interview. Methods:Two experienced standardized patients were trained to portray the same clinical situation by using different coping styles (maximizing information or “monitoring” vs. minimizing information or “blunting”). Interviews of standardized patients by anesthesiologists took place in the preanesthesia clinic and recorded with the knowledge of the subjects. Audio recordings were analyzed, and the visit was separated into nine components. Discussion of the risks/informed consent process was examined, looking for discussion of common morbidities. The standardized patients completed a survey on the patient-centeredness of the interview. Results:Twenty-seven subjects participated in this study. Interviews with the monitor required more time: 17.4 min (confidence interval [CI] 15.2–19.6, n = 24) versus 14.5 min (CI 13.1–16.0, n = 25), P < 0.05. Most interview time was spent in obtaining the history; 2.4 min (CI 1.8–3.1) was spent discussing risks with the monitor, and only 1.6 min (CI 1.2–2.0) was spent with the blunter (P < 0.05). Neither the monitor nor the blunter scored the interview highly for involving the patient in determining the goals of the anesthetic and recovery. Conclusions:Direct recording of interactions with standardized patients is a feasible method of studying the communication skills of anesthesiologists. For this study, the anesthesia providers were able to modify their approach depending on patient type, but the monitor received more information.