C. David Mazer

Functional Disability 5 Years after Acute Respiratory Distress Syndrome

BACKGROUND There have been few detailed, in-person interviews and examinations to obtain follow-up data on 5-year outcomes among survivors of the acute respiratory distress syndrome (ARDS). METHODS We evaluated 109 survivors of ARDS at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit. At each visit, patients were interviewed and examined; underwent pulmonary-function tests, the 6-minute walk test, resting and exercise oximetry, chest imaging, and a quality-of-life evaluation; and reported their use of health care services. RESULTS At 5 years, the median 6-minute walk distance was 436 m (76% of predicted distance) and the Physical Component Score on the Medical Outcomes Study 36-Item Short-Form Health Survey was 41 (mean norm score matched for age and sex, 50). With respect to this score, younger patients had a greater rate of recovery than older patients, but neither group returned to normal predicted levels of physical function at 5 years. Pulmonary function was normal to near-normal. A constellation of other physical and psychological problems developed or persisted in patients and family caregivers for up to 5 years. Patients with more coexisting illnesses incurred greater 5-year costs. CONCLUSIONS Exercise limitation, physical and psychological sequelae, decreased physical quality of life, and increased costs and use of health care services are important legacies of severe lung injury.

A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery

BACKGROUND Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

Acute Kidney Injury After Cardiac Surgery Focus on Modifiable Risk Factors

Background— Acute kidney injury (AKI) after cardiac surgery is a major health issue. Lacking effective therapies, risk factor modification may offer a means of preventing this complication. The objective of the present study was to identify and determine the prognostic importance of such risk factors. Methods and Results— Data from a multicenter cohort of 3500 adult patients who underwent cardiac surgery at 7 hospitals during 2004 were analyzed (using multivariable logistic regression modeling) to determine the independent relationships between 3 thresholds of AKI (>25%, >50%, and >75% decrease in estimated glomerular filtration rate within 1 week of surgery or need for postoperative dialysis) with death rates, as well as to identify modifiable risk factors for AKI. The 3 thresholds of AKI occurred in 24% (n=829), 7% (n=228), and 3% (n=119) of the cohort, respectively. All 3 thresholds were independently associated with a >4-fold increase in the odds of death and could be predicted with several perioperative variables, including preoperative intra-aortic balloon pump use, urgent surgery, and prolonged cardiopulmonary bypass. In particular, 3 potentially modifiable variables were also independently and strongly associated with AKI. These were preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration. Conclusions— AKI after cardiac surgery is highly prevalent and prognostically important. Therapies aimed at mitigating preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration may offer protection against this complication.

The use of transesophageal echocardiography for preload assessment in critically ill patients.

IV volume is often administered to patients in an intensive care unit (ICU) to improve cardiovascular function. We investigated the relationship between stroke volume (SV) and left ventricular (LV) size by using transesophageal echocardiography (TEE) in a population of 20 ICU patients and 21 postoperative cardiac surgical patients. We also examined whether LV end diastolic area (EDA), by TEE, could identify patients who increased SV by 20% or more (responders) after 500 mL of pentastarch administration. There was only a modest relationship (r = 0.60) between the EDA and the SV in all patients. No relationship could be found between the pulmonary capillary wedge pressure (PCWP) and the EDA in all patients. Both responder and nonresponder PCWP increased significantly after volume administration. Only responder EDA increased significantly after volume administration. Responders had significantly lower EDA (15.3 ± 5.4 cm2) and PCWP (12.2 ± 2.2 mm Hg) when compared with nonresponders (20.2 ± 4.8 cm2) and 15.9 ± 3.1 mm Hg, respectively). Few ICU patients and only those with a small EDA responded to volume administration. It was not possible to identify an overall optimal LV EDA below which most patients demonstrate volume-recruitable increases in SV. Implications In a ventilated intensive care unit and cardiac surgical population, transesophageal echocardiography and pulmonary artery catheter are sensitive in detecting changes in preload after volume administration. Few patients demonstrate volume-recruitable increases in stroke volume when compared to cardiac surgical patients. It is not possible to establish an overall end diastolic threshold below which a large proportion of ventilated patients respond to volume administration.

2012 Update to The Society of Thoracic Surgeons Guideline on Use of Antiplatelet Drugs in Patients Having Cardiac and Noncardiac Operations

Division of Cardiovascular and Thoracic Surgery, University of Kentucky, Lexington, Kentucky (VAF and SPS); Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska (JHO); Division of Cardiothoracic Surgery, Oregon Health and Science University Medical Center, Portland, Oregon (HKS); State University of New York, Stony Brook School of Medicine, Stony Brook, New York (TR); Department of Cardiothoracic Surgery, University of Colorado Health Sciences Center, Aurora, Colorado (TBR); Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, Ontario (CDM); Division of Cardiovascular Surgery, Sanger Clinic, Charlotte, North Carolina (CRB); Departments of Anesthesiology, Immunology, and Pathology, Washington University School of Medicine, St. Louis, Missouri (GJD); and The Society of Thoracic Surgeons, Chicago, Illinois (KJ and ERC)

Antiplatelet drugs: a review of their pharmacology and management in the perioperative period.

In the normal course of the delivery of care, anesthesiologists encounter many patients who are receiving drugs that affect platelet function as a fundamental part of primary and secondary management of atherosclerotic thrombotic disease. There are several antiplatelet drugs available for use in clinical practice and several under investigation. Aspirin and clopidogrel (alone and in combination) have been the most studied and have the most favorable risk-benefit profiles of drugs currently available. Prasugrel was recently approved for patients with acute coronary syndrome undergoing percutaneous interventions. Other drugs such as dipyridamole and cilostazol have not been as extensively investigated. There are several newer investigational drugs such as cangrelor and ticagrelor, but whether they confer significant additional benefits remains to be established. Management of patients who are receiving antiplatelet drugs during the perioperative period requires an understanding of the underlying pathology and rationale for their administration, pharmacology and pharmacokinetics, and drug interactions. Furthermore, the risk and benefit assessment of discontinuing or continuing these drugs should be made bearing in mind the proposed surgery and its inherent risk for bleeding complications as well as decisions relating to appropriate use of general or some form of regional anesthesia. In general, the safest approach to prevent thrombosis seems to be continuation of these drugs throughout the perioperative period except where concerns about perioperative bleeding outweigh those associated with the development of thrombotic occlusion. Knowledge of the pharmacodynamics and pharmacokinetics of antiplatelet drugs may allow practitioners to anticipate difficulties associated with drug withdrawal and administration in the perioperative period including the potential for drug interactions.

Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury.

In patients with severe acute kidney injury (AKI) but no urgent indication for renal replacement therapy (RRT), the optimal time to initiate RRT remains controversial. While starting RRT preemptively may have benefits, this may expose patients to unnecessary RRT. To study this, we conducted a 12-center open-label pilot trial of critically ill adults with volume replete severe AKI. Patients were randomized to accelerated (12 h or less from eligibility) or standard RRT initiation. Outcomes were adherence to protocol-defined time windows for RRT initiation (primary), proportion of eligible patients enrolled, follow-up to 90 days, and safety in 101 fully eligible patients (57 with sepsis) with a mean age of 63 years. Median serum creatinine and urine output at enrollment were 268 micromoles/l and 356 ml per 24 h, respectively. In the accelerated arm, all patients commenced RRT and 45/48 did so within 12 h from eligibility (median 7.4 h). In the standard arm, 33 patients started RRT at a median of 31.6 h from eligibility, of which 19 did not receive RRT (6 died and 13 recovered kidney function). Clinical outcomes were available for all patients at 90 days following enrollment, with mortality 38% in the accelerated and 37% in the standard arm. Two surviving patients, both randomized to standard RRT initiation, were still RRT dependent at day 90. No safety signal was evident in either arm. Our findings can inform the design of a large-scale effectiveness randomized control trial.

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

Antifibrinolytic drugs are widely used to reduce blood loss during surgery. One serious adverse effect of these drugs is convulsive seizures; however, the mechanisms underlying such seizures remain poorly understood. The antifibrinolytic drugs tranexamic acid (TXA) and ε-aminocaproic acid (EACA) are structurally similar to the inhibitory neurotransmitter glycine. Since reduced function of glycine receptors causes seizures, we hypothesized that TXA and EACA inhibit the activity of glycine receptors. Here we demonstrate that TXA and EACA are competitive antagonists of glycine receptors in mice. We also showed that the general anesthetic isoflurane, and to a lesser extent propofol, reverses TXA inhibition of glycine receptor-mediated current, suggesting that these drugs could potentially be used to treat TXA-induced seizures. Finally, we measured the concentration of TXA in the cerebrospinal fluid (CSF) of patients undergoing major cardiovascular surgery. Surprisingly, peak TXA concentration in the CSF occurred after termination of drug infusion and in one patient coincided with the onset of seizures. Collectively, these results show that concentrations of TXA equivalent to those measured in the CSF of patients inhibited glycine receptors. Furthermore, isoflurane or propofol may prevent or reverse TXA-induced seizures.

Anemia and Cerebral Outcomes: Many Questions, Fewer Answers

A number of clinical studies have associated acute anemia with cerebral injury in perioperative patients. Evidence of such injury has been observed near the currently accepted transfusion threshold (hemoglobin [Hb] concentration, 7–8 g/dL), and well above the threshold for cerebral tissue hypoxia (Hb 3–4 g/dL). However, hypoxic and nonhypoxic mechanisms of anemia-induced cerebral injury have not been clearly elucidated. In addition, protective mechanisms which may minimize cerebral injury during acute anemia have not been well defined. Vasodilatory mechanisms, including nitric oxide (NO), may help to maintain cerebral oxygen delivery during anemia as all three NO synthase (NOS) isoforms (neuronal, endothelial, and inducible NOS) have been shown to be up-regulated in different experimental models of acute hemodilutional anemia. Recent experimental evidence has also demonstrated an increase in an important transcription factor, hypoxia inducible factor (HIF)-1&agr;, in the cerebral cortex of anemic rodents at clinically relevant Hb concentrations (Hb 6–7 g/dL). This suggests that cerebral oxygen homeostasis may be in jeopardy during acute anemia. Under hypoxic conditions, cytoplasmic HIF-1&agr; degradation is inhibited, thereby allowing it to accumulate, dimerize, and translocate into the nucleus to promote transcription of a number of hypoxic molecules. Many of these molecules, including erythropoietin, vascular endothelial growth factor, and inducible NOS have also been shown to be up-regulated in the anemic brain. In addition, HIF-1&agr; transcription can be increased by nonhypoxic mediators including cytokines and vascular hormones. Furthermore, NOS-derived NO may also stabilize HIF-1&agr; in the absence of tissue hypoxia. Thus, during anemia, HIF-1&agr; has the potential to regulate cerebral cellular responses under both hypoxic and normoxic conditions. Experimental studies have demonstrated that HIF-1&agr; may have either neuroprotective or neurotoxic capacity depending on the cell type in which it is up-regulated. In the current review, we characterize these cellular processes to promote a clearer understanding of anemia-induced cerebral injury and protection. Potential mechanisms of anemia-induced injury include cerebral emboli, tissue hypoxia, inflammation, reactive oxygen species generation, and excitotoxicity. Potential mechanisms of cerebral protection include NOS/NO-dependent optimization of cerebral oxygen delivery and cytoprotective mechanisms including HIF-1&agr;, erythropoietin, and vascular endothelial growth factor. The overall balance of these activated cellular mechanisms may dictate whether or not their up-regulation leads to cytoprotection or cellular injury during anemia. A clearer understanding of these mechanisms may help us target therapies that will minimize anemia-induced cerebral injury in perioperative patients.

Effect of the Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery Clinical Practice Guidelines of the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists upon Clinical Practices

BACKGROUND: The 2007 Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Clinical Practice Guideline for Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery was recently promulgated and has received much attention. Using a survey of cardiac anesthesiologists and perfusionists’ clinical practice, we aimed to assess the current practices of perfusion, anesthesia, and surgery, as recommended by the Guidelines, and to also determine the role the Guidelines had in changing these practices. METHODS: Nontrainee members of the Society of Cardiovascular Anesthesiologists, the American Academy of Cardiovascular Perfusion, the Canadian Society of Clinical Perfusion, and the American Society of ExtraCorporeal Technology were surveyed using a standardized survey instrument that examined clinical practices and responses to the Guidelines. RESULTS: A total of 1402 surveys from 1061 institutions principally in the United States (677 institutions) and Canada (34 institutions) were returned, a 32% response rate. There was wide distribution of the Guidelines with 78% of anesthesiologists and 67% of perfusionists reporting having read all, part, or a summary of the Guidelines. However, only 20% of respondents reported that an institutional discussion had taken place as a result of the Guidelines, and only 14% of respondents reported that an institutional monitoring group had been formed. There was wide variability in current preoperative testing, perfusion, surgical, and pharmacological practices reported by respondents. Twenty-six percent of respondents reported 1 or more practice changes in response to the Guidelines. The changes made were reported to be highly (9%) or somewhat (31%) effective in reducing overall transfusion rates. Only 4 of 38 Guideline recommendations were reported by >5% of respondents to have been changed in response to the Guidelines. CONCLUSIONS: Wide variation in clinical practices of cardiac surgery was reported. Little change in clinical practices was attributed to the Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists Guidelines.