Title The Incidental Finding of a Patent Foramen Ovale During Cardiac Surgery: Should It Always Be Repaired? A Core Review.[Review]
Source Anesthesia & Analgesia. 105(3):602-610, September 2007.
Abstract With the increased use of intraoperative transesophageal echocardiography, patent foramen ovale (PFO) has become a common finding during heart surgery. This finding presents a difficult dilemma for cardiac surgeons, since the impact of intraoperatively diagnosed PFOs on postoperative outcome is unknown. Changes in the surgical plan required for closure of a PFO subject the patient to the possibility of additional risk. On the other hand, a decision to not close a PFO exposes the patient to unclear immediate and long-term consequences. Deciding whether or not to close a PFO currently depends on the clinicians' personal preferences, the probability of intraoperative and postoperative hypoxemia, and any anticipated deviation from the initial surgical plan. Most clinicians agree that an intraoperatively diagnosed PFO must be closed when surgery leads to a high risk of hypoxemia (e.g., left ventricular assist devices placement, heart transplantation); should be closed in most cases when minimal deviation from the initial surgical plan is needed for PFO closure (e.g., mitral valve or tricuspid valve surgeries); and probably, should be closed during heart surgeries performed without atriotomy and bicaval cannulation when the risk of perioperative or remote PFO-related complications is increased. The recent development of percutaneous methods of PFO closure provides a valuable backup for those cases when PFO is not closed and postoperative hypoxemia or other complications may be attributable to the uncorrected PFO.
(C) 2007 by International Anesthesia Research Society.
sexta-feira, 14 de setembro de 2007
Revisão heparina e trombocitopenia
Title Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia.[Review]
Source Anesthesia & Analgesia. 105(3):570-582, September 2007.
Abstract Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%-5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%-76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%-30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5-14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended.
(C) 2007 by International Anesthesia Research Society.
Source Anesthesia & Analgesia. 105(3):570-582, September 2007.
Abstract Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%-5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%-76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%-30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5-14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended.
(C) 2007 by International Anesthesia Research Society.
sábado, 25 de agosto de 2007
Sedação em POI cardiopatia congenita em UTI
Title Remifentanil-midazolam sedation for paediatric patients receiving mechanical ventilation after cardiac surgery+.[Miscellaneous Article]
Source BJA: British Journal of Anaesthesia. 99(2):252-261, August 2007.
Abstract Background: Sedation of critically ill children requiring artificial ventilation remains a therapeutic challenge due to large individual variation in drug effects and a paucity of knowledge of pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of remifentanil in children requiring ventilation after cardiac surgery.
Methods: Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 [micro]g kg-1 h-1 and a remifentanil infusion that was commenced at 0.8 [micro]g kg-1 min-1 for a minimum of 60 min and subsequently decreased by 0.1 [micro]g kg-1 min-1every 20 min until the patient awoke. Arterial blood concentrations of remifentanil and midazolam were measured using high-performance liquid chromatography. Mixed-effects population models were fitted to the remifentanil concentration-time data.
Results: Satisfactory sedation was achieved in all patients as assessed by Comfort score during the initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn from the study due to hypotension. Remifentanil pharmacokinetics were best described using a two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance was 68.3 ml kg-1 min-1, intercompartmental clearance was 80 ml kg-1 min-1, the central compartment volume was 91.7 ml kg-1, and the peripheral compartment volume was 141 ml kg-1.
Conclusions: A combination of remifentanil and midazolam provided satisfactory sedation for these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood concentrations.
Source BJA: British Journal of Anaesthesia. 99(2):252-261, August 2007.
Abstract Background: Sedation of critically ill children requiring artificial ventilation remains a therapeutic challenge due to large individual variation in drug effects and a paucity of knowledge of pharmacokinetics in this population. This study aimed to determine the pharmacokinetics of remifentanil in children requiring ventilation after cardiac surgery.
Methods: Twenty-six ventilated children aged 1 month to 9.25 yr (median 1.77 yr) who had undergone cardiac surgery were sedated with a fixed rate infusion of midazolam 50 [micro]g kg-1 h-1 and a remifentanil infusion that was commenced at 0.8 [micro]g kg-1 min-1 for a minimum of 60 min and subsequently decreased by 0.1 [micro]g kg-1 min-1every 20 min until the patient awoke. Arterial blood concentrations of remifentanil and midazolam were measured using high-performance liquid chromatography. Mixed-effects population models were fitted to the remifentanil concentration-time data.
Results: Satisfactory sedation was achieved in all patients as assessed by Comfort score during the initial maintenance and reduction phase of the remifentanil infusion. One patient was withdrawn from the study due to hypotension. Remifentanil pharmacokinetics were best described using a two-compartment allometric model. For a typical child with a body weight of 10.5 kg, clearance was 68.3 ml kg-1 min-1, intercompartmental clearance was 80 ml kg-1 min-1, the central compartment volume was 91.7 ml kg-1, and the peripheral compartment volume was 141 ml kg-1.
Conclusions: A combination of remifentanil and midazolam provided satisfactory sedation for these patients. Owing to enhanced clearance rates, smaller (younger) children will require higher remifentanil infusion rates than larger (older) children and adults to achieve equivalent blood concentrations.
Revisão de Bolqueio cervical p/ endarterectomia carotidea
Title Superficial or deep cervical plexus block for carotid endarterectomy: a systematic review of complications+.[Review]
Source BJA: British Journal of Anaesthesia. 99(2):159-169, August 2007.
Abstract Carotid endarterectomy is commonly conducted under regional (deep, superficial, intermediate, or combined) cervical plexus block, but it is not known if complication rates differ. We conducted a systematic review of published papers to assess the complication rate associated with superficial (or intermediate) and deep (or combined deep plus superficial/intermediate). The null hypothesis was that complication rates were equal. Complications of interest were: (1) serious complications related to the placement of block, (2) incidence of conversion to general anaesthesia, and (3) serious systemic complications of the surgical-anaesthetic process. We retrieved 69 papers describing a total of 7558 deep/combined blocks and 2533 superficial/intermediate blocks. Deep/combined block was associated with a higher serious complication rate related to the injecting needle when compared with the superficial/intermediate block (odds ratio 2.13, P=0.006). The conversion rate to general anaesthesia was also higher with deep/combined block (odds ratio 5.15, P < 0.0001), but there was an equivalent incidence of other systemic serious complications (odds ratio 1.13, P=0.273; NS). We conclude that superficial/intermediate block is safer than any method that employs a deep injection. The higher rate of conversion to general anaesthesia with the deep/combined block may have been influenced by the higher incidence of direct complications, but may also suggest that the superficial/combined block provides better analgesia during surgery.
Source BJA: British Journal of Anaesthesia. 99(2):159-169, August 2007.
Abstract Carotid endarterectomy is commonly conducted under regional (deep, superficial, intermediate, or combined) cervical plexus block, but it is not known if complication rates differ. We conducted a systematic review of published papers to assess the complication rate associated with superficial (or intermediate) and deep (or combined deep plus superficial/intermediate). The null hypothesis was that complication rates were equal. Complications of interest were: (1) serious complications related to the placement of block, (2) incidence of conversion to general anaesthesia, and (3) serious systemic complications of the surgical-anaesthetic process. We retrieved 69 papers describing a total of 7558 deep/combined blocks and 2533 superficial/intermediate blocks. Deep/combined block was associated with a higher serious complication rate related to the injecting needle when compared with the superficial/intermediate block (odds ratio 2.13, P=0.006). The conversion rate to general anaesthesia was also higher with deep/combined block (odds ratio 5.15, P < 0.0001), but there was an equivalent incidence of other systemic serious complications (odds ratio 1.13, P=0.273; NS). We conclude that superficial/intermediate block is safer than any method that employs a deep injection. The higher rate of conversion to general anaesthesia with the deep/combined block may have been influenced by the higher incidence of direct complications, but may also suggest that the superficial/combined block provides better analgesia during surgery.
ETE e embolia- Revisão
Title Transesophageal Echocardiography and Cardiovascular Sources of Embolism: Implications for Perioperative Management.[Review]
Source Anesthesiology. 107(2):333-346, August 2007.
Abstract Transesophageal echocardiography has become an invaluable investigation in patients with cardioembolic events because of its high sensitivity and specificity for defining detailed structure and function of the cardiovascular system. Patients who receive anesthesia and critical care may be at risk of systemic embolism from various cardiovascular sources. The main factors associated with embolism include intracardiac lesions such as thrombi, vegetations, and tumors; cardiac anomalies; and vascular disease, e.g., aortic atheroma. In this review article, the authors describe how transesophageal echocardiography may be used to identify various cardiovascular sources of embolism, provide risk stratification, influence medical therapy, and refine clinical decision making in patients receiving critical care and anesthesia. With these improvements, it is hoped that better patient outcomes may be achieved in the perioperative period.
Source Anesthesiology. 107(2):333-346, August 2007.
Abstract Transesophageal echocardiography has become an invaluable investigation in patients with cardioembolic events because of its high sensitivity and specificity for defining detailed structure and function of the cardiovascular system. Patients who receive anesthesia and critical care may be at risk of systemic embolism from various cardiovascular sources. The main factors associated with embolism include intracardiac lesions such as thrombi, vegetations, and tumors; cardiac anomalies; and vascular disease, e.g., aortic atheroma. In this review article, the authors describe how transesophageal echocardiography may be used to identify various cardiovascular sources of embolism, provide risk stratification, influence medical therapy, and refine clinical decision making in patients receiving critical care and anesthesia. With these improvements, it is hoped that better patient outcomes may be achieved in the perioperative period.
Procalcitonina x infecção
Title Assessment of the Accuracy of Procalcitonin to Diagnose Postoperative Infection after Cardiac Surgery.[Article]
Source Anesthesiology. 107(2):232-238, August 2007.
Abstract Background: Cardiopulmonary bypass induces a nonspecific inflammatory response. Procalcitonin has been advocated as a specific biomarker for infection. The authors studied the accuracy of procalcitonin to diagnose postoperative infection after cardiac surgery and compared it with those of C-reactive protein, white blood cell count, and interleukins 6 and 8.
Methods: The authors prospectively included 100 patients scheduled to undergo elective cardiac procedures with cardiopulmonary bypass. Blood samples were taken before surgery and each day over the 7-day postoperative period, and measurement of procalcitonin, C-reactive protein, white blood cell count, and interleukins 6 and 8 were performed. Diagnosis of infection was performed by a blinded expert panel. Data are expressed as value [95% confidence interval].
Results: Infection was diagnosed in 16 patients. Procalcitonin was significantly higher in infected patients, with a peak reached on the third postoperative day. Only the areas under the receiver operating curve of procalcitonin (0.88 [0.71-0.95]) and C-reactive protein (0.72 [0.58-0.82]) were significantly different from the no-discrimination curve, and that of procalcitonin was significantly different from those of C-reactive protein, white blood cell count, and interleukins 6 and 8. A procalcitonin value greater than 1.5 ng/ml beyond the second day diagnosed postoperative infection with a sensitivity of 0.93 [0.70-0.99] and a specificity of 0.80 [0.70-0.87]. Procalcitonin was significantly higher in patients who died (27.5 [1.65-40.5] vs. 1.2 [0.7-1.5] ng/ml; P < 0.001).
Conclusion: Procalcitonin is a valuable marker of bacterial infections after cardiac surgery.
Source Anesthesiology. 107(2):232-238, August 2007.
Abstract Background: Cardiopulmonary bypass induces a nonspecific inflammatory response. Procalcitonin has been advocated as a specific biomarker for infection. The authors studied the accuracy of procalcitonin to diagnose postoperative infection after cardiac surgery and compared it with those of C-reactive protein, white blood cell count, and interleukins 6 and 8.
Methods: The authors prospectively included 100 patients scheduled to undergo elective cardiac procedures with cardiopulmonary bypass. Blood samples were taken before surgery and each day over the 7-day postoperative period, and measurement of procalcitonin, C-reactive protein, white blood cell count, and interleukins 6 and 8 were performed. Diagnosis of infection was performed by a blinded expert panel. Data are expressed as value [95% confidence interval].
Results: Infection was diagnosed in 16 patients. Procalcitonin was significantly higher in infected patients, with a peak reached on the third postoperative day. Only the areas under the receiver operating curve of procalcitonin (0.88 [0.71-0.95]) and C-reactive protein (0.72 [0.58-0.82]) were significantly different from the no-discrimination curve, and that of procalcitonin was significantly different from those of C-reactive protein, white blood cell count, and interleukins 6 and 8. A procalcitonin value greater than 1.5 ng/ml beyond the second day diagnosed postoperative infection with a sensitivity of 0.93 [0.70-0.99] and a specificity of 0.80 [0.70-0.87]. Procalcitonin was significantly higher in patients who died (27.5 [1.65-40.5] vs. 1.2 [0.7-1.5] ng/ml; P < 0.001).
Conclusion: Procalcitonin is a valuable marker of bacterial infections after cardiac surgery.
DC em cirurgia cardiaca- comparação de metodos
Title An evaluation of cardiac output by five arterial pulse contour techniques during cardiac surgery.[Article]
Source Anaesthesia. 62(8):760-768, August 2007.
Abstract Summary: The bias, precision and tracking ability of five different pulse contour methods were evaluated by simultaneous comparison of cardiac output values from the conventional thermodilution technique (COtd). The five different pulse contour methods included in this study were: Wesseling's method (cZ); the Modelflow method; the LiDCO system; the PiCCO system and a recently developed Hemac method. We studied 24 cardiac surgery patients undergoing uncomplicated coronary artery bypass grafting. In each patient, the first series of COtd was used to calibrate the five pulse contour methods. In all, 199 series of measurements were accepted by all methods and included in the study. COtd ranged from 2.14 to 7.55 l.min-1, with a mean of 4.81 l.min-1. Bland-Altman analysis showed the following bias and limits of agreement: cZ, 0.23 and - 0.80 to 1.26 l.min-1; Modelflow, 0.00 and - 0.74 to 0.74 l.min-1; LiDCO, - 0.17 and - 1.55 to 1.20 l.min-1; PiCCO, 0.14 and - 1.60 to 1.89 l.min-1; and Hemac, 0.06 and - 0.81 to 0.93 l.min-1. Changes in cardiac output larger than 0.5 l.min-1 (10%) were correctly followed by the Modelflow and the Hemac method in 96% of cases. In this group of subjects, without congestive heart failure, with normal heart rhythm and reasonable peripheral circulation, the best results in absolute values as well as in tracking changes in cardiac output were measured using the Modelflow and Hemac pulse contour methods, based on non-linear three-element Windkessel models.
Source Anaesthesia. 62(8):760-768, August 2007.
Abstract Summary: The bias, precision and tracking ability of five different pulse contour methods were evaluated by simultaneous comparison of cardiac output values from the conventional thermodilution technique (COtd). The five different pulse contour methods included in this study were: Wesseling's method (cZ); the Modelflow method; the LiDCO system; the PiCCO system and a recently developed Hemac method. We studied 24 cardiac surgery patients undergoing uncomplicated coronary artery bypass grafting. In each patient, the first series of COtd was used to calibrate the five pulse contour methods. In all, 199 series of measurements were accepted by all methods and included in the study. COtd ranged from 2.14 to 7.55 l.min-1, with a mean of 4.81 l.min-1. Bland-Altman analysis showed the following bias and limits of agreement: cZ, 0.23 and - 0.80 to 1.26 l.min-1; Modelflow, 0.00 and - 0.74 to 0.74 l.min-1; LiDCO, - 0.17 and - 1.55 to 1.20 l.min-1; PiCCO, 0.14 and - 1.60 to 1.89 l.min-1; and Hemac, 0.06 and - 0.81 to 0.93 l.min-1. Changes in cardiac output larger than 0.5 l.min-1 (10%) were correctly followed by the Modelflow and the Hemac method in 96% of cases. In this group of subjects, without congestive heart failure, with normal heart rhythm and reasonable peripheral circulation, the best results in absolute values as well as in tracking changes in cardiac output were measured using the Modelflow and Hemac pulse contour methods, based on non-linear three-element Windkessel models.
PCR em anestesia em cardiopatia congenita
The Frequency of Anesthesia-Related Cardiac Arrests in Patients with Congenital Heart Disease Undergoing Cardiac Surgery.[Miscellaneous]
Source Anesthesia & Analgesia. 105(2):335-343, August 2007.
Abstract BACKGROUND: The frequency of anesthesia-related cardiac arrests during pediatric anesthesia has been reported between 1.4 and 4.6 per 10,000 anesthetics. ASA physical status >III and younger age are risk factors. Patients with congenital cardiac disease may also be at increased risk. Therefore, in this study, we evaluated the frequency of cardiac arrest in patients with congenital heart disease undergoing cardiac surgery at a large pediatric tertiary referral center.
METHODS: Using an established data registry, all cardiac arrests from January 2000 through December 2005 occurring in the cardiac operating rooms were reviewed. A cardiac arrest was defined as any event requiring external or internal chest compressions, with or without direct cardioversion. Events determined to be anesthesia-related were classified as likely related or possibly related.
RESULTS: There were 41 cardiac arrests in 40 patients (median age, 2.9 mo; range, 2 days to 23 yr) during 5213 anesthetics over the time period, for an overall frequency of 0.79%; 78% were open procedures requiring cardiopulmonary bypass and 22% closed procedures not requiring cardiopulmonary bypass. Eleven cardiac arrests (26.8%) were classified as either likely (n = 6) or possibly related (n = 5) to anesthesia, (21.1 per 10,000 anesthetics) but with no mortality; 30 were categorized as procedure-related. The incidence of anesthesia-related and procedure-related cardiac arrests was highest in neonates (P < 0.001). There was no association with year of event or experience of the anesthesiologist.
CONCLUSION: The frequency of anesthesia-related cardiac arrest in patients undergoing cardiac surgery is increased, but is not associated with an increase in mortality. Neonates and infants are at higher risk. Careful preparation and anticipation is important to ensure timely and effective resuscitation.
Source Anesthesia & Analgesia. 105(2):335-343, August 2007.
Abstract BACKGROUND: The frequency of anesthesia-related cardiac arrests during pediatric anesthesia has been reported between 1.4 and 4.6 per 10,000 anesthetics. ASA physical status >III and younger age are risk factors. Patients with congenital cardiac disease may also be at increased risk. Therefore, in this study, we evaluated the frequency of cardiac arrest in patients with congenital heart disease undergoing cardiac surgery at a large pediatric tertiary referral center.
METHODS: Using an established data registry, all cardiac arrests from January 2000 through December 2005 occurring in the cardiac operating rooms were reviewed. A cardiac arrest was defined as any event requiring external or internal chest compressions, with or without direct cardioversion. Events determined to be anesthesia-related were classified as likely related or possibly related.
RESULTS: There were 41 cardiac arrests in 40 patients (median age, 2.9 mo; range, 2 days to 23 yr) during 5213 anesthetics over the time period, for an overall frequency of 0.79%; 78% were open procedures requiring cardiopulmonary bypass and 22% closed procedures not requiring cardiopulmonary bypass. Eleven cardiac arrests (26.8%) were classified as either likely (n = 6) or possibly related (n = 5) to anesthesia, (21.1 per 10,000 anesthetics) but with no mortality; 30 were categorized as procedure-related. The incidence of anesthesia-related and procedure-related cardiac arrests was highest in neonates (P < 0.001). There was no association with year of event or experience of the anesthesiologist.
CONCLUSION: The frequency of anesthesia-related cardiac arrest in patients undergoing cardiac surgery is increased, but is not associated with an increase in mortality. Neonates and infants are at higher risk. Careful preparation and anticipation is important to ensure timely and effective resuscitation.
terça-feira, 24 de julho de 2007
Staunching Hemorrhage
Staunching Hemorrhage
New England Journal of Medicine reviewers present information about aprotinin, tranexamic acid, EACA, desmopressin, and rFVIIa. New England Journal of Medicine reviewers present information about aprotinin, tranexamic acid, EACA, desmopressin, and rFVIIa.
C_REMARK -->
Uncontrollable bleeding is every physician’s and patient’s nightmare. Such bleeding can be due to disease, injury, surgery, or anticoagulant therapy and can arise from lesions in the brain, lung, liver, or gastrointestinal or genitourinary tract. Most clinicians’ initial responses are to transfuse blood, plasma, and platelets, but adjunctive pharmacologic therapy also is available. The efficacy and safety of some of these pharmaceutical agents were reviewed by two experts in blood coagulation. The agents considered were aprotinin, tranexamic acid, -aminocaproic acid (EACA), desmopressin, and recombinant factor VIIa (rFVIIa).
Aprotinin is a powerful protease inhibitor that is derived from bovine lung tissue; it limits clot dissolution or fibrinolysis and markedly diminishes blood loss and need for transfusion in patients undergoing coronary-artery bypass surgery. However, this activity comes at a price: In one study, aprotinin, compared with placebo, doubled the risk for severe renal failure and led to higher risk for myocardial infarction, heart failure, and stroke (N Engl J Med 2006; 354:353). Other studies have confirmed these results, so aprotinin is recommended mainly for patients who are undergoing complicated procedures with very high bleeding risk.
Tranexamic acid and EACA bind to lysine receptors on plasminogen, which inhibits its conversion to plasmin (the enzyme that lyses fibrin). Although both agents have exhibited clinical efficacy, tranexamic acid is more potent than EACA, and both are weaker than aprotinin. Nevertheless, they do appear to limit blood loss and the need for reoperation. Unfortunately, the safety of these drugs has not been established firmly; a large randomized trial of tranexamic acid in cardiac surgical patients is underway.
Desmopressin induces the release of large multimers of von Willebrand factor from storage organelles in endothelial cells; these multimers enhance platelet adhesion and aggregation. Although desmopressin is quite effective in most patients with von Willebrand disease and in some with mild hemophilia A, trials of desmopressin in cardiac surgery have shown only small decreases in perioperative blood loss. Adverse effects include hyponatremia due to water retention as well as occasional thrombotic events.
Recombinant FVIIa is a potent hemostatic agent that binds to activated platelets at the site of injury and enhances thrombin generation and clot formation. This agent curbs blood loss in a variety of clinical situations, ranging from radical prostatectomy to battlefield injuries. However, not all trials have produced positive results, and no randomized controlled clinical trials have been completed. Furthermore, the optimal dose of rFVIIa is unknown; doses from 20 µg/kg to 200 µg/kg have been used. Whether observed serious thrombotic events are dose-related has not been established. Guidelines for the use of rFVIIa, including indications for treatment and identification of patients in whom treatment should be avoided because of high risk for thrombosis, are needed urgently.
— David Green, MD, PhD
Published in Journal Watch Oncology and Hematology May 30, 2007
Citation(s):
Mannucci PM and Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007 May 31; 356:2301-11.
Original article (Subscription may be required)
Medline abstract (Free)
New England Journal of Medicine reviewers present information about aprotinin, tranexamic acid, EACA, desmopressin, and rFVIIa. New England Journal of Medicine reviewers present information about aprotinin, tranexamic acid, EACA, desmopressin, and rFVIIa.
C_REMARK -->
Uncontrollable bleeding is every physician’s and patient’s nightmare. Such bleeding can be due to disease, injury, surgery, or anticoagulant therapy and can arise from lesions in the brain, lung, liver, or gastrointestinal or genitourinary tract. Most clinicians’ initial responses are to transfuse blood, plasma, and platelets, but adjunctive pharmacologic therapy also is available. The efficacy and safety of some of these pharmaceutical agents were reviewed by two experts in blood coagulation. The agents considered were aprotinin, tranexamic acid, -aminocaproic acid (EACA), desmopressin, and recombinant factor VIIa (rFVIIa).
Aprotinin is a powerful protease inhibitor that is derived from bovine lung tissue; it limits clot dissolution or fibrinolysis and markedly diminishes blood loss and need for transfusion in patients undergoing coronary-artery bypass surgery. However, this activity comes at a price: In one study, aprotinin, compared with placebo, doubled the risk for severe renal failure and led to higher risk for myocardial infarction, heart failure, and stroke (N Engl J Med 2006; 354:353). Other studies have confirmed these results, so aprotinin is recommended mainly for patients who are undergoing complicated procedures with very high bleeding risk.
Tranexamic acid and EACA bind to lysine receptors on plasminogen, which inhibits its conversion to plasmin (the enzyme that lyses fibrin). Although both agents have exhibited clinical efficacy, tranexamic acid is more potent than EACA, and both are weaker than aprotinin. Nevertheless, they do appear to limit blood loss and the need for reoperation. Unfortunately, the safety of these drugs has not been established firmly; a large randomized trial of tranexamic acid in cardiac surgical patients is underway.
Desmopressin induces the release of large multimers of von Willebrand factor from storage organelles in endothelial cells; these multimers enhance platelet adhesion and aggregation. Although desmopressin is quite effective in most patients with von Willebrand disease and in some with mild hemophilia A, trials of desmopressin in cardiac surgery have shown only small decreases in perioperative blood loss. Adverse effects include hyponatremia due to water retention as well as occasional thrombotic events.
Recombinant FVIIa is a potent hemostatic agent that binds to activated platelets at the site of injury and enhances thrombin generation and clot formation. This agent curbs blood loss in a variety of clinical situations, ranging from radical prostatectomy to battlefield injuries. However, not all trials have produced positive results, and no randomized controlled clinical trials have been completed. Furthermore, the optimal dose of rFVIIa is unknown; doses from 20 µg/kg to 200 µg/kg have been used. Whether observed serious thrombotic events are dose-related has not been established. Guidelines for the use of rFVIIa, including indications for treatment and identification of patients in whom treatment should be avoided because of high risk for thrombosis, are needed urgently.
— David Green, MD, PhD
Published in Journal Watch Oncology and Hematology May 30, 2007
Citation(s):
Mannucci PM and Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007 May 31; 356:2301-11.
Original article (Subscription may be required)
Medline abstract (Free)
domingo, 15 de julho de 2007
Tromboelastograma
Qualitative Thrombelastographic Detection of Tissue Factor in Human Plasma.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(1):59-64, January 2007.
Abstract BACKGROUND: Tissue factor (TF) is the principal in vivo initiator of coagulation, with normal circulating TF concentrations reported to be approximately 23-158 pg/mL. However, patients with atherosclerosis or cancer have been reported to have TF concentrations ranging between 800 and 9000 pg/mL. Of interest, thrombelastographic (TEG(R))-based measures of clot initiation and propagation have demonstrated hypercoagulability in such patients at risk for thromboembolic events. Thus, our goal in the present investigation was to establish a concentration-response relationship of the effect of TF on TEG(R) variables, and determine specificity of TF-mediated events with a monoclonal TF antibody.
METHODS: Thrombelastography was performed on normal human plasma exposed to 0, 500, 1000, or 2000 pg/mL TF. Additional experiments with plasma exposed to 0 or 750 pg/mL TF in the presence or absence of a monoclonal TF antibody (1:360 dilution, 10 min incubation) were also performed. Clot initiation time (R) and the speed of clot propagation (MRTG, maximum rate of thrombus generation) were determined.
RESULTS: The addition of TF to normal plasma resulted in a significant, concentration-dependent decrease in R and increase MRTG values. The addition of TF antibody to samples with TF significantly increased R and decreased MRTG values compared to samples with TF addition.
CONCLUSIONS: In conclusion, changes in TEG(R) variables in conjunction with use of a TF antibody can detect pathological concentrations of TF in human plasma in vitro. Further investigation is warranted to determine if TEG(R)-based monitoring could assist in the detection and prevention of TF-initiated thromboembolic events.
Source Anesthesia & Analgesia. 104(1):59-64, January 2007.
Abstract BACKGROUND: Tissue factor (TF) is the principal in vivo initiator of coagulation, with normal circulating TF concentrations reported to be approximately 23-158 pg/mL. However, patients with atherosclerosis or cancer have been reported to have TF concentrations ranging between 800 and 9000 pg/mL. Of interest, thrombelastographic (TEG(R))-based measures of clot initiation and propagation have demonstrated hypercoagulability in such patients at risk for thromboembolic events. Thus, our goal in the present investigation was to establish a concentration-response relationship of the effect of TF on TEG(R) variables, and determine specificity of TF-mediated events with a monoclonal TF antibody.
METHODS: Thrombelastography was performed on normal human plasma exposed to 0, 500, 1000, or 2000 pg/mL TF. Additional experiments with plasma exposed to 0 or 750 pg/mL TF in the presence or absence of a monoclonal TF antibody (1:360 dilution, 10 min incubation) were also performed. Clot initiation time (R) and the speed of clot propagation (MRTG, maximum rate of thrombus generation) were determined.
RESULTS: The addition of TF to normal plasma resulted in a significant, concentration-dependent decrease in R and increase MRTG values. The addition of TF antibody to samples with TF significantly increased R and decreased MRTG values compared to samples with TF addition.
CONCLUSIONS: In conclusion, changes in TEG(R) variables in conjunction with use of a TF antibody can detect pathological concentrations of TF in human plasma in vitro. Further investigation is warranted to determine if TEG(R)-based monitoring could assist in the detection and prevention of TF-initiated thromboembolic events.
Oximetria cerebral e CEC
Monitoring Brain Oxygen Saturation During Coronary Bypass Surgery: A Randomized, Prospective Study.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(1):51-58, January 2007.
Abstract BACKGROUND: Cerebral deoxygenation is associated with various adverse systemic outcomes. We hypothesized, by using the brain as an index organ, that interventions to improve cerebral oxygenation would have systemic benefits in cardiac surgical patients.
METHODS: Two-hundred coronary artery bypass patients were randomized to either intraoperative cerebral regional oxygen saturation (rSO2) monitoring with active display and treatment intervention protocol (intervention, n = 100), or underwent blinded rSO2 monitoring (control, n = 100). Predefined clinical outcomes were assessed by a blinded observer.
RESULTS: Significantly more patients in the control group demonstrated prolonged cerebral desaturation (P = 0.014) and longer duration in the intensive care unit (P = 0.029) versus intervention patients. There was no difference in overall incidence of adverse complications, but significantly more control patients had major organ morbidity or mortality (death, ventilation >48 h, stroke, myocardial infarction, return for re-exploration) versus intervention group patients (P = 0.048). Patients experiencing major organ morbidity or mortality had lower baseline and mean rSO2, more cerebral desaturations and longer lengths of stay in the intensive care unit and postoperative hospitalization, than patients without such complications. There was a significant (r2 = 0.29) inverse correlation between intraoperative rSO2 and duration of postoperative hospitalization in patients requiring >=10 days postoperative length of stay.
CONCLUSION: Monitoring cerebral rSO2 in coronary artery bypass patients avoids profound cerebral desaturation and is associated with significantly fewer incidences of major organ dysfunction.
Source Anesthesia & Analgesia. 104(1):51-58, January 2007.
Abstract BACKGROUND: Cerebral deoxygenation is associated with various adverse systemic outcomes. We hypothesized, by using the brain as an index organ, that interventions to improve cerebral oxygenation would have systemic benefits in cardiac surgical patients.
METHODS: Two-hundred coronary artery bypass patients were randomized to either intraoperative cerebral regional oxygen saturation (rSO2) monitoring with active display and treatment intervention protocol (intervention, n = 100), or underwent blinded rSO2 monitoring (control, n = 100). Predefined clinical outcomes were assessed by a blinded observer.
RESULTS: Significantly more patients in the control group demonstrated prolonged cerebral desaturation (P = 0.014) and longer duration in the intensive care unit (P = 0.029) versus intervention patients. There was no difference in overall incidence of adverse complications, but significantly more control patients had major organ morbidity or mortality (death, ventilation >48 h, stroke, myocardial infarction, return for re-exploration) versus intervention group patients (P = 0.048). Patients experiencing major organ morbidity or mortality had lower baseline and mean rSO2, more cerebral desaturations and longer lengths of stay in the intensive care unit and postoperative hospitalization, than patients without such complications. There was a significant (r2 = 0.29) inverse correlation between intraoperative rSO2 and duration of postoperative hospitalization in patients requiring >=10 days postoperative length of stay.
CONCLUSION: Monitoring cerebral rSO2 in coronary artery bypass patients avoids profound cerebral desaturation and is associated with significantly fewer incidences of major organ dysfunction.
Metformina e cirurgia cardiaca
Recent Metformin Ingestion Does Not Increase In-Hospital Morbidity or Mortality After Cardiac Surgery.[Miscellaneous]
Source Anesthesia & Analgesia. 104(1):42-50, January 2007.
Abstract BACKGROUND: Perioperative treatment of type 2 diabetes with metformin, an oral hypoglycemic drug, is thought to increase the risk of life-threatening postoperative lactic acidosis. In contrast, metformin improves serum glucose control and has beneficial cardiovascular effects, which may decrease the risk of adverse outcomes. In this investigation we sought to determine the influence of metformin treatment on mortality and morbidity compared with treatment with other oral hypoglycemic drugs in diabetic patients undergoing cardiac surgery.
METHODS: In this retrospective investigation, 1284 diabetic patients, with recent oral hypoglycemic ingestion (presumed to be 8-24 h preoperatively), underwent cardiac surgery from 1994-2004. Propensity scores were calculated from a logistic model which included baseline characteristics and perioperative variables. Four-hundred-forty-three (85%) of the metformin-treated patients were matched on nearest propensity score using greedy matching techniques with 443 nonmetformin-treated patients. Postoperative outcomes were compared between matched metformin- and nonmetformin-treated patients.
RESULTS: In-hospital mortality, cardiac, renal, and neurologic morbidities were similar between groups. Metformin-treated patients had less postoperative prolonged tracheal intubation [OR (95% CI), 0.3 (0.1, 0.7), P = 0.003], infection [0.2 (0.1, 0.7), P = 0.007] and overall morbidities [0.4 (0.2, 0.8), P = 0.005].
CONCLUSIONS: These data suggest that recent metformin ingestion is not associated with increased risk of adverse outcome in cardiac surgical patients. Alternatively, metformin treatment may have beneficial effects.
Source Anesthesia & Analgesia. 104(1):42-50, January 2007.
Abstract BACKGROUND: Perioperative treatment of type 2 diabetes with metformin, an oral hypoglycemic drug, is thought to increase the risk of life-threatening postoperative lactic acidosis. In contrast, metformin improves serum glucose control and has beneficial cardiovascular effects, which may decrease the risk of adverse outcomes. In this investigation we sought to determine the influence of metformin treatment on mortality and morbidity compared with treatment with other oral hypoglycemic drugs in diabetic patients undergoing cardiac surgery.
METHODS: In this retrospective investigation, 1284 diabetic patients, with recent oral hypoglycemic ingestion (presumed to be 8-24 h preoperatively), underwent cardiac surgery from 1994-2004. Propensity scores were calculated from a logistic model which included baseline characteristics and perioperative variables. Four-hundred-forty-three (85%) of the metformin-treated patients were matched on nearest propensity score using greedy matching techniques with 443 nonmetformin-treated patients. Postoperative outcomes were compared between matched metformin- and nonmetformin-treated patients.
RESULTS: In-hospital mortality, cardiac, renal, and neurologic morbidities were similar between groups. Metformin-treated patients had less postoperative prolonged tracheal intubation [OR (95% CI), 0.3 (0.1, 0.7), P = 0.003], infection [0.2 (0.1, 0.7), P = 0.007] and overall morbidities [0.4 (0.2, 0.8), P = 0.005].
CONCLUSIONS: These data suggest that recent metformin ingestion is not associated with increased risk of adverse outcome in cardiac surgical patients. Alternatively, metformin treatment may have beneficial effects.
Beta-bloqueador meta-analise
Perioperative [beta]-Blockers for Preventing Surgery-Related Mortality and Morbidity: A Systematic Review and Meta-Analysis.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(1):27-41, January 2007.
Abstract BACKGROUND: Perioperative [beta]-blockers are suggested to reduce cardiovascular mortality, myocardial-ischemia/infarction, and supraventricular arrhythmias after surgery. We reviewed the evidence regarding the effectiveness of perioperative [beta]-blockers for improving patient outcomes after cardiac and noncardiac surgery.
METHODS: Eleven large databases were searched from the time of their inception until October 2005. Various online-resources were consulted for the identification of unpublished trials and conference abstracts. We included randomized, controlled trials comparing perioperative [beta]-blockers with either placebo or the standard-of-care. Of the 3680 retrieved titles, 69 met inclusion criteria for analysis. Odds ratios (OR) assuming random effects were computed in the absence of significant clinical heterogeneity.
RESULTS: [beta]-Blockers reduced the frequency of ventricular tachyarrhythmias [OR (cardiac surgery): 0.28, 95% CI 0.13-0.57; OR (noncardiac surgery): 0.56, 95% CI 0.21-1.45], atrial fibrillation/flutter [OR (cardiac surgery): 0.37, 95% CI 0.28-0.48], other supraventricular arrhythmias [OR (cardiac surgery): 0.25, 95% CI 0.18-0.35; OR (noncardiac surgery): 0.43, 95% CI 0.14-1.37], and myocardial ischemia [OR (cardiac surgery): 0.49, 95% CI 0.17-1.4; OR (noncardiac surgery): 0.38, 95% CI 0.21-0.69]. Length of hospitalization was not reduced [weighted mean difference (cardiac surgery): -0.35 days, 95% CI -0.77-0.07; weighted mean difference (noncardiac surgery): -5.59 days, 95% CI -12.22-1.04] and, in contrast to previous reports, [beta]-blockers did not reduce mortality [OR (cardiac surgery): 0.55, 95% CI 0.17-1.83; OR (noncardiac surgery): 0.78, 95% CI 0.33-1.87], and they had no influence on the occurrence of perioperative myocardial infarction [OR (cardiac surgery): 0.89, 95% CI 0.53-1.5; OR (noncardiac surgery): 0.59; 0.25-1.39].
CONCLUSIONS: [beta]-Blockers reduced perioperative arrhythmias and myocardial ischemia, but they had no effect on myocardial infarction, mortality, or length of hospitalization.
Source Anesthesia & Analgesia. 104(1):27-41, January 2007.
Abstract BACKGROUND: Perioperative [beta]-blockers are suggested to reduce cardiovascular mortality, myocardial-ischemia/infarction, and supraventricular arrhythmias after surgery. We reviewed the evidence regarding the effectiveness of perioperative [beta]-blockers for improving patient outcomes after cardiac and noncardiac surgery.
METHODS: Eleven large databases were searched from the time of their inception until October 2005. Various online-resources were consulted for the identification of unpublished trials and conference abstracts. We included randomized, controlled trials comparing perioperative [beta]-blockers with either placebo or the standard-of-care. Of the 3680 retrieved titles, 69 met inclusion criteria for analysis. Odds ratios (OR) assuming random effects were computed in the absence of significant clinical heterogeneity.
RESULTS: [beta]-Blockers reduced the frequency of ventricular tachyarrhythmias [OR (cardiac surgery): 0.28, 95% CI 0.13-0.57; OR (noncardiac surgery): 0.56, 95% CI 0.21-1.45], atrial fibrillation/flutter [OR (cardiac surgery): 0.37, 95% CI 0.28-0.48], other supraventricular arrhythmias [OR (cardiac surgery): 0.25, 95% CI 0.18-0.35; OR (noncardiac surgery): 0.43, 95% CI 0.14-1.37], and myocardial ischemia [OR (cardiac surgery): 0.49, 95% CI 0.17-1.4; OR (noncardiac surgery): 0.38, 95% CI 0.21-0.69]. Length of hospitalization was not reduced [weighted mean difference (cardiac surgery): -0.35 days, 95% CI -0.77-0.07; weighted mean difference (noncardiac surgery): -5.59 days, 95% CI -12.22-1.04] and, in contrast to previous reports, [beta]-blockers did not reduce mortality [OR (cardiac surgery): 0.55, 95% CI 0.17-1.83; OR (noncardiac surgery): 0.78, 95% CI 0.33-1.87], and they had no influence on the occurrence of perioperative myocardial infarction [OR (cardiac surgery): 0.89, 95% CI 0.53-1.5; OR (noncardiac surgery): 0.59; 0.25-1.39].
CONCLUSIONS: [beta]-Blockers reduced perioperative arrhythmias and myocardial ischemia, but they had no effect on myocardial infarction, mortality, or length of hospitalization.
Guideline Beta Block 2006
ACC/AHA 2006 Guideline Update on Perioperative Cardiovascular Evaluation for Noncardiac Surgery: Focused Update on Perioperative Beta-Blocker Therapy - A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).[Article]
Source Anesthesia & Analgesia. 104(1):15-26, January 2007.
Abstract The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines makes every effort to avoid any actual, potential, or perceived conflict of interest that might arise as a result of an industry relationship or personal interest of the writing committee. Specifically, all members of the writing committee, as well as peer reviewers of the document, were asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing committee at each meeting, and updated and reviewed by the writing committee as changes occur. Please see Appendix 1 for author relationships with industry and Appendix 2 for peer reviewer relationships with industry.
These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care. If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient's best interests. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient.
Source Anesthesia & Analgesia. 104(1):15-26, January 2007.
Abstract The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines makes every effort to avoid any actual, potential, or perceived conflict of interest that might arise as a result of an industry relationship or personal interest of the writing committee. Specifically, all members of the writing committee, as well as peer reviewers of the document, were asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing committee at each meeting, and updated and reviewed by the writing committee as changes occur. Please see Appendix 1 for author relationships with industry and Appendix 2 for peer reviewer relationships with industry.
These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care. If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient's best interests. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient.
Contra-Beta bloqueador
Con: Beta-Blockers Are Indicated for All Adults at Increased Risk Undergoing Noncardiac Surgery
[Cardiovascular Anesthesia: Editorial]
London, Martin J. MD
From the Department of Clinical Anesthesia, University of California, San Francisco, San Francisco, California.
Accepted for publication May 23, 2006.
Address correspondence and reprint requests to Martin J. London, MD, Anesthesia (129), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Address e-mail to londonm@anesthesia.ucsf.edu.
Although anesthesiologists have long recognized the value of using [beta]-adrenergic receptor blocking drugs perioperatively to attenuate adrenergic “stressors,” it is only recently that other specialties have rallied around “perioperative [beta]-blockade” (PBB) (1). This enthusiasm is linked to the publication of two seminal but controversial reports in the New England Journal of Medicine (2–3) and the tentative recommendation for PBB by the American College of Physicians in 1997 (4). Interest in PBB has grown to a “fevered pitch” with its designation as a top tier “safety practice” by the Agency for Healthcare Research and Quality’s report (5) and has become “highly desirable” in the eyes of clinicians interested in optimizing patient outcome, hospital administrators eager to enhance their hospitals status as a provider of “safe care,” and, more recently, by administrative organizations developing performance measures for benchmarking care and reducing costs. From the onset, however, there was skepticism about PBB by clinicians and researchers trained in classical epidemiologic techniques for evaluating efficacy (e.g., results in a highly controlled setting such as the randomized clinical trial with strict inclusion and exclusion criteria) and effectiveness (e.g., results in the larger universe of clinical practice) (6).
Although efficacy (either perioperative or long-term) has been challenged by a few outspoken critics (supported in part by 2 meta-analyses), (7–10) this debate focuses on the evidence that PBB should be routinely administered to all “at-risk patients” and excludes patients already receiving [beta]-blockers or those with clear-cut indications for this therapy regardless of surgery (11). “At-risk” patients are usually considered to belong to either of 2 categories: 1) those undergoing high-risk vascular surgery with no evidence of coronary artery disease (CAD) or with stable CAD but without easily inducible ischemia, and 2) those undergoing nonvascular procedures with comorbidities predictive of CAD identified with traditional risk factors (advanced age, high total and HDL cholesterol, elevated blood pressure, cigarette smoking, family history of premature CAD, and diabetes mellitus). Although vascular surgery is recognized as producing the greatest percentage of perioperative adverse cardiac events, the latter group of patients undergoing noncardiac surgery is numerically much larger and thus, in many respects, of greatest interest.
Central to this debate are several linked questions: Just how large a problem is cardiac morbidity and mortality in patients without overt CAD (and in what types of surgery)? Do risk factors (or even overt CAD) influence short-term or longer-term (e.g., 1–2 yr) “intermediate” outcome after surgery? What does the current literature of PBB report?
With regards to the magnitude of the problem, the literature on the epidemiology of perioperative myocardial infarction (PMI) is derived primarily from investigations of patients with known prior MI and those undergoing vascular surgery (12). Both groups are recognized to have substantially higher risk over the general surgical population. Definitive reports of increased risk for PMI in patients with risk factors alone undergoing nonvascular surgery are lacking. Although accumulating evidence suggests that even low-grade postoperative “troponin leakage” has adverse implications for outcome for up to a year after surgery, even less data are available with regard to patients with CAD risk factors only (13).
Using classic Framingham predictors for CAD to risk stratify patients for PMI is problematic. Although predictive for CAD events over a timeframe measured in decades, these clinical markers are not intended for risk prediction over a period of weeks to months (14). To further confuse matters, the National Cholesterol Education Program-III considers diabetes or peripheral vascular disease as CAD equivalents (based on a 10-yr risk of a CAD event of >=20%) (14). These epidemiologic complexities have contributed to the favored use by consultants of the “revised Cardiac Risk Index”(RCRI), which has identified stronger risk factors such as overt CAD, congestive heart failure, and highest risk surgery as most predictive of adverse perioperative outcomes (15). Although the RCRI has significant limitations, a recent report suggests its predictive ability can be enhanced by incorporating age and additional surgical details (16).
This discussion of the potential efficacy of PBB is complicated not only by the issue of risk factors alone versus overt CAD but also by purported effects of PBB on longer-term outcome after surgery (e.g., 1 to 2 yr). Although anesthesiologists have traditionally focused on perioperative outcomes, extending attention to long-term events entails the probability that one is evaluating the “natural history” of the patient’s surgical indication (e.g., malignancy) or comorbidities (peripheral vascular disease, renal disease, diabetes) along with the impact of other important unmeasured factors (e.g., surgeon skill and outpatient medical care). There is currently no well-defined hypothesis as to why a short course of PBB might influence long-term outcomes leading to poorly substantiated speculation regarding perioperative inflammation and plaque stability as potential mechanisms (17).
Regardless, the existing literature of PBB centers primarily on two well-publicized studies. Mangano et al. (2) evaluated a short perioperative course (immediately before induction to up to 7 days after surgery or the time of hospital discharge) of atenolol versus placebo titrated to heart rate in 200 male veterans selected based on a history of known CAD or the presence of CAD risk factors. Although perioperative outcomes were not different between treatment groups, risk for adverse cardiac events was reduced approximately 65% the first year after surgery. In the other study, Poldermans et al. (3) reported a striking reduction (90%) in perioperative risk in a small study of 112 high-risk patients (easily inducible ischemia on preoperative dobutamine stress echo), recommending a prolonged period of preoperative and postoperative PBB.
It is important to consider the direct precursor for the atenolol trial of Mangano et al. (2), a National Institutes of Health-funded observational study of the predictors of perioperative cardiac morbidity. In this study, 454 male veterans (of which approximately 40% underwent vascular surgery and 50% had known CAD) were evaluated using perioperative Holter monitoring (2 days preoperatively, intraoperatively, and 2 days postoperatively). Postoperative myocardial ischemia occurred in 40% of patients and it imparted a ninefold increased risk of combined cardiac death, nonfatal MI, or unstable angina (18). The latter end-points occurred in only 3.2% of patients. In a subsequent 2-yr follow-up report of this cohort, 11% of patients developed major cardiovascular complications (19). Independent predictors of longer-term adverse cardiac events were known vascular disease, history of congestive heart failure (CHF), known CAD, and perioperative cardiac events that included PMI, unstable stable angina, and Holter-detected myocardial ischemia (hazards ratio, 2.2; P = 0.03) (19). Curiously, the hypotheses and sample size estimations for the subsequent atenolol study (performed at the same center) were presented as dual goals to simultaneously evaluate reduction of in-hospital “surrogate” events (hemodynamic changes, dysrhythmias, and Holter-detected myocardial ischemia) and longer-term outcome, rather than the 3.2% perioperative cardiac event rate (fatal/nonfatal MI or unstable angina) of more interest to clinicians and with the most direct physiologic rationale. However, a properly performed power analysis suggests that the latter hypothesis would require 6,000–10,000 patients. Thus, the rationale for PBB in at-risk patients (particularly the large group of nonvascular surgery patients) was never really supported by existing data, which suggested that known CAD, CHF, and vascular surgery were the major risk factors.
Regardless, in the multivariate analysis of the atenolol trial, diabetes was identified as the major risk factor for adverse long-term outcome (hazard ratio, 2.8; P = 0.01), and atenolol use was actually not a significant protective factor in this model (with a 95% confidence interval of 0.2–1.1; P value of 0.06). This finding is of interest given the preliminary report of a large (more than 900 patients) randomized trial of diabetic patients (DIPOM) that reported that PBB did not influence either perioperative or intermediate adverse cardiac outcomes in this group of patients (20). Furthermore, although Holter-detected myocardial ischemia was reduced by approximately 50% by atenolol in the trial of Mangano et al. (2), it is unclear why this reduction did not influence perioperative outcome given its role as a major prognostic factor in the original “predictors” study (21). This failure is most consistent with the well accepted truism that myocardial ischemia alone is a relatively nonspecific “surrogate outcome.”
The recent large-scale retrospective observational analysis of Lindenauer et al (22) of in-hospital mortality in over 780,000 patients at 329 United States hospitals (predominantly nonteaching facilities) in 2000 and 2001, using data obtained from a large proprietary administrative database, has generated considerable attention with regard to the findings of neutral or even adverse associations of PBB in low and at-risk only patients (22). Of the 85% of patients without contraindications to [beta]-blockers, 18% received them (tracked only during the first 2 hospital days), increasing from 14% in those with no RCRI risk factors (50% of patients) to 44% in those with >=4 risk factors (which notably were present in only <1% of patients). PBB was associated with lower mortality only in patients with 3 or more risk factors (3% of the total cohort). The most controversial findings were that in the lowest-risk patients PBB actually increased mortality. As speculated by the authors, the increased mortality may reflect the use of [beta]-blockers to treat complications, rather than as prophylaxis. Despite its large size, this study has numerous important caveats and limitations, the most important of which is its nonrandomized design. Other preliminary data by Yang et al. (23) in more than 400 patients (MAVS trial) and a recently reported peer-reviewed small (103 patients) randomized controlled trial (POBBLE) (24) found no differences in perioperative outcomes in lower-risk vascular patients with PBB. The peer reviewed results of the MAVS trial are eagerly awaited. A large ongoing multinational randomized trial (POISE) is likely to provide the most definitive data within the next few years regarding the benefits versus risk of PBB, particularly for low-risk patients (10).
To summarize, there is little evidence demonstrating that patients not already identified as having CAD or CHF and not undergoing major vascular surgery (particularly aortic or lower extremity revascularization) are at substantially increased risk for PMI. Further, there has been little effort to document a rational mechanism for the purported long-term protection afforded by a short-term course of PBB. The focus on long-term outcomes in vascular patients is driven by the observation that, in the absence of medical therapy and lifestyle modifications, these patients have a high mortality over time as a result of their underlying cardiovascular disease (25,26). In contrast to the documented benefits of [beta]-adrenergic blockers on secondary prevention in post-MI patients (e.g., prevention of a subsequent recurrent MI with enhanced long-term survival) (27) and their long-term benefits in patients with CHF (28), there is minimal, if any, evidence for primary preventive effects of [beta]-blockers alone, either on development of overt CAD or MI, in patients with risk factors only (particularly in large cohorts of patients treated for hypertension). These medical observations may be analogous to the perioperative setting. There is no debate that [beta]-blockers are a great option that can be offered to any at-risk patient undergoing major surgery. As Devereaux and Yusuf (29) emphasize, evidence-based decision-making should equally use research evidence, the clinical state, the patient’s preference, and the clinician’s expertise. Some patients will clearly be interested in therapy and others will refuse it. The skillful perioperative use of [beta]-adrenergic blockers to control hemodynamic stress is rapidly approaching, if not already established as, standard of care for all patients. Their mandatory use, especially when used as a measure of quality of care, is still a hypothesis awaiting adequate supporting data.
[Cardiovascular Anesthesia: Editorial]
London, Martin J. MD
From the Department of Clinical Anesthesia, University of California, San Francisco, San Francisco, California.
Accepted for publication May 23, 2006.
Address correspondence and reprint requests to Martin J. London, MD, Anesthesia (129), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Address e-mail to londonm@anesthesia.ucsf.edu.
Although anesthesiologists have long recognized the value of using [beta]-adrenergic receptor blocking drugs perioperatively to attenuate adrenergic “stressors,” it is only recently that other specialties have rallied around “perioperative [beta]-blockade” (PBB) (1). This enthusiasm is linked to the publication of two seminal but controversial reports in the New England Journal of Medicine (2–3) and the tentative recommendation for PBB by the American College of Physicians in 1997 (4). Interest in PBB has grown to a “fevered pitch” with its designation as a top tier “safety practice” by the Agency for Healthcare Research and Quality’s report (5) and has become “highly desirable” in the eyes of clinicians interested in optimizing patient outcome, hospital administrators eager to enhance their hospitals status as a provider of “safe care,” and, more recently, by administrative organizations developing performance measures for benchmarking care and reducing costs. From the onset, however, there was skepticism about PBB by clinicians and researchers trained in classical epidemiologic techniques for evaluating efficacy (e.g., results in a highly controlled setting such as the randomized clinical trial with strict inclusion and exclusion criteria) and effectiveness (e.g., results in the larger universe of clinical practice) (6).
Although efficacy (either perioperative or long-term) has been challenged by a few outspoken critics (supported in part by 2 meta-analyses), (7–10) this debate focuses on the evidence that PBB should be routinely administered to all “at-risk patients” and excludes patients already receiving [beta]-blockers or those with clear-cut indications for this therapy regardless of surgery (11). “At-risk” patients are usually considered to belong to either of 2 categories: 1) those undergoing high-risk vascular surgery with no evidence of coronary artery disease (CAD) or with stable CAD but without easily inducible ischemia, and 2) those undergoing nonvascular procedures with comorbidities predictive of CAD identified with traditional risk factors (advanced age, high total and HDL cholesterol, elevated blood pressure, cigarette smoking, family history of premature CAD, and diabetes mellitus). Although vascular surgery is recognized as producing the greatest percentage of perioperative adverse cardiac events, the latter group of patients undergoing noncardiac surgery is numerically much larger and thus, in many respects, of greatest interest.
Central to this debate are several linked questions: Just how large a problem is cardiac morbidity and mortality in patients without overt CAD (and in what types of surgery)? Do risk factors (or even overt CAD) influence short-term or longer-term (e.g., 1–2 yr) “intermediate” outcome after surgery? What does the current literature of PBB report?
With regards to the magnitude of the problem, the literature on the epidemiology of perioperative myocardial infarction (PMI) is derived primarily from investigations of patients with known prior MI and those undergoing vascular surgery (12). Both groups are recognized to have substantially higher risk over the general surgical population. Definitive reports of increased risk for PMI in patients with risk factors alone undergoing nonvascular surgery are lacking. Although accumulating evidence suggests that even low-grade postoperative “troponin leakage” has adverse implications for outcome for up to a year after surgery, even less data are available with regard to patients with CAD risk factors only (13).
Using classic Framingham predictors for CAD to risk stratify patients for PMI is problematic. Although predictive for CAD events over a timeframe measured in decades, these clinical markers are not intended for risk prediction over a period of weeks to months (14). To further confuse matters, the National Cholesterol Education Program-III considers diabetes or peripheral vascular disease as CAD equivalents (based on a 10-yr risk of a CAD event of >=20%) (14). These epidemiologic complexities have contributed to the favored use by consultants of the “revised Cardiac Risk Index”(RCRI), which has identified stronger risk factors such as overt CAD, congestive heart failure, and highest risk surgery as most predictive of adverse perioperative outcomes (15). Although the RCRI has significant limitations, a recent report suggests its predictive ability can be enhanced by incorporating age and additional surgical details (16).
This discussion of the potential efficacy of PBB is complicated not only by the issue of risk factors alone versus overt CAD but also by purported effects of PBB on longer-term outcome after surgery (e.g., 1 to 2 yr). Although anesthesiologists have traditionally focused on perioperative outcomes, extending attention to long-term events entails the probability that one is evaluating the “natural history” of the patient’s surgical indication (e.g., malignancy) or comorbidities (peripheral vascular disease, renal disease, diabetes) along with the impact of other important unmeasured factors (e.g., surgeon skill and outpatient medical care). There is currently no well-defined hypothesis as to why a short course of PBB might influence long-term outcomes leading to poorly substantiated speculation regarding perioperative inflammation and plaque stability as potential mechanisms (17).
Regardless, the existing literature of PBB centers primarily on two well-publicized studies. Mangano et al. (2) evaluated a short perioperative course (immediately before induction to up to 7 days after surgery or the time of hospital discharge) of atenolol versus placebo titrated to heart rate in 200 male veterans selected based on a history of known CAD or the presence of CAD risk factors. Although perioperative outcomes were not different between treatment groups, risk for adverse cardiac events was reduced approximately 65% the first year after surgery. In the other study, Poldermans et al. (3) reported a striking reduction (90%) in perioperative risk in a small study of 112 high-risk patients (easily inducible ischemia on preoperative dobutamine stress echo), recommending a prolonged period of preoperative and postoperative PBB.
It is important to consider the direct precursor for the atenolol trial of Mangano et al. (2), a National Institutes of Health-funded observational study of the predictors of perioperative cardiac morbidity. In this study, 454 male veterans (of which approximately 40% underwent vascular surgery and 50% had known CAD) were evaluated using perioperative Holter monitoring (2 days preoperatively, intraoperatively, and 2 days postoperatively). Postoperative myocardial ischemia occurred in 40% of patients and it imparted a ninefold increased risk of combined cardiac death, nonfatal MI, or unstable angina (18). The latter end-points occurred in only 3.2% of patients. In a subsequent 2-yr follow-up report of this cohort, 11% of patients developed major cardiovascular complications (19). Independent predictors of longer-term adverse cardiac events were known vascular disease, history of congestive heart failure (CHF), known CAD, and perioperative cardiac events that included PMI, unstable stable angina, and Holter-detected myocardial ischemia (hazards ratio, 2.2; P = 0.03) (19). Curiously, the hypotheses and sample size estimations for the subsequent atenolol study (performed at the same center) were presented as dual goals to simultaneously evaluate reduction of in-hospital “surrogate” events (hemodynamic changes, dysrhythmias, and Holter-detected myocardial ischemia) and longer-term outcome, rather than the 3.2% perioperative cardiac event rate (fatal/nonfatal MI or unstable angina) of more interest to clinicians and with the most direct physiologic rationale. However, a properly performed power analysis suggests that the latter hypothesis would require 6,000–10,000 patients. Thus, the rationale for PBB in at-risk patients (particularly the large group of nonvascular surgery patients) was never really supported by existing data, which suggested that known CAD, CHF, and vascular surgery were the major risk factors.
Regardless, in the multivariate analysis of the atenolol trial, diabetes was identified as the major risk factor for adverse long-term outcome (hazard ratio, 2.8; P = 0.01), and atenolol use was actually not a significant protective factor in this model (with a 95% confidence interval of 0.2–1.1; P value of 0.06). This finding is of interest given the preliminary report of a large (more than 900 patients) randomized trial of diabetic patients (DIPOM) that reported that PBB did not influence either perioperative or intermediate adverse cardiac outcomes in this group of patients (20). Furthermore, although Holter-detected myocardial ischemia was reduced by approximately 50% by atenolol in the trial of Mangano et al. (2), it is unclear why this reduction did not influence perioperative outcome given its role as a major prognostic factor in the original “predictors” study (21). This failure is most consistent with the well accepted truism that myocardial ischemia alone is a relatively nonspecific “surrogate outcome.”
The recent large-scale retrospective observational analysis of Lindenauer et al (22) of in-hospital mortality in over 780,000 patients at 329 United States hospitals (predominantly nonteaching facilities) in 2000 and 2001, using data obtained from a large proprietary administrative database, has generated considerable attention with regard to the findings of neutral or even adverse associations of PBB in low and at-risk only patients (22). Of the 85% of patients without contraindications to [beta]-blockers, 18% received them (tracked only during the first 2 hospital days), increasing from 14% in those with no RCRI risk factors (50% of patients) to 44% in those with >=4 risk factors (which notably were present in only <1% of patients). PBB was associated with lower mortality only in patients with 3 or more risk factors (3% of the total cohort). The most controversial findings were that in the lowest-risk patients PBB actually increased mortality. As speculated by the authors, the increased mortality may reflect the use of [beta]-blockers to treat complications, rather than as prophylaxis. Despite its large size, this study has numerous important caveats and limitations, the most important of which is its nonrandomized design. Other preliminary data by Yang et al. (23) in more than 400 patients (MAVS trial) and a recently reported peer-reviewed small (103 patients) randomized controlled trial (POBBLE) (24) found no differences in perioperative outcomes in lower-risk vascular patients with PBB. The peer reviewed results of the MAVS trial are eagerly awaited. A large ongoing multinational randomized trial (POISE) is likely to provide the most definitive data within the next few years regarding the benefits versus risk of PBB, particularly for low-risk patients (10).
To summarize, there is little evidence demonstrating that patients not already identified as having CAD or CHF and not undergoing major vascular surgery (particularly aortic or lower extremity revascularization) are at substantially increased risk for PMI. Further, there has been little effort to document a rational mechanism for the purported long-term protection afforded by a short-term course of PBB. The focus on long-term outcomes in vascular patients is driven by the observation that, in the absence of medical therapy and lifestyle modifications, these patients have a high mortality over time as a result of their underlying cardiovascular disease (25,26). In contrast to the documented benefits of [beta]-adrenergic blockers on secondary prevention in post-MI patients (e.g., prevention of a subsequent recurrent MI with enhanced long-term survival) (27) and their long-term benefits in patients with CHF (28), there is minimal, if any, evidence for primary preventive effects of [beta]-blockers alone, either on development of overt CAD or MI, in patients with risk factors only (particularly in large cohorts of patients treated for hypertension). These medical observations may be analogous to the perioperative setting. There is no debate that [beta]-blockers are a great option that can be offered to any at-risk patient undergoing major surgery. As Devereaux and Yusuf (29) emphasize, evidence-based decision-making should equally use research evidence, the clinical state, the patient’s preference, and the clinician’s expertise. Some patients will clearly be interested in therapy and others will refuse it. The skillful perioperative use of [beta]-adrenergic blockers to control hemodynamic stress is rapidly approaching, if not already established as, standard of care for all patients. Their mandatory use, especially when used as a measure of quality of care, is still a hypothesis awaiting adequate supporting data.
Pro- Beta Bloqueador
Pro: Beta-Blockers Are Indicated for Patients at Risk for Cardiac Complications Undergoing Noncardiac Surgery
[Cardiovascular Anesthesia: Cardiovascular and Thoracic Education: Editorial]
Schouten, Olaf MD; Bax, Jeroen J. MD, FESC; Dunkelgrun, Martin MD; Feringa, Harm H.H. MD; Poldermans, Don MD, FESC
Section Editor(s): Hogue, Charles W. Jr; London, Martin J.
From the Department of Vascular Surgery, Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Accepted for publication May 26, 2006.
Dr. O. Schouten is supported by an unrestricted research grant from The Netherlands Organization for Health Research and Development (ZonMw), The Hague, the Netherlands and an unrestricted research grant from “Lijf & Leven” Foundation, Rotterdam, the Netherlands. Dr. M. Dunkelgrun is supported by an unrestricted research grant (#2003B143) from the Netherland Heart Foundation, The Hague, the Netherlands.
Address correspondence and reprint requests to Prof. Dr. Don Poldermans, Department of Anesthesiology, Room H 921, Erasmus MC, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Address e-mail to d.poldermans@erasmusmc.nl.
Of the estimated 100 million adults undergoing noncardiac surgery annually, approximately 500,000 patients (0.5%) will experience cardiac death perioperatively (1). Lee et al. (2) reported an overall risk for myocardial infarction (MI) after noncardiac surgery to be 1.1%, translating into about 1.1 million MIs annually worldwide. Although the pathophysiology of perioperative MI is not entirely clear, coronary plaque rupture, leading to thrombus formation and subsequent vessel occlusion, is implicated, similar to MI in the nonoperative setting (3). The incidence of plaque rupture is possibly increased by the stress response to major surgery. This response includes sympathetic activation promoting sheer stress on arterial plaques, enhanced vascular reactivity conducive to the development of vasospasm, reduced fibrinolytic activity, platelet activation, and hypercoagulability (4). Heightened sympathetic tone further increases myocardial oxygen demand (e.g., tachycardia and increased contractility), leading to myocardial oxygen supply/demand mismatch that, when sustained, might lead to MI (4,5). At least two studies evaluating the pathophysiology of perioperative MI using noninvasive tests, coronary angiography, and autopsy have shown that coronary plaque rupture and thrombus formation occurred in 50% of all fatal MIs, whereas a sustained oxygen supply/demand mismatch was responsible for the remaining 50% (3,6).
MECHANISM OF THE PROTECTIVE EFFECT OF BETA-BLOCKERS
Because of the role of sympathetic activation in adverse perioperative cardiac outcomes, [beta]-adrenergic receptor blocking drugs have been proposed as a means for providing cardioprotection. Potential cardioprotective mechanisms of [beta]-blockers include a) reduced heart rate and contractility and subsequently lower myocardial oxygen demand; b) a shift in energy metabolism from free fatty acids to the more energy efficient glucose; c) antiarrhythmic effects; d) anti-renin/angiotensin properties; and e) antiinflammatory effects possibly promoting plaque stability (7–9). The effects on heart rate, contractility, and energy substrate shift occur almost instantly, whereas the antiinflammatory effects may be observed only after prolonged use of [beta]-blockers.
CLINICAL EVIDENCE FOR THE EFFECTIVENESS OF PERIOPERATIVE BETA-BLOCKER THERAPY
Although widely prescribed as a means for reducing perioperative cardiac events, the evidence supporting this indication for [beta]-blockers is based mainly on two small, prospectively randomized clinical trials and several observational studies. In the first study, Mangano et al. (10) randomized 200 patients with either known or suspected coronary artery disease undergoing high-risk noncardiac surgery to receive atenolol (50 mg or 100 mg) or placebo. Atenolol therapy was not associated with an improved in-hospital outcome (cardiac death or MI); however, it was associated with a 50% reduction in electrocardiogram evidence of myocardial ischemia detected with continuous 3-lead Holter monitoring during the first 48 h after surgery. Interestingly, patients receiving perioperative atenolol had a reduced rate of cardiac events 6 to 8 mo after surgery compared with the placebo group, suggesting a delayed beneficial response. In the second trial, the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study)-I trial (11), of 112 vascular surgery patients with evidence of myocardial ischemia on preoperative dobutamine stress-echocardiography, Poldermans et al. showed a 10-fold reduction in the incidence of perioperative cardiac death and MI with perioperative bisoprolol use compared with placebo (3.4% versus 34%; P < 0.001). The high incidence of perioperative cardiac events was explained by the selection of high-risk patients for study. From a population of 1351 patients, only 112 met entrance criteria of inducible myocardial ischemia.
These promising results supporting perioperative [beta]-blocker use as a means for improving cardiac outcomes are not supported by two more recent trials. In the POBBLE (PeriOperative Beta-BLockadE) trial (12), only low-risk patients (history of ischemic heart disease was an exclusion) scheduled for vascular surgery were studied. This low-risk population was randomized to receive either metoprolol 25 mg or 50 mg (n = 55) or placebo (n = 48) starting the day before surgery and continued during the first 7 days after surgery. There was no difference in the incidence of perioperative cardiovascular events between the placebo and metoprolol groups (34% versus 32%). The duration of hospitalization though was shorter for those patients receiving metoprolol versus placebo (10 days versus 12 days).
In the DIPOM (Diabetic Postoperative Mortality and Morbidity) study (20) the cardioprotective effect of 100 mg metoprolol started the evening before major noncardiac surgery was compared with placebo in 921 diabetic patients. In that study, there were no difference in 30-day morbidity and mortality (21% versus 20%; P = 0.66). A limitation of the DIPOM study was that it was only powered to detect a 10% difference in mortality after 1 yr of follow-up.
EXPLAINING THE CONFLICTING RESULTS OF PERIOPERATIVE BETA-BLOCKER TRIALS
There are several explanations for the divergent findings from randomized trials of perioperative [beta]-blockers, including the use of a fixed versus individualized dose titrated to the patients heart rate.
In a study of 150 patients, Raby et al. (13) assessed the heart rate threshold for myocardial ischemia before surgery using Holter monitoring. Patients with myocardial ischemia (n = 26) were then randomized to receive a) IV esmolol titrated to aiming at tight heart rate 20% less than the ischemic threshold but >60 bpm or b) placebo. Of the 15 patients receiving esmolol, 9 had mean heart rates below the ischemic threshold and none experienced postoperative ischemia. Four of 11 patients receiving placebo had a mean heart rate below the ischemic threshold, and 3 of the 4 had no postoperative ischemia. Together, of the 13 patients with heart rates below the ischemic threshold, 1 (7.7%) had postoperative electrocardiogram myocardial ischemia versus 12 of 13 (92%) patients with heart rates exceeding the ischemic threshold. Feringa et al. (14) found similar results in a study of 272 patients receiving [beta]-blocker therapy and undergoing vascular surgery. In that study it was shown that higher doses of [beta]-blockers and lower heart rate (HR) were associated with reduced Holter monitoring-detected perioperative myocardial ischemia (HR, 2.49; 95% confidence interval [CI], 1.79-3.48) and troponin T release (HR, 1.53; 95% CI, 1.16-2.03) increased. These data suggest that monitoring of the heart rate and consequent [beta]-blocker dose adjustment is of critical importance.
The conflicting results of perioperative [beta]-blocker trials might be further explained by varying durations of therapy. As mentioned, although the sympathico-inhibitory effects of [beta]-blockers occur almost instantly, the antiinflammatory effects may be observed only after prolonged treatment. As mentioned, in the Mangano et al. study (10), the major benefits of atenolol were observed in the months after surgery. In both the DIPOM and POBBLE trials, [beta]-blocker therapy was initiated on the day before surgery. The DECREASE-I trial showed the largest effect of perioperative [beta]-blocker therapy. The time between [beta]-blocker therapy initiation and surgery was 37 days in this trial (11). Further, withdrawal of [beta]-blocker therapy shortly before surgery, or in the immediate postoperative period, might contribute to adverse myocardial effects resulting from a “rebound” effect resulting in increased arterial blood pressure, HR, and plasma noradrenalin concentrations (15). Redelmeier et al. (16) have recently shown that the long-acting agent atenolol was superior to the short-acting drug, metoprolol, when given perioperatively, probably as the result of acute withdrawal effects from missed doses of short-acting [beta]-blockers.
Finally, recent data from Lanfear et al. (17) suggest that gene polymorphisms might modulate the response to [beta]-blockers. They found that survival for patients receiving [beta]-blocker therapy after an acute coronary syndrome was lower for patients with the 70C and 46A ADRB2 genotypes. In the future, perhaps, identifying patients most likely to benefit from perioperative [beta]-blocker therapy might be possible by genotyping patients before surgery.
SHOULD ALL PATIENTS AT INCREASED CARDIAC RISK RECEIVE PERIOPERATIVE BETA-BLOCKER THERAPY?
The central question asked in these editorials is whether, based on existing evidence, all high-risk patients should receive a [beta]-blocker perioperatively. A simple answer would be “yes.” Perhaps a more critical question involves identifying which patients are at increased risk for perioperative cardiac complications. In a recent cohort study of 663,635 patients, Lindenauer et al. (18) reported that, in patients at intermediate or high risk (i.e., >=2 risk factors according to the Revised Cardiac Risk Index (2), undergoing major noncardiac surgery, [beta]-blocker use was associated with a reduced incidence of in-hospital mortality. On the other hand, patients at low risk for cardiac complications were found to have no benefit from perioperative [beta]-blocker therapy and in fact experienced a higher incidence of in-hospital mortality. This finding indicates that perioperative [beta]-blocker therapy is effective for selected patients, based on their risk for cardiac complications.
CONCLUSION
In high-risk patients, the existing data suggest that perioperative [beta]-blocker use is effective for reducing the frequency of adverse cardiac events when administered in a dose titrated to a heart rate below the ischemic threshold typically between 60 and 65 bpm. Beta-blocker therapy should be started before surgery to achieve the optimal protective effect and most likely it should be continued after surgery, and possibly the treatment should be life-long. For patients at intermediate risk and for diabetics, the benefits of [beta]-blockers are less clear. The results of randomized trials in patients at intermediate risk conducted so far (i.e., DIPOM and POBBLE) cannot be considered conclusive because poor heart rate control and the short interval between initiation and surgery may have seriously influenced the outcome of these two studies. The results of two large ongoing trials might help better define [beta]-blocker use in these populations. In the POISE (PeriOperative ISchemic Evaluation) trial, a fixed dose of [beta]-blockers is compared with placebo in patients at low or intermediate risk for cardiac complications. The DECREASE IV trial will evaluate the effect of [beta]-blockers (aiming at a heart rate between 60 and 65 bpm), statins, or a combination of both in patients at intermediate cardiac risk undergoing major noncardiac surgery (19). These trials may help to determine the effectiveness of perioperative [beta]-blocker use in patients at intermediate risk.
[Cardiovascular Anesthesia: Cardiovascular and Thoracic Education: Editorial]
Schouten, Olaf MD; Bax, Jeroen J. MD, FESC; Dunkelgrun, Martin MD; Feringa, Harm H.H. MD; Poldermans, Don MD, FESC
Section Editor(s): Hogue, Charles W. Jr; London, Martin J.
From the Department of Vascular Surgery, Department of Anesthesiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Accepted for publication May 26, 2006.
Dr. O. Schouten is supported by an unrestricted research grant from The Netherlands Organization for Health Research and Development (ZonMw), The Hague, the Netherlands and an unrestricted research grant from “Lijf & Leven” Foundation, Rotterdam, the Netherlands. Dr. M. Dunkelgrun is supported by an unrestricted research grant (#2003B143) from the Netherland Heart Foundation, The Hague, the Netherlands.
Address correspondence and reprint requests to Prof. Dr. Don Poldermans, Department of Anesthesiology, Room H 921, Erasmus MC, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Address e-mail to d.poldermans@erasmusmc.nl.
Of the estimated 100 million adults undergoing noncardiac surgery annually, approximately 500,000 patients (0.5%) will experience cardiac death perioperatively (1). Lee et al. (2) reported an overall risk for myocardial infarction (MI) after noncardiac surgery to be 1.1%, translating into about 1.1 million MIs annually worldwide. Although the pathophysiology of perioperative MI is not entirely clear, coronary plaque rupture, leading to thrombus formation and subsequent vessel occlusion, is implicated, similar to MI in the nonoperative setting (3). The incidence of plaque rupture is possibly increased by the stress response to major surgery. This response includes sympathetic activation promoting sheer stress on arterial plaques, enhanced vascular reactivity conducive to the development of vasospasm, reduced fibrinolytic activity, platelet activation, and hypercoagulability (4). Heightened sympathetic tone further increases myocardial oxygen demand (e.g., tachycardia and increased contractility), leading to myocardial oxygen supply/demand mismatch that, when sustained, might lead to MI (4,5). At least two studies evaluating the pathophysiology of perioperative MI using noninvasive tests, coronary angiography, and autopsy have shown that coronary plaque rupture and thrombus formation occurred in 50% of all fatal MIs, whereas a sustained oxygen supply/demand mismatch was responsible for the remaining 50% (3,6).
MECHANISM OF THE PROTECTIVE EFFECT OF BETA-BLOCKERS
Because of the role of sympathetic activation in adverse perioperative cardiac outcomes, [beta]-adrenergic receptor blocking drugs have been proposed as a means for providing cardioprotection. Potential cardioprotective mechanisms of [beta]-blockers include a) reduced heart rate and contractility and subsequently lower myocardial oxygen demand; b) a shift in energy metabolism from free fatty acids to the more energy efficient glucose; c) antiarrhythmic effects; d) anti-renin/angiotensin properties; and e) antiinflammatory effects possibly promoting plaque stability (7–9). The effects on heart rate, contractility, and energy substrate shift occur almost instantly, whereas the antiinflammatory effects may be observed only after prolonged use of [beta]-blockers.
CLINICAL EVIDENCE FOR THE EFFECTIVENESS OF PERIOPERATIVE BETA-BLOCKER THERAPY
Although widely prescribed as a means for reducing perioperative cardiac events, the evidence supporting this indication for [beta]-blockers is based mainly on two small, prospectively randomized clinical trials and several observational studies. In the first study, Mangano et al. (10) randomized 200 patients with either known or suspected coronary artery disease undergoing high-risk noncardiac surgery to receive atenolol (50 mg or 100 mg) or placebo. Atenolol therapy was not associated with an improved in-hospital outcome (cardiac death or MI); however, it was associated with a 50% reduction in electrocardiogram evidence of myocardial ischemia detected with continuous 3-lead Holter monitoring during the first 48 h after surgery. Interestingly, patients receiving perioperative atenolol had a reduced rate of cardiac events 6 to 8 mo after surgery compared with the placebo group, suggesting a delayed beneficial response. In the second trial, the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study)-I trial (11), of 112 vascular surgery patients with evidence of myocardial ischemia on preoperative dobutamine stress-echocardiography, Poldermans et al. showed a 10-fold reduction in the incidence of perioperative cardiac death and MI with perioperative bisoprolol use compared with placebo (3.4% versus 34%; P < 0.001). The high incidence of perioperative cardiac events was explained by the selection of high-risk patients for study. From a population of 1351 patients, only 112 met entrance criteria of inducible myocardial ischemia.
These promising results supporting perioperative [beta]-blocker use as a means for improving cardiac outcomes are not supported by two more recent trials. In the POBBLE (PeriOperative Beta-BLockadE) trial (12), only low-risk patients (history of ischemic heart disease was an exclusion) scheduled for vascular surgery were studied. This low-risk population was randomized to receive either metoprolol 25 mg or 50 mg (n = 55) or placebo (n = 48) starting the day before surgery and continued during the first 7 days after surgery. There was no difference in the incidence of perioperative cardiovascular events between the placebo and metoprolol groups (34% versus 32%). The duration of hospitalization though was shorter for those patients receiving metoprolol versus placebo (10 days versus 12 days).
In the DIPOM (Diabetic Postoperative Mortality and Morbidity) study (20) the cardioprotective effect of 100 mg metoprolol started the evening before major noncardiac surgery was compared with placebo in 921 diabetic patients. In that study, there were no difference in 30-day morbidity and mortality (21% versus 20%; P = 0.66). A limitation of the DIPOM study was that it was only powered to detect a 10% difference in mortality after 1 yr of follow-up.
EXPLAINING THE CONFLICTING RESULTS OF PERIOPERATIVE BETA-BLOCKER TRIALS
There are several explanations for the divergent findings from randomized trials of perioperative [beta]-blockers, including the use of a fixed versus individualized dose titrated to the patients heart rate.
In a study of 150 patients, Raby et al. (13) assessed the heart rate threshold for myocardial ischemia before surgery using Holter monitoring. Patients with myocardial ischemia (n = 26) were then randomized to receive a) IV esmolol titrated to aiming at tight heart rate 20% less than the ischemic threshold but >60 bpm or b) placebo. Of the 15 patients receiving esmolol, 9 had mean heart rates below the ischemic threshold and none experienced postoperative ischemia. Four of 11 patients receiving placebo had a mean heart rate below the ischemic threshold, and 3 of the 4 had no postoperative ischemia. Together, of the 13 patients with heart rates below the ischemic threshold, 1 (7.7%) had postoperative electrocardiogram myocardial ischemia versus 12 of 13 (92%) patients with heart rates exceeding the ischemic threshold. Feringa et al. (14) found similar results in a study of 272 patients receiving [beta]-blocker therapy and undergoing vascular surgery. In that study it was shown that higher doses of [beta]-blockers and lower heart rate (HR) were associated with reduced Holter monitoring-detected perioperative myocardial ischemia (HR, 2.49; 95% confidence interval [CI], 1.79-3.48) and troponin T release (HR, 1.53; 95% CI, 1.16-2.03) increased. These data suggest that monitoring of the heart rate and consequent [beta]-blocker dose adjustment is of critical importance.
The conflicting results of perioperative [beta]-blocker trials might be further explained by varying durations of therapy. As mentioned, although the sympathico-inhibitory effects of [beta]-blockers occur almost instantly, the antiinflammatory effects may be observed only after prolonged treatment. As mentioned, in the Mangano et al. study (10), the major benefits of atenolol were observed in the months after surgery. In both the DIPOM and POBBLE trials, [beta]-blocker therapy was initiated on the day before surgery. The DECREASE-I trial showed the largest effect of perioperative [beta]-blocker therapy. The time between [beta]-blocker therapy initiation and surgery was 37 days in this trial (11). Further, withdrawal of [beta]-blocker therapy shortly before surgery, or in the immediate postoperative period, might contribute to adverse myocardial effects resulting from a “rebound” effect resulting in increased arterial blood pressure, HR, and plasma noradrenalin concentrations (15). Redelmeier et al. (16) have recently shown that the long-acting agent atenolol was superior to the short-acting drug, metoprolol, when given perioperatively, probably as the result of acute withdrawal effects from missed doses of short-acting [beta]-blockers.
Finally, recent data from Lanfear et al. (17) suggest that gene polymorphisms might modulate the response to [beta]-blockers. They found that survival for patients receiving [beta]-blocker therapy after an acute coronary syndrome was lower for patients with the 70C and 46A ADRB2 genotypes. In the future, perhaps, identifying patients most likely to benefit from perioperative [beta]-blocker therapy might be possible by genotyping patients before surgery.
SHOULD ALL PATIENTS AT INCREASED CARDIAC RISK RECEIVE PERIOPERATIVE BETA-BLOCKER THERAPY?
The central question asked in these editorials is whether, based on existing evidence, all high-risk patients should receive a [beta]-blocker perioperatively. A simple answer would be “yes.” Perhaps a more critical question involves identifying which patients are at increased risk for perioperative cardiac complications. In a recent cohort study of 663,635 patients, Lindenauer et al. (18) reported that, in patients at intermediate or high risk (i.e., >=2 risk factors according to the Revised Cardiac Risk Index (2), undergoing major noncardiac surgery, [beta]-blocker use was associated with a reduced incidence of in-hospital mortality. On the other hand, patients at low risk for cardiac complications were found to have no benefit from perioperative [beta]-blocker therapy and in fact experienced a higher incidence of in-hospital mortality. This finding indicates that perioperative [beta]-blocker therapy is effective for selected patients, based on their risk for cardiac complications.
CONCLUSION
In high-risk patients, the existing data suggest that perioperative [beta]-blocker use is effective for reducing the frequency of adverse cardiac events when administered in a dose titrated to a heart rate below the ischemic threshold typically between 60 and 65 bpm. Beta-blocker therapy should be started before surgery to achieve the optimal protective effect and most likely it should be continued after surgery, and possibly the treatment should be life-long. For patients at intermediate risk and for diabetics, the benefits of [beta]-blockers are less clear. The results of randomized trials in patients at intermediate risk conducted so far (i.e., DIPOM and POBBLE) cannot be considered conclusive because poor heart rate control and the short interval between initiation and surgery may have seriously influenced the outcome of these two studies. The results of two large ongoing trials might help better define [beta]-blocker use in these populations. In the POISE (PeriOperative ISchemic Evaluation) trial, a fixed dose of [beta]-blockers is compared with placebo in patients at low or intermediate risk for cardiac complications. The DECREASE IV trial will evaluate the effect of [beta]-blockers (aiming at a heart rate between 60 and 65 bpm), statins, or a combination of both in patients at intermediate cardiac risk undergoing major noncardiac surgery (19). These trials may help to determine the effectiveness of perioperative [beta]-blocker use in patients at intermediate risk.
Controle glicemico-editorial
Thinking Like a Pancreas: Perioperative Glycemic Control
[Editorial]
Martinez, Elizabeth A. MD, MHS*†; Williams, Kathleen A. RN, MSN, CRNP**; Pronovost, Peter J. MD, PhD*†
From the Departments of *Anesthesiology and Critical Care Medicine and †Surgery, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Accepted for publication October 26, 2006.
Conflicts of Interest: Dr. Martinez has agreed to be a consultant for Bay City Capital LLC, but has not received any compensation as of this submission. The authors have no other potential conflicts of interest to disclose.
Reprints will not be available from the authors.
Address correspondence to Elizabeth A. Martinez, MD, MHS, ACCM/Adult Critical Care Division, 600 N. Wolfe St., Meyer 296, Baltimore, MD 21287. Address e-mail to emartine@jhmi.edu.
Perioperative glycemic control is related to patient outcome. Although guidelines for glucose management in hospitalized patients have undergone dramatic changes over the last 5 years, most hospital-based physicians, including anesthesiologists, have not changed their approach to glucose management (1). In this editorial, we discuss the article by Duncan et al. (2) appearing in this issue of Anesthesia & Analgesia, review recent recommendations for perioperative glucose management, and highlight areas of uncertainty. We endeavor to improve perioperative glucose management for patients.
There is considerable uncertainty regarding how to manage surgical patients who are taking metformin, an oral hypoglycemic drug. The potential for postoperative lactic acidosis in patients taking this drug has prompted some clinicians and health care systems to routinely cancel surgical procedures if metformin is taken within 48 h of surgery. Other clinicians or health care systems continue metformin, both before and after the surgical procedure. Duncan et al. (2) conducted a retrospective review of a large cohort of diabetic patients admitted for cardiac surgery at their institution who recently took an oral hypoglycemic drug. They compared outcomes among patients who took metformin versus patients taking a non-metformin oral hypoglycemic drug. The authors found that patients taking metformin had lower risks for several complications, and concluded that metformin appeared to be safe for use in the perioperative period.
The article raises several points worthy of reflection. First, the authors used a propensity score to try to account for differences among patients who were taking, versus not taking, metformin. This statistical method used logistic regression, in which metformin becomes the dependent variable. Predictor variables are included in the model (in this case 54 variables) to identify those patient characteristics associated with metformin treatment. The output of this analysis includes a C statistic that is interpreted to mean that, for any given pair of patients, in which one patient received metformin and one did not, how often did the model identify the one receiving metformin? In this analysis, the C statistic was 0.68, suggesting that more than 3 of 10 patients were not correctly classified. Thus, there is the potential that unmeasured differences between groups, and not metformin treatment or nontreatment, could influence the results. Other evidence suggests that propensity scores are no better than standard regressions at controlling for selection bias (3).
Second, the authors evaluated a variety of outcomes, though many were uncommon and did not include explicit definitions, and concluded that metformin was safe. It would be helpful to consider the precise safety of these estimates (3). For example, even if none of the 523 metformin patients had an adverse event in this study, the upper limit of that confidence interval is seven events in 1000 patients. This rate would likely warrant concern from clinicians and lead to alterations of their practice. Rather than thinking of drug safety as a dichotomous variable, (i.e., safe versus unsafe) it may be helpful to think of safety as a continuous variable to help regulators, clinicians, and consumers make a more informed risk/benefit assessment.
Third, and perhaps most concerning, 70% of patients had poor perioperative glycemic control, defined as four consecutive blood glucose levels >200 mg/dL. Granted, the study enrolled patients from 1994 through 2004, and the evidence to support tight glucose control emerged in the latter years of the study. Nevertheless, it seems that this finding is worthy of further reflection. The evidence regarding the management of glucose in perioperative patients has advanced considerably over the last few years.
PHYSIOLOGY OF INSULIN SECRETION
Below we briefly review the physiology of glucose control with insulin and discuss guidelines for perioperative glucose control put forth by the American College of Endocrinology and supported by the American Society of Anesthesiologists (4). The goals of insulin therapy should be to mimic the physiologic activity of the pancreas, which continuously secretes insulin at a mean rate of approximately 1 U/h in response to hepatic gluconeogenesis. Even when patients are not eating, insulin is continuously secreted. In response to a carbohydrate load, though, a normal functioning pancreas will increase the amount of insulin secreted to maintain a serum glucose of approximately 100 mg/dL. If a patient’s blood glucose increases, the pancreas secretes a corrective dose of insulin. Thus insulin secretion by the pancreas can be thought of in three phases: basal, postprandial, and correction.
In trying to mimic this physicality, when using insulin to control glucose in the perioperative period, we need to “think like a pancreas” and replicate the basal, postprandial, and correction phases. All patients, even those who are not eating, require basal insulin. The pancreas normally supplies insulin, and insulin-deficient patients must be given exogenous insulin, either as a continuous IV infusion or as long-acting insulin. Insulin-deficient patients include those with type 1 diabetes who have a history of pancreatectomy or pancreatic dysfunction, wide fluctuations in blood glucose levels, prior diabetic ketoacidosis, insulin use for >5 yr, and/or diabetes for >10 yr. The traditional use of a “sliding scale insulin” regimen does not provide basal insulin. If diabetic patients are eating, clinicians should provide postprandial insulin, generally in the form of short-acting insulin. Finally, sliding scale insulin can be used to correct residual hyperglycemia, though the basal or postprandial dose should subsequently be adjusted to provide better glycemic control (5,6).
There is increasing documentation of the benefits of glycemic control, including decreased rates of surgical site wound infections, and decreased mortality, especially in the perioperative setting (7–10). Given that surgical stress responses increase blood glucose, aggressive glucose control in perioperative patients should be an important priority. The goals of glycemic control in hospitalized patients are well established. The American College of Endocrinology, in conjunction with the American Society of Anesthesiologists, published a position statement that outlines these goals (4) A summary of these guidelines include the following:
1. Always maintain blood glucose below 180 mg/dL. There is biochemical evidence suggesting favorable alterations in myocardial and skeletal muscle metabolism, immune function, inflammation, and endothelial cell and platelet function with normoglycemia (4–6).
2. Maintain blood glucose between 80–110 mg/dL in intensive care unit (ICU) patients. Van den Berghe et al. (9) demonstrated a reduction in mortality in surgical ICU patients with a >5 day ICU stay with intensive insulin therapy, in which goal glucoses of <110 mg/dL were maintained regardless of their diabetes history (8).
3. Avoid oral hypoglycemic drugs unless patients are on a regular diet. Oral hypoglycemic drugs do not maintain tight glycemic control. Although there are no randomized controlled trials evaluating oral drug use in surgical patients, the long half-life of these drugs make titration in the face of changing clinical parameters difficult. Furthermore, many of the oral drugs, (e.g., metformin and thiazolidinediones) do not decrease serum glucose but rather increase tissue sensitivity to insulin. Further, sulfonylureas use has been associated with prolonged hypoglycemia requiring continuing interventions especially in patients with hepatic, renal, and adrenal insufficiency.
4. Provide basal insulin in patients who are insulin-deficient. Insulin-deficient diabetics should always have basal insulin with either continuous IV insulin or long-acting subcutaneous insulin. In these patients, a sliding scale alone is insufficient. Withholding basal insulin in insulin-deficient individuals has reportedly resulted in an increase in serum glucose by 45 mg/dL per hour (7).
5. Create and implement a hypoglycemia prevention and management protocol. Though patients may benefit from tight glucose control, the use of insulin poses the risk for hypoglycemia perioperatively. The Joint Commission on Accreditation of Healthcare Organizations (www.jcaho.org ) considers insulin to be one of the five high alert medications, since medication errors involving insulin can have catastrophic consequences. Caregivers using tight glucose control protocols must educate caregivers to recognize signs of hypoglycemia, understand the potential accuracy of finger-stick measurements of glucose, and know appropriate interventions.
Given our increasing knowledge of the science of patient safety, it is unlikely that health care organizations will achieve these perioperative glucose management goals without creating standardized policies and procedures, educating providers about these policies, and providing clinicians with feedback regarding their performance. Thus, in light of these guidelines, how should the article by Duncan et al. be interpreted? First, we believe this article highlights the likelihood that it is not necessary to cancel cases where patients take metformin up to the morning of surgery, while acknowledging that our estimates of safety allow for the possibility of rare events. Second, when we develop and evaluate interventions to reduce the percent of patients with poor glucose control, oral drugs play a limited role. Rather, clinicians need to start to “think like a pancreas,” and seek to improve perioperative glycemic control.
[Editorial]
Martinez, Elizabeth A. MD, MHS*†; Williams, Kathleen A. RN, MSN, CRNP**; Pronovost, Peter J. MD, PhD*†
From the Departments of *Anesthesiology and Critical Care Medicine and †Surgery, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Accepted for publication October 26, 2006.
Conflicts of Interest: Dr. Martinez has agreed to be a consultant for Bay City Capital LLC, but has not received any compensation as of this submission. The authors have no other potential conflicts of interest to disclose.
Reprints will not be available from the authors.
Address correspondence to Elizabeth A. Martinez, MD, MHS, ACCM/Adult Critical Care Division, 600 N. Wolfe St., Meyer 296, Baltimore, MD 21287. Address e-mail to emartine@jhmi.edu.
Perioperative glycemic control is related to patient outcome. Although guidelines for glucose management in hospitalized patients have undergone dramatic changes over the last 5 years, most hospital-based physicians, including anesthesiologists, have not changed their approach to glucose management (1). In this editorial, we discuss the article by Duncan et al. (2) appearing in this issue of Anesthesia & Analgesia, review recent recommendations for perioperative glucose management, and highlight areas of uncertainty. We endeavor to improve perioperative glucose management for patients.
There is considerable uncertainty regarding how to manage surgical patients who are taking metformin, an oral hypoglycemic drug. The potential for postoperative lactic acidosis in patients taking this drug has prompted some clinicians and health care systems to routinely cancel surgical procedures if metformin is taken within 48 h of surgery. Other clinicians or health care systems continue metformin, both before and after the surgical procedure. Duncan et al. (2) conducted a retrospective review of a large cohort of diabetic patients admitted for cardiac surgery at their institution who recently took an oral hypoglycemic drug. They compared outcomes among patients who took metformin versus patients taking a non-metformin oral hypoglycemic drug. The authors found that patients taking metformin had lower risks for several complications, and concluded that metformin appeared to be safe for use in the perioperative period.
The article raises several points worthy of reflection. First, the authors used a propensity score to try to account for differences among patients who were taking, versus not taking, metformin. This statistical method used logistic regression, in which metformin becomes the dependent variable. Predictor variables are included in the model (in this case 54 variables) to identify those patient characteristics associated with metformin treatment. The output of this analysis includes a C statistic that is interpreted to mean that, for any given pair of patients, in which one patient received metformin and one did not, how often did the model identify the one receiving metformin? In this analysis, the C statistic was 0.68, suggesting that more than 3 of 10 patients were not correctly classified. Thus, there is the potential that unmeasured differences between groups, and not metformin treatment or nontreatment, could influence the results. Other evidence suggests that propensity scores are no better than standard regressions at controlling for selection bias (3).
Second, the authors evaluated a variety of outcomes, though many were uncommon and did not include explicit definitions, and concluded that metformin was safe. It would be helpful to consider the precise safety of these estimates (3). For example, even if none of the 523 metformin patients had an adverse event in this study, the upper limit of that confidence interval is seven events in 1000 patients. This rate would likely warrant concern from clinicians and lead to alterations of their practice. Rather than thinking of drug safety as a dichotomous variable, (i.e., safe versus unsafe) it may be helpful to think of safety as a continuous variable to help regulators, clinicians, and consumers make a more informed risk/benefit assessment.
Third, and perhaps most concerning, 70% of patients had poor perioperative glycemic control, defined as four consecutive blood glucose levels >200 mg/dL. Granted, the study enrolled patients from 1994 through 2004, and the evidence to support tight glucose control emerged in the latter years of the study. Nevertheless, it seems that this finding is worthy of further reflection. The evidence regarding the management of glucose in perioperative patients has advanced considerably over the last few years.
PHYSIOLOGY OF INSULIN SECRETION
Below we briefly review the physiology of glucose control with insulin and discuss guidelines for perioperative glucose control put forth by the American College of Endocrinology and supported by the American Society of Anesthesiologists (4). The goals of insulin therapy should be to mimic the physiologic activity of the pancreas, which continuously secretes insulin at a mean rate of approximately 1 U/h in response to hepatic gluconeogenesis. Even when patients are not eating, insulin is continuously secreted. In response to a carbohydrate load, though, a normal functioning pancreas will increase the amount of insulin secreted to maintain a serum glucose of approximately 100 mg/dL. If a patient’s blood glucose increases, the pancreas secretes a corrective dose of insulin. Thus insulin secretion by the pancreas can be thought of in three phases: basal, postprandial, and correction.
In trying to mimic this physicality, when using insulin to control glucose in the perioperative period, we need to “think like a pancreas” and replicate the basal, postprandial, and correction phases. All patients, even those who are not eating, require basal insulin. The pancreas normally supplies insulin, and insulin-deficient patients must be given exogenous insulin, either as a continuous IV infusion or as long-acting insulin. Insulin-deficient patients include those with type 1 diabetes who have a history of pancreatectomy or pancreatic dysfunction, wide fluctuations in blood glucose levels, prior diabetic ketoacidosis, insulin use for >5 yr, and/or diabetes for >10 yr. The traditional use of a “sliding scale insulin” regimen does not provide basal insulin. If diabetic patients are eating, clinicians should provide postprandial insulin, generally in the form of short-acting insulin. Finally, sliding scale insulin can be used to correct residual hyperglycemia, though the basal or postprandial dose should subsequently be adjusted to provide better glycemic control (5,6).
There is increasing documentation of the benefits of glycemic control, including decreased rates of surgical site wound infections, and decreased mortality, especially in the perioperative setting (7–10). Given that surgical stress responses increase blood glucose, aggressive glucose control in perioperative patients should be an important priority. The goals of glycemic control in hospitalized patients are well established. The American College of Endocrinology, in conjunction with the American Society of Anesthesiologists, published a position statement that outlines these goals (4) A summary of these guidelines include the following:
1. Always maintain blood glucose below 180 mg/dL. There is biochemical evidence suggesting favorable alterations in myocardial and skeletal muscle metabolism, immune function, inflammation, and endothelial cell and platelet function with normoglycemia (4–6).
2. Maintain blood glucose between 80–110 mg/dL in intensive care unit (ICU) patients. Van den Berghe et al. (9) demonstrated a reduction in mortality in surgical ICU patients with a >5 day ICU stay with intensive insulin therapy, in which goal glucoses of <110 mg/dL were maintained regardless of their diabetes history (8).
3. Avoid oral hypoglycemic drugs unless patients are on a regular diet. Oral hypoglycemic drugs do not maintain tight glycemic control. Although there are no randomized controlled trials evaluating oral drug use in surgical patients, the long half-life of these drugs make titration in the face of changing clinical parameters difficult. Furthermore, many of the oral drugs, (e.g., metformin and thiazolidinediones) do not decrease serum glucose but rather increase tissue sensitivity to insulin. Further, sulfonylureas use has been associated with prolonged hypoglycemia requiring continuing interventions especially in patients with hepatic, renal, and adrenal insufficiency.
4. Provide basal insulin in patients who are insulin-deficient. Insulin-deficient diabetics should always have basal insulin with either continuous IV insulin or long-acting subcutaneous insulin. In these patients, a sliding scale alone is insufficient. Withholding basal insulin in insulin-deficient individuals has reportedly resulted in an increase in serum glucose by 45 mg/dL per hour (7).
5. Create and implement a hypoglycemia prevention and management protocol. Though patients may benefit from tight glucose control, the use of insulin poses the risk for hypoglycemia perioperatively. The Joint Commission on Accreditation of Healthcare Organizations (www.jcaho.org ) considers insulin to be one of the five high alert medications, since medication errors involving insulin can have catastrophic consequences. Caregivers using tight glucose control protocols must educate caregivers to recognize signs of hypoglycemia, understand the potential accuracy of finger-stick measurements of glucose, and know appropriate interventions.
Given our increasing knowledge of the science of patient safety, it is unlikely that health care organizations will achieve these perioperative glucose management goals without creating standardized policies and procedures, educating providers about these policies, and providing clinicians with feedback regarding their performance. Thus, in light of these guidelines, how should the article by Duncan et al. be interpreted? First, we believe this article highlights the likelihood that it is not necessary to cancel cases where patients take metformin up to the morning of surgery, while acknowledging that our estimates of safety allow for the possibility of rare events. Second, when we develop and evaluate interventions to reduce the percent of patients with poor glucose control, oral drugs play a limited role. Rather, clinicians need to start to “think like a pancreas,” and seek to improve perioperative glycemic control.
Beta-bloqueador - editorial
Perioperative [beta]-Blockade: How Best to Translate Evidence into Practice
[Editorial]
Fleisher, Lee A. MD
From the Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Accepted for publication October 5, 2006.
Conflict of Interest: Dr. Fleisher is currently Chair, American College of Cardiology/American Heart Association Task Force Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).
Address correspondence and reprint requests to Lee A. Fleisher, MD, Department of Anesthesia, University of Pennsylvania School of Medicine, 3400 Spruce St. Dulles 680, Philadelphia, PA 19104. Address e-mail to fleishel@uphs.upenn.edu.
During the 1980s, preoperative testing to identify patients with significant coronary artery disease and coronary revascularization was the mainstay of therapy to reduce the cardiac risk of noncardiac surgery (1). Beginning in the mid-1990s, several groups began to focus on postoperative monitoring and therapy, including the perioperative administration of [beta]-adrenergic blocking drugs (or [beta]-blockers) as a more effective approach (2,3). In 2002, Shojania et al. (4) published an evidence-based review funded by the Agency for Healthcare Research and Quality which identified perioperative [beta]-blockade for noncardiac surgery as a practice with the strongest basis in the literature. This followed a review of the literature on the use of perioperative [beta]-blockers that included clinical recommendations (5,6). These articles were followed by the establishment of perioperative quality of care measures by groups such as Leapfrog and the National Quality Forum which included perioperative [beta]-blockade. This in turn has led many groups of perioperative caregivers, including surgeons, anesthesiologists, cardiologists, and medical physicians, to debate the best protocols to accomplish this goal. In this issue of Anesthesia & Analgesia, the editors have chosen to publish a series of articles to help frame this debate, and better inform the clinician. By publishing the Guidelines from the American Heart Association/American College of Cardiology (ACC/AHA), a new meta-analysis, and a pro–con debate from leaders in the field, they hope to provide the individual practitioner with sufficient information to make his or her own informed decision and define the best protocol for their own interventions (7–10).
In trying to translate evidence into clinical practice, it is important to understand the different forms of evidence that frame this debate and how best to apply them (11). As all the articles published this month indicate, the strongest evidence for perioperative [beta] blockade comes from prospective randomized trials. Although several small randomized trials demonstrated a strong beneficial effect, others did not (12). Randomized trials offer the advantage of providing the strongest internal validity, but their external validity (i.e., ability to generalize the results) is less robust. In contrast, large cohort studies [e.g., administrative datasets used in the article by Lindenauer et al. (13)] offer insights into the efficacy of an intervention in routine clinical practice (i.e., external validity), but have much less internal validity. It is within this framework that the four articles are discussed.
The meta-analysis by Wiesbauer et al. (10) adds to a growing number of such analyses on this topic (12,14,15). The authors of the current meta-analysis focused on randomized controlled trials and included both published manuscripts and abstracts. By analytically combining these trials, the authors were unable to demonstrate an effect of [beta]-blockers on the hard end points of perioperative myocardial infarction or mortality. The clinician could therefore assume that either 1) [beta]-blockers are not effective, or 2) the studies included in the meta-analysis should not have been combined in the manner performed in the analysis because the populations or protocols used are different. If the latter is true, then the clinician should exert caution in specifics with regard to implementation of the protocols.
The pro–con debate (7,8) nicely illustrates this last point by outlining the issues related to interpretation of the data and how two groups of experts in this area choose to approach their own practice. On the pro side, the Dutch group led by Dr. Poldermans (8) clearly believes that many of the other trials did not control heart rate as tightly or provide perioperative [beta]-blockade for as long a duration as in their own studies. The importance of these comments is highlighted by two articles published by the group (16,17), after the editorial was accepted, which further demonstrate the beneficial effect of [beta]-blocker dosage and heart rate control on outcome. In contrast, Dr. London (7) presents a less expansive view with regard to the use of perioperative [beta]-blockade. He argues that the evidence is insufficient to generalize beyond the known literature, and outlines some of the deficiencies in both the evidence and the theoretical underpinnings of widespread treatment. As he notes in his conclusion, given the evidence, it is important to separate the mandatory use of [beta]-blockers as a quality assurance measure from their judicious use in the armamentarium to manage high risk patients.
It is in the context of this debate that the ACC/AHA produced a Focused Update on Perioperative Beta Blockade (9). Specifically, the American Medical Association Physician Consortium on Performance Improvement and the Surgical Care Improvement Project had both begun to evaluate the class and level of evidence to determine the appropriateness of developing performance measures based on continuation and initiation of perioperative [beta]-blockade in noncardiac surgery. It became increasingly important that the appropriate specialty societies weigh in and develop evidence-based guidelines upon which performance measures can be developed. As outlined in the introduction to the Guidelines, the American College of Cardiology has issued a formal position statement indicating that performance measures should be limited to Class I or Class III recommendations—those recommendations in which patients should or should not have the form of therapy—and that they should not include Class IIa or IIb recommendations, in which the evidence is less strong and for which opinion dictates the class of indications. The ACC/AHA mandates that only published trials be included in defining recommendations, and therefore, some of the literature discussed in the meta-analysis could not be included. Importantly, in developing Table 1 (see Ref. 9), we attempted to review the published literature and develop a schemata whereby recommendations for individual cohorts of patients can be easily changed to reflect new evidence.
So, how would I put it all together? Clearly, Class I recommendations should be followed, and therefore, patients receiving [beta]-blockers should be continued on [beta]-blockers, and patients with a positive stress test undergoing vascular surgery should be started on [beta]-blockers. There are large groups of patients currently not taking [beta]-blockers but who have Class I indications for [beta]-blockers independent of noncardiac surgery. For example, [beta]-blockers should be started and continued indefinitely in all patients who have myocardial infarction, acute coronary syndrome, or left ventricular dysfunction, with or without heart failure symptoms, unless contraindicated (18). As shown in multiple studies, many patients who are not taking [beta]-blockers present to vascular surgery with a history of a myocardial infarction (19,20). Therefore, there are patients who should be taking [beta]-blockers for long-term benefits, but for whom there is no evidence to demonstrate that acute administration in the perioperative period will impact outcome. For this reason, we considered such instances as Class IIa indications in the new guidelines, suggesting that they are likely beneficial but that this indication lacks evidence to mandate inclusion as a quality of care measure. In patients who do not have the above indications for [beta]-blockers independent of noncardiac surgery, there are now several trials and the meta-analysis that demonstrate no effect. The use of perioperative [beta]-blockers in the latter group thus represents a Class IIb indication. Finally, Lindenauer et al. (13) suggest harm in subpopulations of surgical patients without any coronary artery disease risk factors. If this harmful effect is shown in randomized trials, then this would qualify as a Class III indication.
The question remains regarding the best protocol to initiate perioperative [beta]-blockade. Ideally, these drugs should be started a week before surgery similar to the protocol by Poldermans et al. and titrated to heart rate-decreasing effect, but this is not always practical. Given emerging data suggesting that inadequate [beta]-blockade and heart rate control may be associated with worse outcomes, it is important to ensure that any protocol will yield the desired effect and not cause harm. Given the lack of data regarding the efficacy of starting [beta]-blockade the morning of surgery versus intraoperatively, the Surgical Care Improvement Project recently defined “appropriate” [beta]-blockade for patients who have not received this therapy before arrival at the operating room as initiating treatment before arriving in the postanesthesia care unit. This allows the caregivers to individualize therapy. In my opinion, further data are needed to understand the risks and benefits of starting [beta]-blockers in this group of patients, and that the results of the Perioperative Ischemic Evaluation (POISE) trial (21), a randomized controlled trial of metoprolol versus placebo in 10,000 patients undergoing noncardiac surgery, are eagerly awaited. The information and opinions in these four articles should allow clinicians to develop their own best approach to perioperative [beta]-blocker therapy in specific patient populations.
[Editorial]
Fleisher, Lee A. MD
From the Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Accepted for publication October 5, 2006.
Conflict of Interest: Dr. Fleisher is currently Chair, American College of Cardiology/American Heart Association Task Force Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).
Address correspondence and reprint requests to Lee A. Fleisher, MD, Department of Anesthesia, University of Pennsylvania School of Medicine, 3400 Spruce St. Dulles 680, Philadelphia, PA 19104. Address e-mail to fleishel@uphs.upenn.edu.
During the 1980s, preoperative testing to identify patients with significant coronary artery disease and coronary revascularization was the mainstay of therapy to reduce the cardiac risk of noncardiac surgery (1). Beginning in the mid-1990s, several groups began to focus on postoperative monitoring and therapy, including the perioperative administration of [beta]-adrenergic blocking drugs (or [beta]-blockers) as a more effective approach (2,3). In 2002, Shojania et al. (4) published an evidence-based review funded by the Agency for Healthcare Research and Quality which identified perioperative [beta]-blockade for noncardiac surgery as a practice with the strongest basis in the literature. This followed a review of the literature on the use of perioperative [beta]-blockers that included clinical recommendations (5,6). These articles were followed by the establishment of perioperative quality of care measures by groups such as Leapfrog and the National Quality Forum which included perioperative [beta]-blockade. This in turn has led many groups of perioperative caregivers, including surgeons, anesthesiologists, cardiologists, and medical physicians, to debate the best protocols to accomplish this goal. In this issue of Anesthesia & Analgesia, the editors have chosen to publish a series of articles to help frame this debate, and better inform the clinician. By publishing the Guidelines from the American Heart Association/American College of Cardiology (ACC/AHA), a new meta-analysis, and a pro–con debate from leaders in the field, they hope to provide the individual practitioner with sufficient information to make his or her own informed decision and define the best protocol for their own interventions (7–10).
In trying to translate evidence into clinical practice, it is important to understand the different forms of evidence that frame this debate and how best to apply them (11). As all the articles published this month indicate, the strongest evidence for perioperative [beta] blockade comes from prospective randomized trials. Although several small randomized trials demonstrated a strong beneficial effect, others did not (12). Randomized trials offer the advantage of providing the strongest internal validity, but their external validity (i.e., ability to generalize the results) is less robust. In contrast, large cohort studies [e.g., administrative datasets used in the article by Lindenauer et al. (13)] offer insights into the efficacy of an intervention in routine clinical practice (i.e., external validity), but have much less internal validity. It is within this framework that the four articles are discussed.
The meta-analysis by Wiesbauer et al. (10) adds to a growing number of such analyses on this topic (12,14,15). The authors of the current meta-analysis focused on randomized controlled trials and included both published manuscripts and abstracts. By analytically combining these trials, the authors were unable to demonstrate an effect of [beta]-blockers on the hard end points of perioperative myocardial infarction or mortality. The clinician could therefore assume that either 1) [beta]-blockers are not effective, or 2) the studies included in the meta-analysis should not have been combined in the manner performed in the analysis because the populations or protocols used are different. If the latter is true, then the clinician should exert caution in specifics with regard to implementation of the protocols.
The pro–con debate (7,8) nicely illustrates this last point by outlining the issues related to interpretation of the data and how two groups of experts in this area choose to approach their own practice. On the pro side, the Dutch group led by Dr. Poldermans (8) clearly believes that many of the other trials did not control heart rate as tightly or provide perioperative [beta]-blockade for as long a duration as in their own studies. The importance of these comments is highlighted by two articles published by the group (16,17), after the editorial was accepted, which further demonstrate the beneficial effect of [beta]-blocker dosage and heart rate control on outcome. In contrast, Dr. London (7) presents a less expansive view with regard to the use of perioperative [beta]-blockade. He argues that the evidence is insufficient to generalize beyond the known literature, and outlines some of the deficiencies in both the evidence and the theoretical underpinnings of widespread treatment. As he notes in his conclusion, given the evidence, it is important to separate the mandatory use of [beta]-blockers as a quality assurance measure from their judicious use in the armamentarium to manage high risk patients.
It is in the context of this debate that the ACC/AHA produced a Focused Update on Perioperative Beta Blockade (9). Specifically, the American Medical Association Physician Consortium on Performance Improvement and the Surgical Care Improvement Project had both begun to evaluate the class and level of evidence to determine the appropriateness of developing performance measures based on continuation and initiation of perioperative [beta]-blockade in noncardiac surgery. It became increasingly important that the appropriate specialty societies weigh in and develop evidence-based guidelines upon which performance measures can be developed. As outlined in the introduction to the Guidelines, the American College of Cardiology has issued a formal position statement indicating that performance measures should be limited to Class I or Class III recommendations—those recommendations in which patients should or should not have the form of therapy—and that they should not include Class IIa or IIb recommendations, in which the evidence is less strong and for which opinion dictates the class of indications. The ACC/AHA mandates that only published trials be included in defining recommendations, and therefore, some of the literature discussed in the meta-analysis could not be included. Importantly, in developing Table 1 (see Ref. 9), we attempted to review the published literature and develop a schemata whereby recommendations for individual cohorts of patients can be easily changed to reflect new evidence.
So, how would I put it all together? Clearly, Class I recommendations should be followed, and therefore, patients receiving [beta]-blockers should be continued on [beta]-blockers, and patients with a positive stress test undergoing vascular surgery should be started on [beta]-blockers. There are large groups of patients currently not taking [beta]-blockers but who have Class I indications for [beta]-blockers independent of noncardiac surgery. For example, [beta]-blockers should be started and continued indefinitely in all patients who have myocardial infarction, acute coronary syndrome, or left ventricular dysfunction, with or without heart failure symptoms, unless contraindicated (18). As shown in multiple studies, many patients who are not taking [beta]-blockers present to vascular surgery with a history of a myocardial infarction (19,20). Therefore, there are patients who should be taking [beta]-blockers for long-term benefits, but for whom there is no evidence to demonstrate that acute administration in the perioperative period will impact outcome. For this reason, we considered such instances as Class IIa indications in the new guidelines, suggesting that they are likely beneficial but that this indication lacks evidence to mandate inclusion as a quality of care measure. In patients who do not have the above indications for [beta]-blockers independent of noncardiac surgery, there are now several trials and the meta-analysis that demonstrate no effect. The use of perioperative [beta]-blockers in the latter group thus represents a Class IIb indication. Finally, Lindenauer et al. (13) suggest harm in subpopulations of surgical patients without any coronary artery disease risk factors. If this harmful effect is shown in randomized trials, then this would qualify as a Class III indication.
The question remains regarding the best protocol to initiate perioperative [beta]-blockade. Ideally, these drugs should be started a week before surgery similar to the protocol by Poldermans et al. and titrated to heart rate-decreasing effect, but this is not always practical. Given emerging data suggesting that inadequate [beta]-blockade and heart rate control may be associated with worse outcomes, it is important to ensure that any protocol will yield the desired effect and not cause harm. Given the lack of data regarding the efficacy of starting [beta]-blockade the morning of surgery versus intraoperatively, the Surgical Care Improvement Project recently defined “appropriate” [beta]-blockade for patients who have not received this therapy before arrival at the operating room as initiating treatment before arriving in the postanesthesia care unit. This allows the caregivers to individualize therapy. In my opinion, further data are needed to understand the risks and benefits of starting [beta]-blockers in this group of patients, and that the results of the Perioperative Ischemic Evaluation (POISE) trial (21), a randomized controlled trial of metoprolol versus placebo in 10,000 patients undergoing noncardiac surgery, are eagerly awaited. The information and opinions in these four articles should allow clinicians to develop their own best approach to perioperative [beta]-blocker therapy in specific patient populations.
Ventilação x translocação bacteriana
The Effects of Airway Pressure and Inspiratory Time on Bacterial Translocation.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(2):391-396, February 2007.
Abstract BACKGROUND: Mechanical ventilation with high peak inspiratory pressure (PIP) induces lung injury and bacterial translocation from the lung into the systemic circulation. We investigated the effects of increased inspiratory time on translocation of intratracheally inoculated bacteria during mechanical ventilation with and without extrinsic positive end-expiratory pressure (PEEP).
METHODS: Rats were ventilated in pressure-controlled mode with 14 cm H2O PIP, 0 cm H2O PEEP, I:E ratio 1/2, and Fio2 1.0. Subsequently, 0.5 mL of 105 cfu/mL Pseudomonas aeruginosa was inoculated through tracheostomy and rats were randomly assigned to six groups; two low-pressure groups (LP)1/2, 14 cm H2O PIP, 0 cm H2O PEEP, I:E = 1/2, and LP2/1 14 cm H2O PIP, 0 cm H2O PEEP, I:E = 2/1; two high-pressure groups (HP)1/2, 30 cm H2O PIP, 0 cm H2O PEEP, I:E = 1/2, and HP2/1, 30 cm H2O PIP, 0 cm H2O PEEP, I:E = 2/1; two HP PEEP groups (HPP)1/2, 30 cm H2O PIP, 10 cm H2O PEEP, I:E = 1/2, and HPP2/1, 30 cm H2O PIP, 10 cm H2O PEEP, I:E = 2/1. Blood cultures were obtained every 30 min. The rats were killed and their lungs were processed.
RESULTS: When compared with baseline values, Pao2 decreased in the LP1/2, LP2/1, HP1/2, and HP2/1 groups at the last time point, but the decline in Pao2 reached statistical significance in only the HP1/2 group. The bacterial translocation rate was greater in group HPP2/1 than group HPP1/2 (P = 0.01).
CONCLUSIONS: We found that high PIP, with or without prolonged inspiratory time, increased the rate of bacterial dissemination. PEEP prevented bacterial translocation in the high PIP group. However, the protective effect of PEEP was lost when inspiratory time was prolonged.
Source Anesthesia & Analgesia. 104(2):391-396, February 2007.
Abstract BACKGROUND: Mechanical ventilation with high peak inspiratory pressure (PIP) induces lung injury and bacterial translocation from the lung into the systemic circulation. We investigated the effects of increased inspiratory time on translocation of intratracheally inoculated bacteria during mechanical ventilation with and without extrinsic positive end-expiratory pressure (PEEP).
METHODS: Rats were ventilated in pressure-controlled mode with 14 cm H2O PIP, 0 cm H2O PEEP, I:E ratio 1/2, and Fio2 1.0. Subsequently, 0.5 mL of 105 cfu/mL Pseudomonas aeruginosa was inoculated through tracheostomy and rats were randomly assigned to six groups; two low-pressure groups (LP)1/2, 14 cm H2O PIP, 0 cm H2O PEEP, I:E = 1/2, and LP2/1 14 cm H2O PIP, 0 cm H2O PEEP, I:E = 2/1; two high-pressure groups (HP)1/2, 30 cm H2O PIP, 0 cm H2O PEEP, I:E = 1/2, and HP2/1, 30 cm H2O PIP, 0 cm H2O PEEP, I:E = 2/1; two HP PEEP groups (HPP)1/2, 30 cm H2O PIP, 10 cm H2O PEEP, I:E = 1/2, and HPP2/1, 30 cm H2O PIP, 10 cm H2O PEEP, I:E = 2/1. Blood cultures were obtained every 30 min. The rats were killed and their lungs were processed.
RESULTS: When compared with baseline values, Pao2 decreased in the LP1/2, LP2/1, HP1/2, and HP2/1 groups at the last time point, but the decline in Pao2 reached statistical significance in only the HP1/2 group. The bacterial translocation rate was greater in group HPP2/1 than group HPP1/2 (P = 0.01).
CONCLUSIONS: We found that high PIP, with or without prolonged inspiratory time, increased the rate of bacterial dissemination. PEEP prevented bacterial translocation in the high PIP group. However, the protective effect of PEEP was lost when inspiratory time was prolonged.
Hipertensão Pulmonar em criança e anestesia
Perioperative Complications in Children with Pulmonary Hypertension Undergoing Noncardiac Surgery or Cardiac Catheterization.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(3):521-527, March 2007.
Abstract BACKGROUND: Pulmonary arterial hypertension (PAH) can lead to significant cardiac dysfunction and is considered to be associated with an increased risk of perioperative cardiovascular complications.
METHODS: We reviewed the medical records of children with PAH who underwent anesthesia or sedation for noncardiac surgical procedures or cardiac catheterizations from 1999 to 2004. The incidence, type, and associated factors of complications occurring intraoperatively through 48 h postoperatively were examined.
RESULTS: Two hundred fifty-six procedures were performed in 156 patients (median age 4.0 yr). PAH etiology was 56% idiopathic (primary), 21% congenital heart disease, 14% chronic lung disease, 4% chronic airway obstruction, and 4% chronic liver disease. Baseline pulmonary artery pressure was subsystemic in 68% patients, systemic in 19%, and suprasystemic in 13%. The anesthetic techniques were 22% sedation, 58% general inhaled, 20% general IV. Minor complications occurred in eight patients (5.1% of patients, 3.1% of procedures). Major complications, including cardiac arrest and pulmonary hypertensive crisis, occurred in seven patients during cardiac catheterization procedures (4.5% of patients, 5.0% of cardiac catheterization procedures, 2.7% of all procedures). There were two deaths associated with pulmonary hypertensive crisis (1.3% of patients, 0.8% of procedures). Baseline suprasystemic PAH was a significant predictor of major complications by multivariate logistic regression analysis (OR = 8.1, P = 0.02). Complications were not significantly associated with age, etiology of PAH, type of anesthetic, or airway management.
CONCLUSION: Children with suprasystemic PAH have a significant risk of major perioperative complications, including cardiac arrest and pulmonary hypertensive crisis.
Source Anesthesia & Analgesia. 104(3):521-527, March 2007.
Abstract BACKGROUND: Pulmonary arterial hypertension (PAH) can lead to significant cardiac dysfunction and is considered to be associated with an increased risk of perioperative cardiovascular complications.
METHODS: We reviewed the medical records of children with PAH who underwent anesthesia or sedation for noncardiac surgical procedures or cardiac catheterizations from 1999 to 2004. The incidence, type, and associated factors of complications occurring intraoperatively through 48 h postoperatively were examined.
RESULTS: Two hundred fifty-six procedures were performed in 156 patients (median age 4.0 yr). PAH etiology was 56% idiopathic (primary), 21% congenital heart disease, 14% chronic lung disease, 4% chronic airway obstruction, and 4% chronic liver disease. Baseline pulmonary artery pressure was subsystemic in 68% patients, systemic in 19%, and suprasystemic in 13%. The anesthetic techniques were 22% sedation, 58% general inhaled, 20% general IV. Minor complications occurred in eight patients (5.1% of patients, 3.1% of procedures). Major complications, including cardiac arrest and pulmonary hypertensive crisis, occurred in seven patients during cardiac catheterization procedures (4.5% of patients, 5.0% of cardiac catheterization procedures, 2.7% of all procedures). There were two deaths associated with pulmonary hypertensive crisis (1.3% of patients, 0.8% of procedures). Baseline suprasystemic PAH was a significant predictor of major complications by multivariate logistic regression analysis (OR = 8.1, P = 0.02). Complications were not significantly associated with age, etiology of PAH, type of anesthetic, or airway management.
CONCLUSION: Children with suprasystemic PAH have a significant risk of major perioperative complications, including cardiac arrest and pulmonary hypertensive crisis.
Pediatria
Use of Anesthetic Agents in Neonates and Young Children.[Article]
Source Anesthesia & Analgesia. 104(3):509-520, March 2007.
Abstract BACKGROUND: Some drugs used for sedation and anesthesia produce histopathologic central nervous system changes in juvenile animal models. These observations have raised concerns regarding the use of these drugs in pediatric patients. We summarized the findings in developing animals and describe the steps that the Food and Drug Administration (FDA) and others are taking to assess potential risks in pediatric patients. The FDA views this communication as opening a dialog with the anesthesia community to address this issue.
METHODS: We reviewed the available animal studies literature examining the potential neurotoxic effects of commonly used anesthetic drugs on the developing brain. The search strategy involved crossing the keywords neurotoxic and neuroapoptosis with the following general and specific terms: anesthetic, N-methyl-d-aspartate (NMDA), ketamine, midazolam, lorazepam, fentanyl, methadone, morphine, meperidine, isoflurane, nitrous oxide, sevoflurane, halothane, enflurane, desflurane, propofol, etomidate, barbiturate, methoxyflurane, and chloral hydrate. We summarized several studies sponsored by the FDA in rats and monkeys, initially examining the potential for ketamine, as a prototypical agent, to induce neurodegeneration in the developing brain.
RESULTS: Numerous animal studies in rodents indicate that NMDA receptor antagonists, including ketamine, induce neurodegeneration in the developing brain. The effects of ketamine are dose dependent. The data suggest that limiting exposure limits the potential for neurodegeneration. There is also evidence that other general anesthetics, such as isoflurane, can induce neurodegeneration in rodent models, which may be exacerbated by concurrent administration of midazolam or nitrous oxide. There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models. However, the studies that have been reported suggest subtle, but prolonged, behavioral changes in rodents. Although the doses and durations of ketamine exposure that resulted in neurodegeneration were slightly larger than those used in the clinical setting, those associated with isoflurane were not. There are insufficient human data to either support or refute the clinical applicability of these findings.
CONCLUSIONS: Animal studies suggest that neurodegeneration, with possible cognitive sequelae, is a potential long-term risk of anesthetics in neonatal and young pediatric patients. The existing nonclinical data implicate not only NMDA-receptor antagonists, but also drugs that potentiate [gamma]-aminobutyric acid signal transduction, as potentially neurotoxic to the developing brain. The potential for the combination of drugs that have activity at both receptor systems or that can induce more or less neurotoxicity is not clear; however, recent nonclinical data suggest that some combinations may be more neurotoxic than the individual components. The lack of information to date precludes the ability to designate any one anesthetic agent or regimen as safer than any other. Ongoing studies in juvenile animals should provide additional information regarding the risks. The FDA anticipates working with the anesthesia community and pharmaceutical industry to develop strategies for further assessing the safety of anesthetics in neonates and young children, and for providing data to guide clinicians in making the most informed decisions possible when choosing anesthetic regimens for their pediatric patients.
Source Anesthesia & Analgesia. 104(3):509-520, March 2007.
Abstract BACKGROUND: Some drugs used for sedation and anesthesia produce histopathologic central nervous system changes in juvenile animal models. These observations have raised concerns regarding the use of these drugs in pediatric patients. We summarized the findings in developing animals and describe the steps that the Food and Drug Administration (FDA) and others are taking to assess potential risks in pediatric patients. The FDA views this communication as opening a dialog with the anesthesia community to address this issue.
METHODS: We reviewed the available animal studies literature examining the potential neurotoxic effects of commonly used anesthetic drugs on the developing brain. The search strategy involved crossing the keywords neurotoxic and neuroapoptosis with the following general and specific terms: anesthetic, N-methyl-d-aspartate (NMDA), ketamine, midazolam, lorazepam, fentanyl, methadone, morphine, meperidine, isoflurane, nitrous oxide, sevoflurane, halothane, enflurane, desflurane, propofol, etomidate, barbiturate, methoxyflurane, and chloral hydrate. We summarized several studies sponsored by the FDA in rats and monkeys, initially examining the potential for ketamine, as a prototypical agent, to induce neurodegeneration in the developing brain.
RESULTS: Numerous animal studies in rodents indicate that NMDA receptor antagonists, including ketamine, induce neurodegeneration in the developing brain. The effects of ketamine are dose dependent. The data suggest that limiting exposure limits the potential for neurodegeneration. There is also evidence that other general anesthetics, such as isoflurane, can induce neurodegeneration in rodent models, which may be exacerbated by concurrent administration of midazolam or nitrous oxide. There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models. However, the studies that have been reported suggest subtle, but prolonged, behavioral changes in rodents. Although the doses and durations of ketamine exposure that resulted in neurodegeneration were slightly larger than those used in the clinical setting, those associated with isoflurane were not. There are insufficient human data to either support or refute the clinical applicability of these findings.
CONCLUSIONS: Animal studies suggest that neurodegeneration, with possible cognitive sequelae, is a potential long-term risk of anesthetics in neonatal and young pediatric patients. The existing nonclinical data implicate not only NMDA-receptor antagonists, but also drugs that potentiate [gamma]-aminobutyric acid signal transduction, as potentially neurotoxic to the developing brain. The potential for the combination of drugs that have activity at both receptor systems or that can induce more or less neurotoxicity is not clear; however, recent nonclinical data suggest that some combinations may be more neurotoxic than the individual components. The lack of information to date precludes the ability to designate any one anesthetic agent or regimen as safer than any other. Ongoing studies in juvenile animals should provide additional information regarding the risks. The FDA anticipates working with the anesthesia community and pharmaceutical industry to develop strategies for further assessing the safety of anesthetics in neonates and young children, and for providing data to guide clinicians in making the most informed decisions possible when choosing anesthetic regimens for their pediatric patients.
USG e CVC
A Survey of the Use of Ultrasound During Central Venous Catheterization.[Miscellaneous Article]
Source Anesthesia & Analgesia. 104(3):491-497, March 2007.
Abstract BACKGROUND: Complications during central venous catheterization (CVC) are not rare and can be serious. The use of ultrasound (US) during CVC has been recommended to improve patient safety. We performed a survey to evaluate the frequency of, and factors influencing, US use.
METHODS: We conducted an electronic survey of all members of the Society of Cardiovascular Anesthesiologists. Univariate and multivariate logistic regressions were used to assess the association between the frequency of US use and hospital and physician factors. All tests were two-sided, and a P value <0.05 was considered statistically significant.
RESULTS: Of the 4235 members, 1494 responded (response rate = 35.3%). Two-thirds of the respondents never, or almost never, use US, whereas only 15% always, or almost always, use US. Thirty-three percent of the respondents never, or almost never, have US available, whereas 41% stated that US is always, or almost always, available. Availability of US equipment was strongly associated with US use for CVC (adj OR = 18.9; P value <0.001). The most common reason cited for not using US was "no apparent need for the use of US" (46%). When US was used, rescue or screening approaches were more common (72%) than real-time use (26%).
CONCLUSIONS: The use of US during CVC remains limited and is most strongly associated with the availability of equipment. Screening and rescue use of US are more common than real-time guidance. Our survey suggests that current use of US during CVC differs from existing evidence-based recommendations.
Source Anesthesia & Analgesia. 104(3):491-497, March 2007.
Abstract BACKGROUND: Complications during central venous catheterization (CVC) are not rare and can be serious. The use of ultrasound (US) during CVC has been recommended to improve patient safety. We performed a survey to evaluate the frequency of, and factors influencing, US use.
METHODS: We conducted an electronic survey of all members of the Society of Cardiovascular Anesthesiologists. Univariate and multivariate logistic regressions were used to assess the association between the frequency of US use and hospital and physician factors. All tests were two-sided, and a P value <0.05 was considered statistically significant.
RESULTS: Of the 4235 members, 1494 responded (response rate = 35.3%). Two-thirds of the respondents never, or almost never, use US, whereas only 15% always, or almost always, use US. Thirty-three percent of the respondents never, or almost never, have US available, whereas 41% stated that US is always, or almost always, available. Availability of US equipment was strongly associated with US use for CVC (adj OR = 18.9; P value <0.001). The most common reason cited for not using US was "no apparent need for the use of US" (46%). When US was used, rescue or screening approaches were more common (72%) than real-time use (26%).
CONCLUSIONS: The use of US during CVC remains limited and is most strongly associated with the availability of equipment. Screening and rescue use of US are more common than real-time guidance. Our survey suggests that current use of US during CVC differs from existing evidence-based recommendations.
Haesteril e voluven - pros e contras
The Pros and Cons of Hydroxyethyl Starch Solutions
[Editorial]
Vincent, Jean-Louis MD, PhDFrom the Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.
Accepted for publication December 20, 2006.
Address correspondence and reprint requests to Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. Address e-mail to jlvincen@ulb.ac.be.
The optimal type of fluid for intravascular volume resuscitation in critically ill patients remains a matter of debate. With their higher molecular weight, colloids remain in the intravascular space longer, and, therefore, provide more rapid hemodynamic stabilization than crystalloids, which extravasate to a greater degree so that more fluids are required to achieve the same end points. However, colloids are more expensive than crystalloids, in particular albumin, so that other colloids have been developed, including gelatins, dextrans, and hydroxyethyl starch (HES) solutions.
Hydroxyethyl starch solutions have evolved since they were first developed in the Unite States in the 1970s. The first HES solutions included HES molecules of relatively high molecular weight and high degree of substitution, in an attempt to prolong their vascular persistence. These solutions were associated with an increased risk of bleeding (1,2) and renal failure (3–5). Prolonged persistence in the body also raised concern (6), and there are numerous reports of delayed itching in the dermatologic literature (7). Lower molecular weight HES solutions and solutions with lesser degrees of substitution have since been developed that may have an improved pharmacological profile, with fewer negative effects on coagulation and renal function, and more rapid tissue clearance (8,9).
Importantly, in addition to their effects as intravascular volume expanders, HES solutions may have other properties. As early as the 1980s, Zikria et al. (10,11) reported that HES solutions could reduce microvascular permeability, leading to the concept that they could “plug” the leaks created in the endothelium during various disease processes, including sepsis and burns (12). In this issue of Anesthesia & Analgesia, Feng et al. (13) show that, in a model of cecal ligation and perforation, rats that received HES or gelatin solutions had reduced pulmonary capillary leakage compared with those that received normal saline. In addition, HES administration was associated with reduced expression of various proinflammatory mediators, including tumor necrosis factor and interleukin-1, while gelatin administration was not.
In their present study, these authors have extended their previous data in rats, which showed that HES significantly reduced lipopolysaccharide-induced increases in lung capillary permeability, and inhibited lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and nuclear factor-[kappa] B activation (14). Their results also agree with experimental studies from other groups demonstrating the antiinflammatory effects of HES solutions (15–19). Hydroxyethyl starch has been shown to restore macrophage integrity and prevent the increase in interleukin-6 in mice after trauma-hemorrhage (15), to alter the interaction of neutrophils with activated endothelium (16,17), to decrease the neutrophil respiratory burst induced by Escherichia coli (18), and to attenuate hypoxia-induced increases in vascular leakage and acute inflammation (19). Boldt et al. (20), in patients undergoing major abdominal surgery, reported that the administration of HES was associated with reduced markers of inflammation and endothelial activation compared with crystalloid.
The Feng et al. data (13) thus seem consistent with previous studies, but interpretation remains difficult. An important question is whether the observed effects are due to the solution itself or, rather, due to the effectiveness of the fluid resuscitation. In in vivo studies it is difficult to separate the specific effects of the individual fluids on the vessels from the general effects of fluid resuscitation. These difficulties are well illustrated by Marx et al. (21) in their study in a porcine model, where the early administration of HES solution restored tissue oxygenation better than Ringer’s lactate solution; however, there were no differences in the albumin escape rate, suggesting that the changes observed were due more to hemodynamic than to specific antiinflammatory effects.
Prolonged tissue hypoperfusion with regional tissue hypoxia can increase the inflammatory response. Even in the absence of inflammation, prolonged severe hypoxia results in increased endothelial permeability, believed to be a key factor in the development of organ failure (22); thus, the longer a shock state persists, the greater the likelihood that the patient will develop organ failure. In patients with severe sepsis, we (23) recently showed that the duration of vasopressor requirement was directly related to the risk of subsequent organ failure.
Intravascular fluid resuscitation has been shown to reduce the inflammatory response. For example, improved resuscitation after hemorrhage is associated with reduced pulmonary dysfunction and lung inflammation (24,25), and preemptive intravascular volume administration prevents lipopolysaccharide-induced microcirculatory changes (26). In other septic models, intravascular fluid resuscitation attenuated the release of cytokines or platelet activating factor (27,28). Logically, therefore, rapid reversal of acute circulatory failure should result in a shorter and less intense inflammatory reaction, with fewer permeability alterations and less edema formation.
In the study by Feng et al. (13), the effects of HES were compared with those of an identical amount of gelatin, a colloid with a molecular weight only half that of albumin. Hence, the intravascular volume effects may have been greater in the HES group than in the other group. Arterial blood pressure was similar in the various groups, but this provides only a rough estimate of hemodynamic stability. Even measurements of cardiac output would not be entirely reassuring. Indeed, macrohemodynamic variables can be restored while the microhemodynamic status remains altered (29). Studies in rats, like that by Feng et al. (13), cannot explore these differences reliably, and one would like to see similar experiments in larger animals, or even in humans, and with a more effective colloid (such as albumin) for comparison. In summary, the intensity of the intravascular fluid resuscitation may be more important than the type of fluid itself, and HES solutions have very effective vascular effects.
In the meantime, if the evidence is strong enough to support the antiinflammatory effects of HES, the question then becomes, Do these antiinflammatory properties give HES solutions a definitive advantage over other fluids? Perhaps not. First, a reduced inflammatory response does not necessarily translate into clinical benefit. Decreased capillary leak may be globally beneficial, but decreased neutrophil activation may have unwanted, as well as wanted, consequences. Second, assuming that the antiinflammatory effects are beneficial, other fluids may have similar advantages. Albumin, for example, has been shown to have antiinflammatory and antioxidant effects (30–33). Hydroxyethyl starch solutions may have other drawbacks, including the risk of altered hemostasis and the persistence of HES molecules in the body. In addition, there is new concern about the increased risks of renal failure associated with HES administration. A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure. (Data presented at the 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.)
So, where does this leave us in the big fluid debate? The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture and to better determine where each fluid fits. Although we use these fluids every day, we still know surprisingly little about them.
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12. Vincent JL. Plugging the leaks? New insights into synthetic colloids. Crit Care Med 1991;19:316–8. Buy Now Bibliographic Links [Context Link]
13. Feng X, Liu J, Yu M, et al. Hydroxyethyl starch, but not modified fluid gelatin, affects inflammatory response in a rat model of polymicrobial sepsis with capillary leakage. Anesth Analg 2007;104:624–30. Ovid Full Text Bibliographic Links [Context Link]
14. Tian J, Lin X, Guan R, Xu JG. The effects of hydroxyethyl starch on lung capillary permeability in endotoxic rats and possible mechanisms. Anesth Analg 2004;98:768–74. Ovid Full Text Bibliographic Links [Context Link]
15. Schmand JF, Ayala A, Morrison MH, Chaudry IH. Effects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating IL-6 levels. Crit Care Med 1995;23:806–14. Ovid Full Text Bibliographic Links [Context Link]
16. Handrigan MT, Burns AR, Donnachie EM, Bowden RA. Hydroxyethyl starch inhibits neutrophil adhesion and transendothelial migration. Shock 2005;24:434–9. Buy Now Bibliographic Links [Context Link]
17. Hoffmann JN, Vollmar B, Laschke MW, et al. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology 2002;97:460–70. Ovid Full Text Bibliographic Links [Context Link]
18. Jaeger K, Heine J, Ruschulte H, et al. Effects of colloidal resuscitation fluids on the neutrophil respiratory burst. Transfusion 2001; 41:1064–8. Bibliographic Links [Context Link]
19. Dieterich HJ, Weissmuller T, Rosenberger P, Eltzschig HK. Effect of hydroxyethyl starch on vascular leak syndrome and neutrophil accumulation during hypoxia. Crit Care Med 2006; 34:1775–82. Ovid Full Text Bibliographic Links [Context Link]
20. Boldt J, Ducke M, Kumle B, et al. Influence of different volume replacement strategies on inflammation and endothelial activation in the elderly undergoing major abdominal surgery. Intensive Care Med 2004;30:416–22. Bibliographic Links [Context Link]
21. Marx G, Pedder S, Smith L, et al. Resuscitation from septic shock with capillary leakage: hydroxyethyl starch (130 kd), but not Ringer’s solution maintains plasma volume and systemic oxygenation. Shock 2004;21:336–41. Buy Now Bibliographic Links [Context Link]
22. Ali MH, Schlidt SA, Hynes KL, et al. Prolonged hypoxia alters endothelial barrier function. Surgery 1998;124:491–7. Bibliographic Links [Context Link]
23. Levy MM, Macias WL, Vincent JL, et al. Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med 2005;33:2194–201. Ovid Full Text Bibliographic Links [Context Link]
24. Claridge JA, Schulman AM, Young JS. Improved resuscitation minimizes respiratory dysfunction and blunts interleukin-6 and nuclear factor-kappa B activation after traumatic hemorrhage. Crit Care Med 2002;30:1815–9. Ovid Full Text Bibliographic Links [Context Link]
25. Kiang JG, Lu X, Tabaku LS, et al. Resuscitation with lactated Ringer solution limits the expression of molecular events associated with lung injury after hemorrhage. J Appl Physiol 2005;98:550–6. Bibliographic Links [Context Link]
26. Anning PB, Finney SJ, Singh S, et al. Fluids reverse the early lipopolysaccharide-induced albumin leakage in rodent mesenteric venules. Intensive Care Med 2004;30:1944–9. Bibliographic Links [Context Link]
27. Wilson MA, Chou MC, Spain DA, et al. Fluid resuscitation attenuates early cytokine mRNA expression after peritonitis. J Trauma 1996; 41:622–7. Buy Now Bibliographic Links [Context Link]
28. Zhang C, Hsueh W, Caplan MS, Kelly A. Platelet activating factor-induced shock and intestinal necrosis in the rat: role of endogenous platelet-activating factor and effect of saline infusion. Crit Care Med 1991;19:1067–72. Buy Now Bibliographic Links [Context Link]
29. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004;32:1825–31. Ovid Full Text Bibliographic Links [Context Link]
30. Zhang WJ, Frei B. Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res 2002;55:820–9. Bibliographic Links [Context Link]
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[Editorial]
Vincent, Jean-Louis MD, PhDFrom the Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.
Accepted for publication December 20, 2006.
Address correspondence and reprint requests to Jean-Louis Vincent, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium. Address e-mail to jlvincen@ulb.ac.be.
The optimal type of fluid for intravascular volume resuscitation in critically ill patients remains a matter of debate. With their higher molecular weight, colloids remain in the intravascular space longer, and, therefore, provide more rapid hemodynamic stabilization than crystalloids, which extravasate to a greater degree so that more fluids are required to achieve the same end points. However, colloids are more expensive than crystalloids, in particular albumin, so that other colloids have been developed, including gelatins, dextrans, and hydroxyethyl starch (HES) solutions.
Hydroxyethyl starch solutions have evolved since they were first developed in the Unite States in the 1970s. The first HES solutions included HES molecules of relatively high molecular weight and high degree of substitution, in an attempt to prolong their vascular persistence. These solutions were associated with an increased risk of bleeding (1,2) and renal failure (3–5). Prolonged persistence in the body also raised concern (6), and there are numerous reports of delayed itching in the dermatologic literature (7). Lower molecular weight HES solutions and solutions with lesser degrees of substitution have since been developed that may have an improved pharmacological profile, with fewer negative effects on coagulation and renal function, and more rapid tissue clearance (8,9).
Importantly, in addition to their effects as intravascular volume expanders, HES solutions may have other properties. As early as the 1980s, Zikria et al. (10,11) reported that HES solutions could reduce microvascular permeability, leading to the concept that they could “plug” the leaks created in the endothelium during various disease processes, including sepsis and burns (12). In this issue of Anesthesia & Analgesia, Feng et al. (13) show that, in a model of cecal ligation and perforation, rats that received HES or gelatin solutions had reduced pulmonary capillary leakage compared with those that received normal saline. In addition, HES administration was associated with reduced expression of various proinflammatory mediators, including tumor necrosis factor and interleukin-1, while gelatin administration was not.
In their present study, these authors have extended their previous data in rats, which showed that HES significantly reduced lipopolysaccharide-induced increases in lung capillary permeability, and inhibited lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and nuclear factor-[kappa] B activation (14). Their results also agree with experimental studies from other groups demonstrating the antiinflammatory effects of HES solutions (15–19). Hydroxyethyl starch has been shown to restore macrophage integrity and prevent the increase in interleukin-6 in mice after trauma-hemorrhage (15), to alter the interaction of neutrophils with activated endothelium (16,17), to decrease the neutrophil respiratory burst induced by Escherichia coli (18), and to attenuate hypoxia-induced increases in vascular leakage and acute inflammation (19). Boldt et al. (20), in patients undergoing major abdominal surgery, reported that the administration of HES was associated with reduced markers of inflammation and endothelial activation compared with crystalloid.
The Feng et al. data (13) thus seem consistent with previous studies, but interpretation remains difficult. An important question is whether the observed effects are due to the solution itself or, rather, due to the effectiveness of the fluid resuscitation. In in vivo studies it is difficult to separate the specific effects of the individual fluids on the vessels from the general effects of fluid resuscitation. These difficulties are well illustrated by Marx et al. (21) in their study in a porcine model, where the early administration of HES solution restored tissue oxygenation better than Ringer’s lactate solution; however, there were no differences in the albumin escape rate, suggesting that the changes observed were due more to hemodynamic than to specific antiinflammatory effects.
Prolonged tissue hypoperfusion with regional tissue hypoxia can increase the inflammatory response. Even in the absence of inflammation, prolonged severe hypoxia results in increased endothelial permeability, believed to be a key factor in the development of organ failure (22); thus, the longer a shock state persists, the greater the likelihood that the patient will develop organ failure. In patients with severe sepsis, we (23) recently showed that the duration of vasopressor requirement was directly related to the risk of subsequent organ failure.
Intravascular fluid resuscitation has been shown to reduce the inflammatory response. For example, improved resuscitation after hemorrhage is associated with reduced pulmonary dysfunction and lung inflammation (24,25), and preemptive intravascular volume administration prevents lipopolysaccharide-induced microcirculatory changes (26). In other septic models, intravascular fluid resuscitation attenuated the release of cytokines or platelet activating factor (27,28). Logically, therefore, rapid reversal of acute circulatory failure should result in a shorter and less intense inflammatory reaction, with fewer permeability alterations and less edema formation.
In the study by Feng et al. (13), the effects of HES were compared with those of an identical amount of gelatin, a colloid with a molecular weight only half that of albumin. Hence, the intravascular volume effects may have been greater in the HES group than in the other group. Arterial blood pressure was similar in the various groups, but this provides only a rough estimate of hemodynamic stability. Even measurements of cardiac output would not be entirely reassuring. Indeed, macrohemodynamic variables can be restored while the microhemodynamic status remains altered (29). Studies in rats, like that by Feng et al. (13), cannot explore these differences reliably, and one would like to see similar experiments in larger animals, or even in humans, and with a more effective colloid (such as albumin) for comparison. In summary, the intensity of the intravascular fluid resuscitation may be more important than the type of fluid itself, and HES solutions have very effective vascular effects.
In the meantime, if the evidence is strong enough to support the antiinflammatory effects of HES, the question then becomes, Do these antiinflammatory properties give HES solutions a definitive advantage over other fluids? Perhaps not. First, a reduced inflammatory response does not necessarily translate into clinical benefit. Decreased capillary leak may be globally beneficial, but decreased neutrophil activation may have unwanted, as well as wanted, consequences. Second, assuming that the antiinflammatory effects are beneficial, other fluids may have similar advantages. Albumin, for example, has been shown to have antiinflammatory and antioxidant effects (30–33). Hydroxyethyl starch solutions may have other drawbacks, including the risk of altered hemostasis and the persistence of HES molecules in the body. In addition, there is new concern about the increased risks of renal failure associated with HES administration. A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure. (Data presented at the 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.)
So, where does this leave us in the big fluid debate? The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture and to better determine where each fluid fits. Although we use these fluids every day, we still know surprisingly little about them.
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