Surgery causes changes in hemostasis, leading to a hypercoagulable state that has been linked to both arterial and venous thrombotic complications.The etiology of this state is unknown, but many investigators have hypothesized that perioperative neuroendocrine changes are responsible. We have previously demonstrated minimal increases in hemostatic function with a stress hormone infusion. This study was undertaken to further examine the relationship between neuroendocrine hormones and hemostatic function. Seventeen healthy volunteers were administered a stress hormone cocktail IV (epinephrine, cortisol, glucagon, angiotensin II, and vasopressin) for 24 h in a blind, placebo-controlled, cross-over design in our clinical research center. Venous blood samples were obtained for measurement of hemostatic function before the infusion and at 2, 8, and 24 h. There were no demonstrable increases in any measure of hypercoagulability. Alternatively, there was an increase in tissue plasminogen activator and protein C activity. These changes are consistent with an inhibition of coagulation and improved fibrinolysis. These data suggest that this combination of neuroendocrine hormones is not responsible for the postoperative hypercoagulable state. Implications: Infusion of five stress hormones (epinephrine, cortisol, glucagon, vasopressin, and angiotensin II) to normal volunteers does not cause increases in procoagulant proteins and platelet reactivity or decreases in fibrinolytic proteins. Alternatively, these five hormones caused increased levels of fibrinolytic proteins (tissue plasminogen activator) and endogenous anticoagulants (protein C antigen and activity). (Anesth Analg 1998;86:640-5)
Background Platelet--leukocyte conjugates have been observed in patients with unstable coronary syndromes and after cardiopulmonary bypass. In vitro, the binding of platelet P-selectin to leukocyte P-selectin glycoprotein ligand-1 (PSGL1) mediates conjugate formation; however, the hemostatic implications of these cell--cell interactions are unknown. The aims of this study were to determine the ability of leukocytes to modulate platelet agonist--induced aggregation and secretion in the blood milieu, and to investigate the role of P-selectin and PSGL-1 in mediating these responses. Methods Blood was drawn from healthy volunteers for in vitro analysis of platelet agonist--induced aggregation, secretion (adenosine triphosphate, beta-thromboglobulin, and thromboxane), and platelet-leukocyte conjugate formation. Experiments were performed on live cells in whole blood or plasma to simulate physiologic conditions. Whole-blood impedance and optical aggregometry, flow cytometry, and enzyme-linked immunosorbent assays were performed in the presence and absence of blocking antibodies to P-selectin and PSGL1. The platelet-specific agonists, thrombin receptor activating peptide and adenosine diphosphate, were used to elicit platelet activation responses. Results Inhibition of platelet--leukocyte adherence by P- selectin and PSGL1 antibodies decreased agonist--induced aggregation in whole blood. The presence of leukocytes in platelet-rich plasma increased aggregation, and this increase was attenuated by P-selectin blocking antibodies. Data from flow cytometry confirmed that platelet-leukocyte conjugate formation contributed to aggregation responses. Blocking antibodies reduced platelet agonist--induced thromboxane release but had no impact on adenosine triphosphate and beta-thomboglobulin secretion. Conclusions Leukocytes can enhance platelet agonist--induced aggregation and thromboxane release in whole blood and platelet-rich plasma under shear conditions in vitro. Interaction of platelet P-selectin with leukocyte PSGL1 contributes substantially to these effects.
Venous stasis occurs when people are at bedrest, because of altered venous flow characteristics. This is commonly believed to be one etiology behind the development of deep venous thrombosis (DVT). The hemostatic effects of bedrest and their possible role in DVT development have not been fully examined. We hypothesized that bedrest would lead to increases in hemostatic function and that these increases could be important in the development of DVT. Twelve non-smoking volunteers were studied during supine positioning for 36 hours. Platelet reactivity and plasma concentrations of fibrinogen, alpha 2-antiplasmin, plasminogen, thromboxane beta 2, plasminogen activator inhibitor-1, tissue plasminogen activator and neuroendocrine hormones (cortisol, epinephrine and norepinephrine) were measured at 8:00 a.m., 10:00 a.m., 4:00 p.m. and 8:00 a.m. Cortisol demonstrated an early morning increase while catecholamines were unchanged throughout. Fibrinogen, alpha 2-antiplasmin, plasminogen and platelet reactivity were no different at any time point. Fibrinolytic proteins changed over time, manifested by decreased PAI-1 antigen and activity levels at 24 h. Based upon the parameters measured, bedrest causes no increase in hemostatic function. In fact, bedrest causes the potential for enhanced fibrinolysis, that differs from that previously reported for normal activity over 24 h. This may represent a protective mechanism to counter the effects of stasis from bedrest.
Twenty-four adults who were undergoing operations on the abdominal aorta were enrolled in a randomized, double-blind, placebo-controlled study in which epidural morphine sulfate (6 mg) was employed to attenuate the sympathoadrenal response to surgery to evaluate the possible contribution of sympathetic nervous system hyperactivity to postoperative hypertension. Patients who received epidural morphine required less parenteral morphine in the 24 hours following surgery, had lower analogue pain scores, and had markedly lower plasma norepinephrine levels when compared with patients in the control group who received an identical volume of saline in the epidural space. Epidural morphine had no effect on plasma epinephrine or arginine vasopressin levels. Fewer patients in the morphine group (4 of 12 vs 9 of 12 patients in the saline group) required treatment for hypertension (mean arterial blood pressure, greater than or equal to 110 mm Hg) in the 24 hours following surgery. In addition, patients in the morphine group had lower blood pressures in the 24 hours following surgery. These data suggest that sympathetic nervous system activity and not adrenal epinephrine or pituitary secretion of arginine vasopressin is responsible for the development of hypertension following aortic surgery. Furthermore, epidural narcotics appear to provide a means of attenuating this response.
Brian A. Rosenfeld, M.D., F.C.C.M., Associate Professor, Anesthesiology, Medicine and Surgery.Michael J. Breslow, M.D., F.C.C.M., Assistant Professor, Anesthesiology, Medicine and Surgery.Todd Dorman, M.D., Assistant Professor, Anesthesiology and Surgery, Adult Critical Care Division, Anesthesiology and Critical Care Medicine, Johns Hopkins, 600 North Wolfe Street, Meyer 299A, Baltimore, Maryland 21287-7294.To the Editor:--As clinicians who run a preoperative evaluation center and provide intraoperative anesthesia and postoperative intensive care, we, like Mangano, [1]have been frustrated with the problem of preoperative cardiac risk assessment. However, as we question whether "a cardiac risk assessment paradigm is possible," our answer is slightly different. Whereas Mangano concludes with a call for development of screening algorithms and large-scale trials assessing testing technologies, we suggest that a more sensitive, specific, and cost-effective paradigm is probably not feasible and, equally important, may not be necessary. Rather, we believe that the focus should be shifted from preoperative testing to development of improved methodologies for postoperative ischemia detection and treatment.For the past two decades, the conventional approach to cardiac risk management in anesthesia has been preoperative screening (to detect high-risk patients) and special intraoperative monitoring and interventions (to avert or immediately correct evolving ischemia). A variety of screening tests have been proposed to identify high-risk patients who are either asymptomatic or have stable symptomatology; however, these tests have a low positive predictive value and a real incidence of false negatives. The positive predictive value of these tests is low, not because the tests are unable to detect significant coronary disease, but rather, because current management strategies have reduced the likelihood of patients with coronary disease experiencing major cardiac complications. Moreover, because plaque rupture can occur in physiologically insignificant lesions, there always will be a low but real incidence of false negatives.The current economic environment is challenging all of us to examine our practice patterns and evaluate whether they are cost-effective. We believe that the way preoperative cardiac screening tests are used does not meet the challenge of cost-effectiveness. Available tests are expensive, and detection of unrecognized coronary stenosis, by necessity, entails fairly widespread testing. Data on the societal costs of preoperative cardiac testing are difficult to obtain, but a recent survey [2]indicates widespread preoperative testing in vascular surgery patients (60% of 400,000 cases/year). According to current estimates, 9 million patients are at risk for cardiac complications each year [1]; whereas the actual number undergoing preoperative testing is unknown, the cost of cardiac screening is enormous. Cost-effective testing also requires that the results can be used to change outcome. Available data do not support that this is the case for preoperative cardiac screening tests. When angiography and angioplasty or bypass surgery are performed for the sole purpose of reducing perioperative risk, overall morbidity and mortality is not reduced and may be increased. [3].The perioperative period can be viewed as a stress test, subjecting the body to neuroendocrine, hemodynamic, thermal, and coagulation changes. These stresses are thought to account for most perioperative myocardial infarctions. The preponderance of available data indicates that the postoperative period has the highest incidence of cardiac events. [4,5]Yet, we have invested relatively little effort and resources in postoperative research and management strategies. Therefore, we believe that the potential for novel discoveries and cost-effective therapies may be comparatively greater. One possible approach would use continuous 12-lead electrocardiographic monitoring in at-risk patients during the first 48 h after surgery. Systems are available with central alarm capabilities that can be used on a general surgical floor. Based on recent data showing that ischemia precedes postoperative cardiac events in most patients [4-6]and that there is an apparent threshold of 120 min of postoperative ischemia before development of major morbid events, [5,6]prompt ischemia detection should allow for timely intervention and a reduced incidence of postoperative infarction. Because postoperative ischemia also predicts long-term cardiac morbidity and mortality, [7,8]improved methods for ischemia detection could use the physiologic stress of the perioperative period as a "surgical stress test."In summary, if we wish to reduce perioperative cardiac complications, we need to develop a comprehensive approach that deploys our resources throughout the perioperative period most effectively. We contend that systematic study and consideration to the relatively unexplored avenues of postoperative management should be made before we make additional and massive investments in approaches that have been in place for decades.Brian A. Rosenfeld, M.D., F.C.C.M., Associate Professor, Anesthesiology, Medicine and Surgery.Michael J. Breslow, M.D., F.C.C.M., Associate Professor, Anesthesiology, Medicine and Surgery.Todd Dorman, M.D., Assistant Professor, Anesthesiology and Surgery, Adult Critical Care Division, Anesthesiology and Critical Care Medicine, Johns Hopkins, 600 North Wolfe Street, Meyer 299A, Baltimore, Maryland 21287-7294.
Intensive care units (ICUs) are major sites for medical errors and adverse events. Suboptimal outcomes reflect a widespread failure to implement care delivery systems that successfully address the complexity of modern ICUs. Whereas other industries have used information technologies to fundamentally improve operating efficiency and enhance safety, medicine has been slow to implement such strategies. Most ICUs do not even track performance; fewer still have the capability to examine clinical data and use this information to guide quality improvement initiatives. This article describes a technology-enabled care model (electronic ICU, or eICU) that represents a new paradigm for delivery of critical care services. A major component of the model is the use of telemedicine to leverage clinical expertise and facilitate a round-the-clock proactive care by intensivist-led teams of ICU caregivers. Novel data presentation formats, computerized decision support, and smart alarms are used to enhance efficiency, increase effectiveness, and standardize clinical and operating processes. In addition, the technology infrastructure facilitates performance improvement by providing an automated means to measure outcomes, track performance, and monitor resource utilization. The program is designed to support the multidisciplinary intensivist-led team model and incorporates comprehensive ICU re-engineering efforts to change practice behavior. Although this model can transform ICUs into centers of excellence, success will hinge on hospitals accepting the underlying value proposition and physicians being willing to change established practices.
Objective To examine whether a supplemental remote intensive care unit (ICU) care program, implemented by an integrated delivery network using a commercial telemedicine and information technology system, can improve clinical and economic performance across multiple ICUs. Design Before-and-after trial to assess the effect of adding the supplemental remote ICU telemedicine program. Setting Two adult ICUs of a large tertiary care hospital. Patients A total of 2,140 patients receiving ICU care between 1999 and 2001. Interventions The remote care program used intensivists and physician extenders to provide supplemental monitoring and management of ICU patients for 19 hrs/day (noon to 7 am) from a centralized, off-site facility (eICU). Supporting software, including electronic data display, physician note- and order-writing applications, and a computer-based decision-support tool, were available both in the ICU and at the remote site. Clinical and economic performance during 6 months of the remote intensivist program was compared with performance before the intervention. Measurements and Main Results Hospital mortality for ICU patients was lower during the period of remote ICU care (9.4% vs. 12.9%; relative risk, 0.73; 95% confidence interval [CI], 0.55–0.95), and ICU length of stay was shorter (3.63 days [95% CI, 3.21–4.04] vs. 4.35 days [95% CI, 3.93–4.78]). Lower variable costs per case and higher hospital revenues (from increased case volumes) generated financial benefits in excess of program costs. Conclusions The addition of a supplemental, telemedicine-based, remote intensivist program was associated with improved clinical outcomes and hospital financial performance. The magnitude of the improvements was similar to those reported in studies examining the impact of implementing on-site dedicated intensivist staffing models; however, factors other than the introduction of off-site intensivist staffing may have contributed to the observed results, including the introduction of computer-based tools and the increased focus on ICU performance. Although further studies are needed, the apparent success of this on-going multiple-site program, implemented with commercially available equipment, suggests that telemedicine may provide a means for hospitals to achieve quality improvements associated with intensivist care using fewer intensivists.
PRONOVOST, PETER J.; JENCKES, MOLLIE W.; DORMAN, TODD; GARRETT, ELIZABETH; BRESLOW, MICHAEL J.; ROSENFELD, BRIAN A.; LIPSETT, PAMELA A.; BASS, ERIC Author Information
alpha2-adrenergic agonists are receiving attention as possible anesthetic adjuncts. They provide sedation [1] and may reduce both anesthetic and analgesic requirements [2-4]. A marked reduction in sympathetic activity appears to be their most pronounced effect, resulting in attenuated intraoperative blood pressure lability [2,5-8] and lower postoperative serum catecholamine levels [2,7,8]. There are concerns that these sympatholytic effects, although beneficial for patients at risk of myocardial ischemia, could adversely affect cardiovascular responses to hypotension and other life-threatening events. We report a case in which septic shock developed within 12 hours of surgery that had incorporated clonidine in the anesthetic plan. Despite the use of clonidine, serum epinephrine and norepinephrine levels increased markedly in response to hypotension, which suggests preserved sympathetic responsiveness. Case Report A 57-yr-old man with a history of insulin-dependent diabetes and a pancreatic pseudocyst was admitted to the Johns Hopkins Hospital with painless jaundice, pruritus, and weight loss. A peripancreatic abscess was discovered and treated with percutaneous drainage and antibiotics. The patient later underwent partial pancreatectomy and drainage of peripancreatic abscess. Preoperative vital signs were: temperature (T) 37.8-38.2 degrees C, respiratory rate (R) 24 breaths per minute, pulse (P) 84-90 bpm, arterial blood pressure (BP) 120-140/70-90 mm Hg, and weight 68.6 kg. Medications included insulin, gentamicin, metronidazole, and ceftriaxone. The patient consented to enroll in a trial evaluating the effects of clonidine on stress hormones after moderate upper abdominal, nonvascular surgery [9]. He received clonidine 0.2 mg per os and a 10.3-cm2 clonidine patch (Catapres-TTS) at 11 PM the night prior to surgery and clonidine 0.3 mg per os at 6:15 AM the morning of surgery. The operation began at 7:45 AM and concluded at 1:45 PM. Intraoperative medications included thiamylal, lidocaine, pancuronium, morphine (20 mg total, titrated over the first hour of the case), isoflurane (0.6%-0.8%), and intermittent boluses of labetalol (30 mg total) for hypertension. At the end of the procedure, neuromuscular block was reversed (glycopyrrolate 0.6 mg and neostigmine 3 mg). The patient was tracheally extubated and admitted to the surgical intensive care unit. Estimated intraoperative blood loss was 500 mL, urine output was 700 mL, and fluid replacement included 4.1 L lactated Ringer's solution and 2 units packed red blood cells. On arrival at the surgical intensive care unit, vital signs were T 37.5 degrees C, P 96 bpm, R 12 breaths per minute (spontaneous), BP 137/89 mm Hg, and central venous pressure 2 cm H2 O. Maintenance fluids were begun at 126 mL/h. Over the next several hours, diminishing urine output, decreasing BP, increasing heart rate, and low central venous pressure prompted aggressive fluid resuscitation (1 L hetastarch, 2 units packed red blood cells, and 6 L crystalloid in addition to maintenance fluids). There was no indication of active bleeding. Increasing fever (Tmax 39.4 degrees C at 1 PM) was treated with 1.2 g rectal acetaminophen. Despite these maneuvers, vital signs 18 h postoperatively were T 38.1 degrees C, P 130 bpm, R 22 breaths per minute, and BP 79/44 mm Hg. The clonidine patch was removed, and vasopressor support (phenylephrine) was begun. Blood samples were obtained immediately prior to induction, as well as at 1, 6, 12, and 18 h postoperatively for determination of clonidine, norepinephrine, and/or epinephrine concentrations (high-pressure liquid chromatography, electrochemical detection). Plasma clonidine concentrations (Figure 1) were between 1 and 2 ng/mL and were similar to those of the nonseptic patients (n = 35) enrolled in the parent study. In contrast, serum epinephrine levels, although similar to preoperative values, were dramatically higher postoperatively in our patient and did not follow the normal pattern of slow postoperative decline (Figure 2a). Preoperative norepinephrine levels were comparable to those seen in clonidine-treated nonseptic patients but increased markedly postoperatively (Figure 2b). Serum norepinephrine levels are presented in the context of hemodynamic and other vital signs data in Figure 3.Figure 1: Serum clonidine concentrations immediately prior to induction and 1 and 18 h after arrival at the surgical intensive care unit. Concentrations in our patient (hatched bars) were similar to those of a cohort of 35 patients who received the same clonidine regimen and who underwent similar surgery (solid bar).Figure 2: Serum epinephrine (a) and norepinephrine (b) concentrations of our septic patient (hatched bar) and those of a cohort of 35 similarly treated patients (solid bar) immediately prior to induction and 1, 6, 12, and 18 h after arrival at the surgical intensive care unit.Figure 3: The serum norepinephrine concentration levels of our patient are shown in the context of vital signs simultaneously measured preoperatively and 1, 6, 12, and 18 h after arrival at the surgical intensive care unit.Discussion This patient received a clonidine regimen that provided therapeutic plasma clonidine levels throughout the perioperative period and is associated with improved intraoperative hemodynamic stability [1]. Despite the presence of this alpha2 agonist, the patient was able to generate a sympathetic response to sepsis and hypotension. This suggests that anesthetically effective doses of clonidine do not prevent increases in serum catecholamines in response to life-threatening events in the perioperative period. Clonidine can reduce blood pressure by inhibiting lower brainstem stimulation of sympathetic preganglionic neurons [10-12], which inhibits spinal preganglionic neurons [13] or inhibits peripheral norepinephrine release [14]. However, clonidine does not prevent reflex modulation of efferent sympathetic nerve traffic [15-18]. This persistent baroreceptor sensitivity is associated with the preserved ability to mount a catecholamine response [19] and may explain why patients who receive clonidine do not experience severe orthostasis [20,21]. Although our patient's perioperative plasma clonidine levels were similar to those observed in patients who received the same clonidine regimen as part of a concurrent trial, the initial postoperative plasma catecholamine levels in our septic patient were higher than those seen in the nonseptic clonidine-treated patients. Furthermore, while the nonseptic patients had decreasing serum epinephrine concentrations and constant serum norepinephrine levels postoperatively [2,3,22], serum catecholamine levels continued to increase postoperatively in the septic patient. This rise in catecholamine levels was likely due to the sepsis-induced decrease in blood pressure and suggests that the sympathetic nervous system retains the capacity to respond to hemodynamic stress despite the presence of alpha2 agonist therapy. Data regarding the "normal" catecholamine response to septic hypotension are not available. We cannot exclude the possibility that clonidine particularly attenuated the hypotension-induced increase in sympathetic nervous system activity. Epidural clonidine, which achieves similar plasma levels and higher cerebrospinal fluid levels than systemic clonidine [23], blunts the epinephrine response to hemorrhage-induced hypotension in sheep but not the norepinephrine response [24]. By reducing baseline catecholamine levels [25], alpha2 agonists may also induce changes in adrenergic receptor expression and/or signal transduction that alter the perioperative hemodynamic response to catecholamine [26]. However, the marked increase in catecholamine concentrations in response to hypotension demonstrated by our patient strongly suggests that the perioperative use of clonidine does not abolish adrenergic responses to stress.
