Search

Objectives: Appropriate resuscitation from hemorrhagic shock is critical to restore tissue perfusion and to avoid over-resuscitation. The objective of this study was to test the ability of a closed-loop diagnosis and resuscitation algorithm called resuscitation from shock using functional hemodynamic monitoring using invasive monitoring (ReFit1) and minimally invasive monitoring (ReFit2) to identify, treat, and stabilize a porcine model of severe hemorrhagic shock., Design: We created a ReFit algorithm using dynamic hemodynamic parameters of pulse pressure variation (PPV), stroke volume variation (SVV), dynamic arterial elastance (Eadyn = PPV/SVV), driven by mean arterial pressure (MAP), mixed venous oxygen saturation, and heart rate targets to define the need for fluids, vasopressors, and inotropes., Setting: University-based animal laboratory., Subjects: Twenty-seven female pigs., Interventions: Anesthetized, intubated, and ventilated (8 mL/kg) pigs were bled at 10 mL/min until a MAP of less than 40 mm Hg, held for 30 minutes, then resuscitated. The ReFit algorithm used the above dynamic parameters to drive computer-controlled infusion pumps to deliver blood, lactated Ringer's solution, norepinephrine, and in ReFit1 dobutamine. In four animals, after initial resuscitation from hemorrhagic shock, the ability of the ReFit1 algorithm to treat acute air embolism-induced pulmonary hypertension and right heart failure was also tested., Main Results: In 10 ReFit1 and 17 ReFit2 animals, the time to stabilization from shock was not dissimilar to open controlled resuscitation performed by an expert physician (52 ± 12, 50 ± 13, and 60 ± 15 min, respectively) with similar amounts of fluids and norepinephrine needed. In four ReFit1 animals after initial stabilization, the algorithm successfully resuscitated the animals after inducing an acute air embolism right heart failure, with all animals recovering stability within 30 minutes., Conclusions: Our physiologically based functional hemodynamic monitoring-centered closed-loop resuscitation system can effectively diagnose and treat cardiovascular shock due to hemorrhage and air embolism., Competing Interests: Dr. Pinsky, Wertz, and Dubrawski’s institutions received funding from the U.S. Department of Defense (DoD). Dr. Pinsky received funding from Baxter Medical and Masimo; he received support for article research from the National Institutes of Health and the DoD (BAA W81XWH-19-C-0101). Drs. Pinsky and Wertz disclosed the off-label product use of closed-loop control but of existing Food and Drug Administration-approved monitoring devices used in the approved fashion. Dr. Gomez’s institution received funding from the DoD (Trauma Care in a Rucksack, grant number: BAAW81XWH-17-R-BAA180061, Department of Defense), Baxter, and bioMerieux; he received funding from Trilinear Bioventures AcelRx. Dr. Poropatich received support for article research from the DoD; he disclosed government work. Mr. Leonard has disclosed that he does not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support., Data Sources: Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated., Study Selection, Data Extraction, and Synthesis: Data from relevant publications were reviewed and applied as indicated., Conclusions: The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside., Competing Interests: Dr. Gomez’s institution received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, Baxter, and bioMérieux; he received funding from Trilinear Bioventures, AclRx, Novartis, and the National Kidney Foundation. Dr. Burkhoff received funding from PVLoops. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Sepsis remains the leading cause of mortality in critically ill patients, and mortality is increased when acute kidney injury (AKI) occurs. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends the implementation of supportive measures in patients at high risk for AKI. However, it remains unclear to what extent these nephroprotective measures are implemented in daily clinical practice in critically ill patients, especially those with high-risk exposures such as sepsis., Methods: We analyzed the Medical Information Mart for Intensive Care IV (MIMIC-IV) database to identify septic patients with and without AKI. The primary outcome of interest was the adherence to the KDIGO bundle consisting of avoidance of nephrotoxic agents, implementation of a functional hemodynamic monitoring, optimization of perfusion pressure and volume status, close monitoring of renal function, avoidance of hyperglycemia, and avoidance of radiocontrast agents. Secondary outcomes included the development of AKI, progression of AKI, the use of renal replacement therapy (RRT), mortality, and a composite end point consisting of progression of AKI and mortality within 7 days., Results: Our analysis included 34,679 patients with sepsis with 1.6% receiving the complete bundle (10% received 5, 42.3% 4, 35.4% 3, and 9.8% 2 bundle components). In 56.4%, nephrotoxic agents were avoided, and hemodynamic optimization was reached in 86.5%. Secondary end points were improved in patients with bundle adherence. Avoidance of nephrotoxic drugs and optimization of hemodynamics were significantly associated with lower rates of AKI and improved patient outcomes, including 30-day mortality., Conclusions: Implementation of the KDIGO bundle is poor in patients with sepsis but may be associated with improved outcomes., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 International Anesthesia Research Society.)

This study evaluated differences in efficacy and safety outcomes with bivalirudin compared with unfractionated heparin (UFH) in patients with cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation (VA ECMO). We performed a retrospective study at an academic medical center that included patients greater than 18 years of age supported with VA ECMO due to cardiogenic shock from January 2009 to February 2021. The primary endpoint was ECMO-associated thrombotic events normalized to duration of ECMO support. Secondary safety endpoints included major bleeding (per ELSO criteria) and blood product administration. Overall, 143 patients were included in our analysis with 54 having received bivalirudin and 89 having received UFH. Median duration of ECMO support was 92 (interquartile range, 56-172) hours. ECMO-associated thrombotic events per ECMO day were significantly less among those that received bivalirudin ( P < 0.001). In adjusted regression, bivalirudin was independently associated with an increased time to thrombosis when compared with UFH (Exp[B] -3.8; 95% confidence interval, 1.7-8.8; P = 0.002). Patients receiving bivalirudin experienced less major bleeding events ( P = 0.02) with less total red blood cell and fresh frozen plasma administration ( P = 0.04 and P = 0.03, respectively). Bivalirudin is a safe and efficacious alternative to UFH in patients requiring VA ECMO for cardiogenic shock., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2022.)

Objectives: Extracorporeal membrane oxygenation is a life-sustaining therapy for severe respiratory failure. Extracorporeal membrane oxygenation circuits require systemic anticoagulation that creates a delicate balance between circuit-related thrombosis and bleeding-related complications. Although unfractionated heparin is most widely used anticoagulant, alternative agents such as bivalirudin have been used. We sought to compare extracorporeal membrane oxygenation circuit thrombosis and bleeding-related outcomes in respiratory failure patients receiving either unfractionated heparin or bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation support., Design: Retrospective cohort study., Setting: Single-center, cardiothoracic ICU., Patients: Consecutive patients requiring venovenous extracorporeal membrane oxygenation who were maintained on anticoagulation between 2013 and 2020., Internventions: IV bivalirudin or IV unfractionated heparin., Measurements and Main Results: Primary outcomes were the presence of extracorporeal membrane oxygenation in-circuit-related thrombotic complications and volume of blood products administered during extracorporeal membrane oxygenation duration. One hundred sixty-two patients receiving unfractionated heparin were compared with 133 patients receiving bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation. In patients receiving bivalirudin, there was an overall decrease in the number of extracorporeal membrane oxygenation circuit thrombotic complications (p < 0.005) and a significant increase in time to circuit thrombosis (p = 0.007). Multivariable Cox regression found that heparin was associated with a significant increase in risk of clots (Exp[B] = 2.31, p = 0.001). Patients who received bivalirudin received significantly less volume of packed RBCs, fresh frozen plasma, and platelet transfusion (p < 0.001 for each). There was a significant decrease in the number major bleeding events in patients receiving bivalirudin, 40.7% versus 11.7%, p < 0.001., Conclusions: Patients receiving bivalirudin for systemic anticoagulation on venovenous extracorporeal membrane oxygenation experienced a decrease in the number of extracorporeal membrane oxygenation circuit-related thrombotic events as well as a significant decrease in volume of blood products administered., Competing Interests: Dr. Gomez’s institution received funding from TES Pharma. Dr. Arlia disclosed off-label product use of extracorporeal membrane oxygenation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: To compare 5% albumin with 0.9% saline for large-volume resuscitation (> 60 mL/Kg within 24 hr), on mortality and development of acute kidney injury., Design: Retrospective cohort study., Setting: Patients admitted to ICUs in 13 hospitals across Western Pennsylvania. We analyzed two independent cohorts, the High-Density Intensive Care databases: High-Density Intensive Care-08 (July 2000 to October 2008, H08) and High-Density Intensive Care-15 (October 2008 to December 2014, H15)., Patients: Total of 18,629 critically ill patients requiring large-volume resuscitation., Interventions: Five percent of albumin in addition to saline versus 0.9% saline., Measurements and Main Results: After excluding patients with acute kidney injury prior to large-volume resuscitation, 673 of 2,428 patients (27.7%) and 1,814 of 16,201 patients (11.2%) received 5% albumin in H08 and H15, respectively. Use of 5% albumin was associated with decreased 30-day mortality by multivariate regression in H08 (odds ratio 0.65; 95% CI 0.49-0.85; p = 0.002) and in H15 (0.52; 95% CI 0.44-0.62; p < 0.0001) but was associated with increased acute kidney injury in H08 (odds ratio 1.98; 95% CI 1.56-2.51; p < 0.001) and in H15 (odds ratio 1.75; 95% CI 1.58-1.95; p < 0.001). However, 5% albumin was not associated with persistent acute kidney injury and resulted in decreased major adverse kidney event at 30, 90, and 365 days. Propensity matched analysis confirmed similar associations with mortality and acute kidney injury., Conclusions: During large-volume resuscitation, 5% albumin was associated with reduced mortality and major adverse kidney event at 30, 90, and 365 days. However, a higher rate of acute kidney injury of any stage was observed that did not translate into persistent renal dysfunction., Competing Interests: Dr. Gomez’s institution received funding from the National Institutes of Health (NIH)/National Institute of General Medical Sciences K08 grant 1K08GM117310-01A1 and TES Pharma. Drs. Gomez, Bataineh, Clermont, and Kellum received support for article research from the NIH. Drs. Bataineh’s and Kellum’s institutions received funding from Grifols and the NIH. Dr. Clermont received funding from the NIH and the National Science Foundation, and he disclosed that he is also Chief Medical Officer and owns equity in NOMA AI Inc. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.

Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014., Competing Interests: Declaration of interest: C.I. has received research grants the Dutch Kidney Foundation (grant C 09.2290 and grant 14OIP11), Bussum, The Netherlands. C.I. has also received honoraria and independent research grants from Fresenius-Kabi, Bad Homburg, Germany; Baxter Health Care, Deerfield, Illinois and AM-Pharma, Bunnik, The Netherlands. C.I. has developed SDF imaging and is listed as inventor on related patents commercialized by MicroVision Medical (MVM) under a license from the Academic Medical Center (AMC). C.I. has received consultant fees from MVM in the past, but has not been involved with this company for more than five years now, except that he still holds shares. Braedius Medical, a company owned by a relative of C.I., has developed and designed a hand-held microscope called Cyto-Cam-IDF imaging; however, C.I. has no financial relation with Braedius Medical of any sort. P.M., T.N., G.O., H.G., and G.H. have no declared interests. J.K. has received consulting fees from Abbott, Aethlon, Alere, Alung, AM Pharma, Astute Medical, Atox Bio, Baxter, Cytosorbents, venBio, Gambro, Grifols, Roche, Spectral Diagnostics, Sangart, and Siemens. J.K. has also received research grants from Alere, Astute Medical, Atox Bio, Bard, Baxter, Cytosorbents, Gambro, Grifols, Kaneka, and Spectral Diagnostics, and has licensed technologies through the University of Pittsburgh to Astute Medical, Cytosorbents, and Spectral Diagnostics. P.M. has received consulting fees from AM Pharma, Abbvie, FAST Diagnostics. He has also received research funding from Abbott, Alere, EKF Diagnostics. D.D.B. is a member of the Advisory Board Baxter-Gambro renal, and Nestlé Health Sciences. He received research grants and material for studies from Edwards Lifesciences, Vytech, and Imacor. P.M., T.N., G.O., H.G., and G.H. have no declared interests.

Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long-term morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness. However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used both as a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide.

Unlabelled: Traumatic injury is a significant cause of morbidity and mortality worldwide. Microcirculatory activation and injury from hemorrhage contribute to organ injury. Many adaptive responses occur within the microcirculatory beds to limit injury including upregulation of heme oxygenase (HO) enzymes, the rate-limiting enzymes in the breakdown of heme to carbon monoxide (CO), iron, and biliverdin. Here we tested the hypothesis that CO abrogates trauma-induced injury and inflammation protecting the microcirculatory beds., Methods: C57Bl/6 mice underwent sham operation or hemorrhagic shock to a mean arterial pressure of 25 mmHg for 120 minutes. Mice were resuscitated with lactated Ringer's at 2× the volume of maximal shed blood. Mice were randomized to receive CO-releasing molecule or inactive CO-releasing molecule at resuscitation. A cohort of mice was pretreated with tin protoporphyrin-IX to inhibit endogenous CO generation by HOs. Primary mouse liver sinusoidal endothelial cells were cultured for in vitro experiments., Results: Carbon monoxide-releasing molecule protected against hemorrhagic shock/resuscitation organ injury and systemic inflammation and reduced hepatic sinusoidal endothelial injury. Inhibition of HO activity with tin protoporphyrin-IX exacerbated liver hepatic sinusoidal injury. Hemorrhagic shock/resuscitation in vivo or cytokine stimulation in vitro resulted in increased endothelial expression of adhesion molecules that was associated with decreased leukocyte adhesion in vivo and in vitro., Conclusions: Hemorrhagic shock/resuscitation is associated with endothelial injury. Heme oxygenase enzymes and CO are involved in part in diminishing this injury and may prove useful as a therapeutic adjunct that can be harnessed to protect against endothelial activation and damage.

Objectives: Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables., Design: Multicenter observational point prevalence study., Setting: The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide., Patients: A heterogeneous ICU population consisting of 501 patients., Interventions: None., Measurements and Main Results: Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10-21), a Sequential Organ Failure Assessment score of 5 (2-8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67-4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963-0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11-3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28-3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30-8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients., Conclusions: In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

Purpose of Review: Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI. Considerable evidence now suggests that the pathogenic mechanisms of sepsis-induced AKI are different from those seen in other causes of AKI. This review focuses on the recent advances in this area and discusses possible therapeutic interventions that might derive from these new insights into the pathogenesis of sepsis-induced AKI., Recent Findings: The traditional paradigm that sepsis-induced AKI arises from ischemia has been challenged by recent evidence that total renal blood flow in is not universally impaired during sepsis, and AKI can develop in the presence of normal or even increased renal blood flow. Animal and human studies suggest that adaptive responses of tubular epithelial cells to injurious signals are responsible for renal dysfunction. Simultaneously occurring renal inflammation and microcirculatory dysfunction further amplify these mechanisms., Summary: An understanding of the pathologic mechanisms of sepsis-induced AKI emphasizes the important role of maladaptive responses to the septic insult. Preventive and therapeutic measures should be based on counteracting these maladaptive responses of tubular epithelial cells, inflammation, and microvascular dysfunction.

Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a "unifying theory" to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI.

This study evaluated the outcome of severe cerebral palsy patients (Gross Motor Function Classification System level IV and V) treated by simultaneous percutaneous pelvic osteotomy and intertrochanteric varus shortening osteotomy for hip subluxation or dislocation between 2002 and 2011. Twenty-four patients (30 hips) with an average age of 9.4 years (5-16.5) were reviewed at a mean follow-up of 35.9 months (6-96). Percutaneous pelvic osteotomy lasted on average 30 min/patient per side (25-40) and was always performed through a skin incision of 2-3 cm. The migration percentage and acetabular angle were assessed on plain radiographs. The mean Reimers' migration percentage improved from 67.1% (42-100) preoperatively to 7.7% (0-70) at the last follow-up and the mean acetabular angle improved from 31.8° (22-48) to 15.7° (5-27). Five patients presented complications: one redislocation, one bone graft dislodgement, and three with avascular necrosis of the femoral head. This study should be considered as a pilot study. These results indicate that this combined approach is an effective, reliable, and minimally invasive alternative method for the treatment of spastic dislocated hips in severe cerebral palsy patients with an outcome similar to standard techniques reported in the literature.

Ten hypertensive subjects were studied at the Vargas Medical School in Caracas, Venezuela. They were submitted to submaximal treadmill exercises according to Bruce's protocol under treatment with dopaminergic drugs (metoclopramide, bromocriptine). Before and during submaximal exercises, metoclopramide caused a hypotensive effect accompanied by an increased heart rate, which was blocked by the administration of bromocriptine. We conclude that a probable dopaminergic modulatory influence takes place during exercise.

Enalapril is an effective agent in the treatment of mild to severe hypertension. It is equally effective in elderly and young adult patients but appears to be more effective in white than in black hypertensive patients. Following treatment with enalapril, an assessment of maximum exercise performance found a decrease in total peripheral resistance without significant changes in cardiac output, heart rate, or stroke volume compared with pretreatment values. In addition, there have been reports of reversal of left ventricular hypertrophy in enalapril-treated hypertensive patients. Enalapril is also effective and well tolerated in hypertensive patients with renal impairment of varying etiology. The most common adverse experiences reported in controlled clinical trials were headache (5.2%), dizziness (4.3%), and fatigue (3.0%). In high-risk hypertensive patients, no enalapril-treated neutropenia, proteinuria, dysgeusia, or ageusia were reported. It may be concluded that the benefit-to-risk ratio of enalapril is among the best of the antihypertensive therapies currently available.

Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6-8 h after oral dosing. Lisinopril bioavailability (approximately 25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2-3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reductions is 11-15% in systolic and 13-17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.

Enalapril, a long-acting, non-sulfhydryl, angiotensin converting enzyme (ACE) inhibitor, is well absorbed after oral administration, and hydrolised to its bioactive form, enalaprilic acid (EA). Administration with food does not affect its bioavailability; elimination is predominantly renal. Peak serum EA concentrations occur 4 h after an oral dose; its serum half-life is approximately 35 h, and steady state is achieved by the fourth day of treatment. Enalapril controls blood pressure in essential and renovascular hypertension without affecting heart rate or cardiovascular reflexes. It also decreases serum concentrations of ACE (for greater than 24 h), angiotensin II and aldosterone, and increases plasma renin activity. Once and twice-daily regimens are equally effective. In patients with congestive heart failure refractory to digitalis and diuretics, enalapril increases cardiac output and decreases pulmonary capillary wedge pressure. Long-term treatment produces improvement in NYHA functional classification, exercise capacity and ejection fraction. Human experience to date indicates that enalapril is safe and well tolerated.

This study was undertaken to evaluate whether, after long-term enalapril administration tachyphylaxis to the blockade of angiotensin II (Ang II) generation occurs. After a mean follow-up of 24 months, six patients taking enalapril once daily with or without an associated diuretic were studied for 7 h in hospital. Blood pressure, heart rate, plasma converting enzyme activity, angiotension I (Ang I), Ang II and aldosterone were measured before and 2, 4 and 6 h after the morning dose of enalapril. While blood pressure remained unchanged after drug administration, Ang II and aldosterone levels fell following enalapril to very low levels, similar to those observed during the initial study, at the time of peak effect of enalapril. After enalapril administration, there was no correlation between plasma Ang I and Ang II suggesting that blockade of Ang II generation was complete, excluding the possibility of Ang I related interference with the Ang II measurements. These results indicate that virtually complete angiotension converting enzyme inhibition can still be achieved after prolonged use of enalapril.

Enalapril is administered as the ethyl ester of the potent angiotensin converting enzyme (ACE) inhibitor enalaprilat. As such, it is 60% absorbed and 40% bioavailable as the active species. Absorption is not affected by food. Serum concentrations are proportional to dose, less a small drug residue apparently bound to the enzyme. The half-life for accumulation is approximately 11 h. The drug is eliminated by the kidney without further metabolism. Maximum inhibition of plasma ACE occurs 2-4 h after administration and persists for more than 24 h with clinical doses. ACE inhibition is associated with increases in plasma renin and angiotensin I levels, decreases in angiotensin II and aldosterone concentrations and reduction in blood pressure. All of these events are closely correlated when analysed statistically. The clinical and haemodynamic effects of these actions are addressed in other papers.

The acute hypotensive response to oral and parenteral enalapril (E) and lisinopril (LI) was assessed in 24 patients with chronic congestive heart failure in two open, randomized, balanced, crossover studies. In the E study, 12 patients received each of three treatments: a single oral dose of 10 mg E, a single intravenous bolus of 5 mg E, and a single intravenous bolus of 5 mg enalaprilat (ET). In the LI study, 12 patients received each of two treatments: a single oral dose of 10 mg LI and a single intravenous bolus of 5 mg LI. Intraarterial blood pressure was measured continuously. Significant decreases from baseline in mean arterial pressure (MAP) were observed in all cases, starting at 15 min. The maximal hypotensive effect (MAP; mean +/- SD) was greatest and the nadir earliest for intravenous ET (-30 +/- 7 mm Hg at 75 min) compared with oral E (-25 +/- 10 mm Hg at 210 min) and intravenous E (-19 +/- 10 mm Hg at 195 min). Oral E and intravenous E had similar onsets of action. The maximal reduction following oral LI (-19 +/- 13 mm Hg at 210 min) was similar to oral E and intravenous E. The effect of intravenous LI (-25 +/- 9 mm Hg at 105 min) was similar to that of intravenous ET. Among the parenteral treatments, E produced the most gradual and least pronounced reduction in blood pressure, and may be best suited for use in the acute situation to minimize the risk of abrupt hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)