End-organ Effects Research Articles

The cardiac neuronal hierarchy and susceptibility to arrhythmias

The cardiac neuronal hierarchy and susceptibility to arrhythmias

AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions

AbstractAbstract 4044 Background:Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims:To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods:Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results:A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with <10% plasma cells (p=NS). Discussion:As defined by bone marrow plasma cell involvement, a strikingly high percentage (84%) of AL amyloidosis patients would be considered to have concurrent myeloma. This figure is much higher than has been traditionally quoted in the literature, likely due to the utilization of newer methods of counting plasma cells. There was a low prevalence of myeloma-associated end-organ effects (hypercalcemia, anemia, renal insufficiency, lytic bone lesions), and a myeloma diagnosis had no impact on survival. Conclusion:In this cohort of AL amyloid patients, concomitant myeloma was present in the vast majority of patients using modern diagnostic techniques. The significance of this diagnosis appears to be minimal – calling into question whether the diagnostic criteria for myeloma should be redefined in this population. Disclosures:Witteles:Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding.

Advances in the treatment of gastroenteropancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and heterogeneous class of neoplasms. While surgical resection is the mainstay of treatment, non-surgical therapies play a role in the setting of unresectable and metastatic disease. The goals of medical therapy are directed both at alleviating symptoms of peptide release and shrinking tumor mass. Biotherapies such as somatostatin analogs and interferon can decrease the secretion of peptides and inhibit their end-organ effects. A second objective for treatment of unresectable GEP-NETs is limiting tumor growth. Options for limiting tumor growth include somatostatin analogs, systemic chemotherapy, locoregional therapies, ionizing radiation, external beam radiation, and newer targeted agents. In particular, angiogenesis inhibitors, tyrosine kinase inhibitors, and mTOR inhibitors have shown early promising results. The rarity of these tumors, their resistance to standard chemotherapy, and the excellent performance status of most of these patients, make a strong argument for consideration of novel therapeutic trials.

Prediction of Adverse Drug Reactions Using Decision Tree Modeling

Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

Autonomic Nervous System Monitoring of Patients with Excess Parasympathetic Responses to Sympathetic Challenges—Clinical Observations

A common assumption regarding the autonomic nervous system is that one branch either opposes the other or does not respond during physiological challenges. Recently, this assumption has been challenged based on clinical observations of unprovoked parasympathetic (P) excess (PE) during sympathetic (S) stimulation, an abnormal response. Over a three-year period, serial autonomic profiling of 1,340 patients was performed using the P and S method, which yields independent measures of P and S activity obtained from time–frequency analyses of respiratory activity and heart rate variability (ANX 3.0, ANSAR Medical Technologies, Inc., Philadelphia, PA). Within this cohort, patients with PE reported symptoms of sleep difficulties, poor peripheral circulation, general malaise, depression, frequent headache or migraines, gastrointestinal upset, and dizziness when standing. However, they demonstrated normal heart rate and blood pressure and no other apparent causes for their symptoms. The results of this study highlight the clinical effects of PE and indicate that, depending on patient history, carvedilol may be effective for patients with cardiovascular disease (CVD) and low-dose anticholinergics for patients without CVD. In cases where end-organ effects are not yet presented, patients may be weaned from therapy once PE is resolved.

Differences in pharmacology and their translation into differences in clinical efficacy – a comparison of the renin angiotensin blocking agents irbesartan and losartan

Importance of the field: Guidelines recommend five antihypertensive drug classes, but which particular drug to choose is up to the treating physician. We aimed at an in-depth comparison of two frequently used angiotensin receptor blockers to provide evidence for this decision.Areas covered in this review: Pharmacology of irbesartan and losartan, their blood-pressure-lowering efficacy, their tolerability/safety, end-organ protective effects and economic evaluation.What the reader will gain: Both drugs differ in their oral bioavailability, potential for food interactions, degree of metabolism, dosing interval, time to peak, volume of distribution and terminal half-life. Irbesartan provides a greater and longer-lasting antihypertensive effect and was determined to be cost effective over losartan in Denmark and Sweden. Irbesartan was more effective in preventing deterioration of kidney function in patients with diabetic nephropathy, being cost effective from a German perspective. There is only one end point trial for either drug in patients with left ventricular hypertrophy, heart failure and atrial fibrillation, but no direct comparison.Take home message: There is an incremental clinical benefit of irbesartan over losartan in the treatment of hypertension and diabetic nephropathy which can be substantiated by corresponding preclinical study evidence. This has translated into an economic benefit in a number of country-specific evaluations.

Inhalational Anesthesia: Basic Pharmacology, End Organ Effects, and Applications in the Treatment of Status Asthmaticus

The potent inhalational anesthetic agents are used on a daily basis to provide intraoperative anesthesia. Given their beneficial effects on airway tone and reactivity, they also have a role in the treatment of status asthmaticus that is refractory to standard therapy. Although generally not of clinical significance, these agents can affect various physiological functions. The potent inhalational anesthetic agents decrease mean arterial pressure and myocardial contractility. The decrease in mean arterial pressure reduces renal and hepatic blood flow. Secondary effects on end-organ function may result from the metabolism of these agents and the release of inorganic fluoride. The following article reviews the history of inhalational anesthesia, the physical structure of the inhalational anesthetic agents, their end-organ effects, reports of their use for the treatment of refractory status asthmaticus in the intensive care unit (ICU) patient, and special considerations for their administration in this setting including equipment for their delivery, scavenging, and monitoring.

Low-frequency tuning in the human vestibular–ocular projection is determined by both peripheral and central mechanisms

We recently reported that a major contribution to the low-frequency tuning and sensitivity of the human vestibular system is the biomechanical properties of the vestibular end-organs. In the current paper, we investigate the contribution of additional mechanisms to low-frequency tuning. We compared the response properties of the vestibular system in 6 human volunteers to trains of 2ms pulses of sound and transmastoid vibration using pulse repetition frequencies of 12.5, 25, 50, 100, 200 and 400Hz. Measurements were made using two separate pathways arising from the vestibular apparatus: to the neck using vestibular evoked myogenic potentials (VEMPs), and to the eyes using ocular vestibular evoked myogenic potentials (OVEMPs). For both sound and vibration the two response pathways produced different tuning to pulse trains. The vestibulo-ocular pathway was characterised by a band-pass tuning with best frequency of 100Hz whereas the vestibulo-collic pathway showed a peak at 400Hz with sound only. These results suggest that properties of the vestibulo-ocular pathway also contribute to the low-frequency tuning that occurs for the OVEMP, in addition to previously reported end-organ effects.

How Can Urine Microscopy Influence the Differential Diagnosis of AKI?

Acute kidney injury (AKI), which is associated with increased morbidity and mortality, is a relatively common complication in hospitalized patients (1–3). The most common cause of AKI in hospitalized patients is acute tubular necrosis (ATN) followed by prerenal azotemia (4). Because therapies and prognoses for prerenal azotemia and ATN differ substantially, early clinical differentiation is desirable to assist the clinician in patient treatment. For example, an early diagnosis of prerenal azotemia would facilitate early treatment to correct volume status and potentially prevent ATN. Also, in the setting of AKI from ATN, it would avoid worsening of the clinical course with incorrect therapies such as excessive volume resuscitation leading to pulmonary edema and other untoward end organ effects. Presently, the diagnosis of AKI is primarily based on changes in serum creatinine concentration, blood urea nitrogen, and urine output. These biomarkers are very helpful in diagnosis of AKI but rarely help in discriminating between ATN and prerenal azotemia. Urine biochemistry measures, such as fractional excretion of sodium and urea, also provide important information in the differentiation of AKI into traditional categories of prerenal azotemia and ATN (5–9) when the patient is not on diuretics or does not have underlying chronic kidney disease. Urinalysis and urine microscopy are also commonly used to differentiate these two causes of AKI and are generally accepted as critical for the evaluation of patients with kidney disease. Urine microscopy is the best surrogate for the histologic state of the kidney and is not affected by underlying chronic kidney disease or presence of medications. As a result, urine sediment analysis is considered an integral part of the clinical workup of kidney disease in hospitalized patients with AKI. Urinary microscopy in patients with ATN classically is described as containing renal tubular epithelial cells, renal tubular epithelial …

Murine Models of Vpr-Mediated Pathogenesis

HIV viral protein r (Vpr) exerts a variety of cellular effects, including modulation of transcription and cytokine production, apoptosis, and cell cycle arrest. Vpr induces these affects by mechanisms that include inhibition of NF-kappaB activation, inducing mitochondrial injury, and promoting proteasomal degradation of cellular factor(s) leading to cell cycle arrest. Murine models have provided invaluable contributions to our understanding of HIV pathogenesis, however many of the HIV-1 proteins, including Vpr, differ in their cellular effects depending upon cell type and species-specific factors. Since the majority of in vivo studies elucidating the role of Vpr in disease pathogenesis have utilized murine models, it is critical to understand the species-specific factors that may affect Vpr function. In this manuscript, we review the cellular pathways and end organ effects of Vpr that have been studied in murine cell lines and mouse models, and discuss the relevance of these studies to the role of Vpr in disease in persons living with HIV/AIDS.

Hyperglycemia Induces a Dynamic Cooperativity of Histone Methylase and Demethylase Enzymes Associated With Gene-Activating Epigenetic Marks That Coexist on the Lysine Tail

OBJECTIVEResults from the Diabetes Control Complications Trial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) Study and more recently from the U.K. Prospective Diabetes Study (UKPDS) have revealed that the deleterious end-organ effects that occurred in both conventional and more aggressively treated subjects continued to operate >5 years after the patients had returned to usual glycemic control and is interpreted as a legacy of past glycemia known as “hyperglycemic memory.” We have hypothesized that transient hyperglycemia mediates persistent gene-activating events attributed to changes in epigenetic information.RESEARCH DESIGN AND METHODSModels of transient hyperglycemia were used to link NFκB-p65 gene expression with H3K4 and H3K9 modifications mediated by the histone methyltransferases (Set7 and SuV39h1) and the lysine-specific demethylase (LSD1) by the immunopurification of soluble NFκB-p65 chromatin.RESULTSThe sustained upregulation of the NFκB-p65 gene as a result of ambient or prior hyperglycemia was associated with increased H3K4m1 but not H3K4m2 or H3K4m3. Furthermore, glucose was shown to have other epigenetic effects, including the suppression of H3K9m2 and H3K9m3 methylation on the p65 promoter. Finally, there was increased recruitment of the recently identified histone demethylase LSD1 to the p65 promoter as a result of prior hyperglycemia.CONCLUSIONSThese studies indicate that the active transcriptional state of the NFκB-p65 gene is linked with persisting epigenetic marks such as enhanced H3K4 and reduced H3K9 methylation, which appear to occur as a result of effects of the methyl-writing and methyl-erasing histone enzymes.

Coronary blood flow responses to physiological stress in humans

Animal reports suggest that reflex activation of cardiac sympathetic nerves can evoke coronary vasoconstriction. Conversely, physiological stress may induce coronary vasodilation to meet an increased metabolic demand. Whether the sympathetic nervous system can modulate coronary vasomotor tone in response to stress in humans is unclear. Coronary blood velocity (CBV), an index of coronary blood flow, can be measured in humans by noninvasive duplex ultrasound. We studied 11 healthy volunteers and measured beat-by-beat changes in CBV, blood pressure, and heart rate during 1) static handgrip for 20 s at 10% and 70% of maximal voluntary contraction; 2) lower body negative pressure at -10 and -30 mmHg for 3 min each; 3) cold pressor test for 90 s; and 4) hypoxia (10% O(2)), hyperoxia (100% O(2)), and hypercapnia (5% CO(2)) for 5 min each. At the higher level of handgrip, mean blood pressure increased (P < 0.001), whereas CBV did not change [P = not significant (NS)]. In addition, during lower body negative pressure, CBV decreased (P < 0.02; and P < 0.01, for -10 and -30 mmHg, respectively), whereas blood pressure did not change (P = NS). The dissociation between the responses of CBV and blood pressure to handgrip and lower body negative pressure is consistent with coronary vasoconstriction. During hypoxia, CBV increased (P < 0.02) and decreased during hyperoxia (P < 0.01), although blood pressure did not change (P = NS), suggesting coronary vasodilation during hypoxia and vasoconstriction during hyperoxia. In contrast, concordant increases in CBV and blood pressure were noted during the cold pressor test, and hypercapnia had no effects on either parameter. Thus the physiological stress known to be associated with sympathetic activation can produce coronary vasoconstriction in humans. Contrasting responses were noted during systemic hypoxia and hyperoxia where mechanisms independent of autonomic influences appear to dominate the vascular end-organ effects.

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

Complete estrogen blockade remains under investigation as a means to optimize anti-estrogen therapy in breast cancer thus both the efficacy and end-organ toxicities are of interest with combinations. We hypothesized that a steroidal aromatase inhibitor (AI) atamestane (ATA) alone, and in combination with the anti-estrogens tamoxifen (TAM) or toremifene (TOR) would have beneficial effects in ovariectomized (OVX) rats on key end-organ functions including bone and lipid metabolism and on the endometrium. Significant positive effects on bone were noted with ATA, TOR, TAM, ATA + TOR, or ATA + TAM. TOR, TAM, ATA + TOR, or ATA + TAM caused significant decreases in serum cholesterol and low-density lipoprotein cholesterol whereas ATA had no effect. Uterine weight and epithelium lining height were not increased by ATA but were by TOR and TAM. No significant differences were found in the key parameters outlined above between OVX rats given TOR and ATA + TOR, or TAM and ATA + TAM. Our data show that ATA in combination with TOR or TAM is equivalent to TOR or TAM alone in terms of end-organ effects within a range of clinically relevant doses. Further studies of combinations of AIs with anti-estrogens on end-organ function are merited.

Pharmacogenetics and pharmacogenomics of endocrine agents for breast cancer

The clinician caring for women with early breast cancer is keenly aware of the variability observed when endocrine therapy with tamoxifen or the aromatase inhibitors (AIs) is employed. This is seen in outcomes of the disease in terms of recurrence but also, strikingly in some cases, in terms of adverse events. This can be seen in the case of AIs, in which some women develop disabling musculoskeletal events that result in their discontinuing therapy, whereas the majority develops no such adverse events. The same is true of other adverse events such as deep venous thrombosis, endometrial cancer and hot flashes in the case of tamoxifen. In the past, the focus in selection of therapy for women with breast cancer has been almost exclusively on the characteristics of the tumour (for example, oestrogen receptor [ER] and human epidermal growth factor receptor [HER]-2), with essentially no attention given to the genetic make-up of the patient. Pharmacogenetics and pharmacogenomics involve the study of the role played by inheritance in individual variation in drug response phenotypes such as disease outcomes and end organ effects, including adverse events. These terms are often used interchangeably but, strictly speaking, pharmacogenetics refers to the study of a gene or a number of genes, such as those involved with a pathway, whereas pharmacogenomics involves the entire genome. We have truly entered the era of pharmacogenomics with the introduction of genome-wide association studies (GWASs). Pharmacogenetics/pharmacogenomics have the clinical goals of better selecting responsive patients, maximizing drug efficacy and minimizing adverse reactions. Pharmacokinetics considers factors such as metabolism and transport that influence drug concentrations at the target(s), whereas pharmacodynamics considers factors that influence the response of the target(s), for example receptors, enzymes, transporters and downstream signalling molecules, to the drug. Endocrine therapy represents the most important therapeutic modality for those women whose tumours are potentially endocrine sensitive, as indicated by expression of the ER and/or progesterone receptor. The selective ER modulator tamoxifen has been the most important therapeutic agent in breast cancer for the past three decades. Tamoxifen has received approval from the US Food and Drug Administration for the full spectrum of breast cancer from metastatic disease to those women who are at higher risk for developing breast cancer. In addition, tamoxifen has received approval for treatment of men with metastatic breast cancer and is commonly used in the adjuvant setting. During the past decade the third generation AIs anastrozole, exemestane and letrozole have emerged as important additions to the clinician's armamentarium against breast cancer. They appear to be more efficacious than tamoxifen in the advanced disease setting [1], have become clearly established in the adjuvant setting [2] and are a major focus of ongoing trials in the prevention setting in postmenopausal women [3]. Tamoxifen and the AIs have recently become foci of intense pharmacogenetic/pharmacogenomic research [4].

Preliminary Experience With Dexmedetomidine for Monitored Anesthesia Care During ENT Surgical Procedures

Dexmedetomidine is an alpha2-adrenergic agonist that produces anxiolysis, amnesia, sedation, potentiation of opioid analgesia, and sympatholysis. It is currently approved by the U.S. Food & Drug Administration for the sedation of adults in the intensive care setting for up to 24 hours during mechanical ventilation. Given its beneficial sedative and anxiolytic properties and limited adverse effect profile, it has been used in several other clinical scenarios. The authors present their experience using dexmedetomidine for monitored anesthesia care (MAC) during "awake" ENT procedures such as thyroplasty, a procedure requiring a patient to verbalize when requested but to otherwise remain immobile to allow for completion of the procedure, and in a patient with post-polio syndrome with poor pulmonary reserve requiring esophagoscopy with dilation and botulinum toxin injection for cricopharyngeal dysfunction. Our preliminary experience suggests that dexmedetomidine provides effective sedation as the primary agent for MAC during such procedures in adult patients. The end-organ effects of dexmedetomidine and previous reports of its use during MAC are reviewed.

Left Ventricular Mass Index in Children with White Coat Hypertension

To determine whether children with white coat hypertension (WCH) have evidence of target-organ damage by comparing the left ventricular mass index (LVMI) of subjects with WCH with that of matched normotensive and hypertensive controls. Each subject in the WCH group was matched by body mass index (BMI; +/- 10%), age (+/- 1 year), and sex to a normotensive control and a hypertensive control. Echocardiograms were reviewed to determine the LVMI for each subject. These triple matches were analyzed using repeated-measures analysis of variance to detect differences in LVMI among the 3 groups. A total of 27 matched triplets were established. The groups were comparable for sex, age, and BMI. Mean LVMI was 29.2 g/m(2.7) for the normotensive group, 32.3 g/m(2.7) for the WCH group, and 35.1 g/m(2.7) for the sustained hypertensive group (normotensive vs WCH, P = .028; WCH vs sustained hypertension, P = .07). Left ventricular hypertrophy was not present in any subject in the normotensive or WCH groups, but was found in 26% of the sustained hypertensive subjects (P < .001). After controlling closely for BMI, the LVMI in the subjects with WCH was between that of the normotensives and sustained hypertensives, suggesting that WCH may be associated with hypertensive end-organ effects.

Therapeutic applications and uses of inhalational anesthesia in the pediatric intensive care unit*

To review the physical properties, end-organ effects, therapeutic applications, and delivery techniques of inhalational anesthetic agents in the pediatric intensive care unit. A computerized, bibliographic search regarding intensive care unit applications of inhalational anesthetic agents. Although the end-organ effects of inhalational anesthetic agents vary depending on the agent, general effects include a dose-related depression of ventilatory and cardiovascular function. With increasing anesthetic depth, there is a decrease in alveolar ventilation with a reduction in tidal volume and an increase in PaCO2 in spontaneously breathing patients. The potent inhalational anesthetic agents decrease mean arterial pressure and myocardial contractility. The decrease in mean arterial pressure reduces renal and hepatic blood flow. Secondary effects on end-organ function may result from the metabolism of these agents and the release of inorganic fluoride. Beneficial effects include sedation, amnesia, and anxiolysis, making these agents effective for sedation during mechanical ventilation. Bronchodilatory and anticonvulsant properties have led to their use as therapeutic agents in patients with refractory status asthmaticus and epilepticus. Issues regarding their delivery in the intensive care unit include equipment for their delivery, scavenging, and monitoring. The literature contains reports of the therapeutic use of the potent inhalational anesthetic agents in the pediatric intensive care unit. Potential applications include sedation during mechanical ventilation as well as therapeutic use for the treatment of status asthmaticus and epilepticus.

Summary of aromatase inhibitor clinical trials in postmenopausal women with early breast cancer

Five years of adjuvant therapy with tamoxifen was considered the gold-standard treatment for postmenopausal women with estrogen receptor-positive breast cancer for many years. Data from a core group of clinical trials investigating the safety and efficacy of aromatase inhibitors (AIs) have challenged this perception. These studies were designed to evaluate the safety and efficacy of AIs in the following clinical settings: 1) as initial adjuvant therapy (the Arimidex, Tamoxifen, Alone or in Combination trial, Breast International Group Trial 1-98), 2) in a "switched setting" after 2 to 3 years of treatment with tamoxifen (Arimidex-Nolvadex 95, the Austrian Breast and Colorectal Cancer Study Group 8 [ABCSG 8] trial, the Italian Tamoxifen Anastrozole study, the Intergroup Exemestane Study), and 3) in extended settings (National Cancer Institute of Canada Trial MA.17, ABCSG 6a, National Surgical Adjuvant Breast and Bowel Project 33). The efficacy data from these studies suggested that AIs have added substantial benefit in terms of disease outcome. AIs were tolerated well, and patients who received them experienced fewer thrombolic events and less endometrial cancer, hot flashes, night sweats, and vaginal bleeding compared with patients who receive tamoxifen. However, patients who received tamoxifen had less skeletal events and accelerated bone resorption compared with women who received AIs. AIs should be considered when planning a patient's endocrine therapy, taking into account the differences in tolerability and end-organ effects of the classes of endocrine therapy. Outstanding issues to optimize AI therapy include identifying the optimal duration, agent, and patients for these therapies.

Pro: Dexmedetomidine Should Be Used for Infants and Children Undergoing Cardiac Surgery

THE LANDMARK WORK OF Anand et al 1 Anand K.J. Sippell W.G. Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: Effects on the stress response. Lancet. 1987; 1: 62-66 Abstract PubMed Scopus (395) Google Scholar , 2 Anand K.J. Hickey P.R. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992; 326: 1-9 Crossref PubMed Scopus (688) Google Scholar has documented the potential impact of anesthetic practice on morbidity and mortality after surgery for congenital heart disease. Nearly 20 years later, the anesthetic management of pediatric patients with congenital heart lesions is a delicate balance between the successful ablation of the harmful perioperative stress responses and the potential untoward sequelae of effective analgesia and sedation including prolonged ventilator dependence, adverse end-organ effects, and iatrogenic tolerance and dependency syndromes. Anesthesiologists remain intimately involved in the perioperative care of children undergoing cardiac surgery and continue to seek new modalities of perioperative analgesia and sedation in an attempt to limit these complications. Dexmedetomidine increasingly has been used by anesthesiologists and intensive care physicians to provide effective pain relief, sedation, and anxiolysis in critically ill infants and children while mitigating the adverse effects of ventilator and opioid dependency. Given its beneficial physiologic effects and limited adverse effect profile, there may be several potential applications for dexmedetomidine in the perioperative care of infants and children with congenital heart disease.

Insulin glulisine, insulin lispro and regular human insulin show comparable end‐organ metabolic effects: an exploratory study

To compare the end-organ metabolic effects of insulin glulisine (glulisine), insulin lispro (lispro) and regular human insulin (RHI) in patients with type 1 diabetes mellitus. Eighteen patients with type 1 diabetes mellitus (mean age 36.9 +/- 8.6 years, BMI 23.6 +/- 2.8 kg/m(2), haemoglobin A(1c) 7.4 +/- 0.9%) were randomized in this single-centre, double-blind, three-period cross-over, standard Latin-square, euglycaemic glucose clamp trial. Patients received sequential, primed stepwise intravenous infusions of glulisine, lispro or RHI (infusion rates were increased in a stepwise manner from an initial rate of 0.33 [180 min] to 0.66 [180 min] and 1.00 [180 min] mU/kg/min). The primary variables were the suppression of endogenous glucose production (S(EGP)) and glucose uptake (GU). Mean basal endogenous glucose production (EGP) was 1.88, 2.12 and 2.12 mg/kg/min for glulisine, lispro and RHI respectively. Mean (+/-s.e.) maximum absolute S(EGP) (adjusted for basal EGP) was -1.64 +/- 0.06, -1.72 +/- 0.05 and -1.56 +/- 0.05 mg/kg/min respectively. Mean (+/-s.e.) maximum absolute increase in GU (adjusted for basal GU) was 6.46 +/- 0.26, 6.23 +/- 0.24 and 6.72 +/- 0.24 mg/kg/min respectively. There were no clinically relevant differences between the three insulin treatments with respect to serum insulin, free fatty acid (FFA), glycerol or lactate levels. No serious adverse events and no episodes of severe hypoglycaemia were reported. This study shows that glulisine, lispro and RHI have similar effects on S(EGP), GU, FFA, glycerol and lactate levels, providing evidence for similar end-organ metabolic effects.