Examining Risk: A Systematic Review of Perioperative Cardiac Risk Prediction Indices.

OBJECTIVE: To conduct a systematic review of published cardiac risk indices relevant to patients undergoing noncardiac surgery and to provide clinically meaningful recommendations to physicians regarding the use of these indices. METHODS: A literature search of articles published from January 1, 1999, through December 28, 2018, was conducted in Ovid (MEDLINE), PubMed, Embase, CINAHL, and Web of Science. Publications describing models predicting risk of cardiac complications after noncardiac surgery were included and citation chaining was used to identify additional studies for inclusion. RESULTS: Eleven risk indices involving 2,910,297 adult patients were included in this analysis. Studies varied in size, population, quality, risk of bias, outcome event definitions, risk factors identified, index outputs, accuracy, and clinical usefulness. Studies considered 6 to 83 variables to develop their models. Among the identified models, the factors with the highest predictiveness for adverse cardiac outcomes included congestive heart failure, type of surgery, creatinine, diabetes, history of stroke or transient ischemic attack, and emergency surgery. Substantial data from the large studies also supports advancing age, American Society of Anesthesiology physical status classification, functional status, and hypertension as additional risks. CONCLUSION: The risk indices identified generally fell into two groups - those with higher accuracy for predicting a narrow range of cardiac outcomes and those with lower accuracy for predicting a broader range of cardiac outcomes. Using one index from each group may be the most clinically useful approach. Risk factors identified varied widely among studies. In addition to judicious use of predictive indices, reasoned clinical judgment remains indispensable in assessing perioperative cardiac risk.

Diabetic neuropathy.

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.

Analysis of Daily Laboratory Orders at a Large Urban Academic Center: A Multifaceted Approach to Changing Test Ordering Patterns.

OBJECTIVES: We sought to address concerns regarding recurring inpatient laboratory test order practices (daily laboratory tests) through a multifaceted approach to changing ordering patterns. METHODS: We engaged in an interdepartmental collaboration to foster mindful test ordering through clinical policy creation, electronic clinical decision support, and continuous auditing and feedback. RESULTS: Annualized daily order volumes decreased from approximately 25,000 to 10,000 during a 33-month postintervention review. This represented a significant change from preintervention order volumes (95% confidence interval, 0.61-0.64; P < 10-16). Total inpatient test volumes were not affected. CONCLUSIONS: Durable changes to inpatient order practices can be achieved through a collaborative approach to utilization management that includes shared responsibility for establishing clinical guidelines and electronic decision support. Our experience suggests auditing and continued feedback are additional crucial components to changing ordering behavior. Curtailing daily orders alone may not be a sufficient strategy to reduce in-laboratory costs.

An Educational and Administrative Intervention to Promote Rational Laboratory Test Ordering on an Academic General Medicine Service.

BACKGROUND: Overuse of clinical laboratory testing in the inpatient setting is a common problem. The objective of this project was to develop an inexpensive and easily implemented intervention to promote rational laboratory use without compromising resident education or patient care. METHODS: The study comprised of a cluster-randomized, controlled trial to assess the impact of a multifaceted intervention of education, guideline development, elimination of recurring laboratory orders, unbundling of laboratory panels, and redesign of the daily progress note on laboratory test ordering. The population included all patients hospitalized "general medicine" was duplicated during 2 consecutive months on a general medicine teaching service within a 999-bed tertiary care hospital in Boston, Massachusetts. The primary outcome was the total number of commonly used laboratory tests per patient day during 2 months in 2008. Secondary outcomes included a subgroup analysis of each individual test per patient day, adverse events, and resident and nursing satisfaction. RESULTS: A total of 5392 patient days were captured. The intervention produced a 9% decrease in aggregate laboratory use (rate ratio, 0.91; P = .021; 95% confidence interval, 0.84-0.98). Six instances of delayed diagnosis of acute kidney injury and 11 near misses were reported in the intervention arm. CONCLUSIONS: A bundled educational and administrative intervention promoting rational ordering of laboratory tests on a single academic general medicine service led to a modest but significant decrease in laboratory use. To our knowledge, this was the first study to examine the daily progress note as a tool to limit excessive test ordering. Unadjudicated near misses and possible harm were reported with this intervention. This finding warrants further study.

Peripheral nervous system insulin resistance in ob/ob mice.

BACKGROUND: A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. RESULTS: The results indicate that insulin signaling abnormalities documented in other "insulin sensitive" tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. CONCLUSIONS: These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.

In vivo peripheral nervous system insulin signaling.

Alterations in peripheral nervous system (PNS) insulin support may contribute to diabetic neuropathy (DN); yet, PNS insulin signaling is not fully defined. Here, we investigated in vivo insulin signaling in the PNS and compared the insulin responsiveness to that of muscle, liver, and adipose. Non-diabetic mice were administered increasing doses of insulin to define a dose-response relationship between insulin and Akt activation in the dorsal root ganglion (DRG) and sciatic nerve. Resulting EC50 doses were used to characterize the PNS insulin signaling time course and make comparisons between insulin signaling in the PNS and other peripheral tissues (i.e., muscle, liver, and adipose). The results demonstrate that the PNS is responsive to insulin and that differences in insulin signaling pathway activation exist between PNS compartments. At a therapeutically relevant dose, Akt was activated in the muscle, liver, and adipose at 30 min, correlating with the changes in blood glucose levels. Interestingly, the sciatic nerve showed a similar signaling profile as insulin-sensitive tissues; however, there was not a comparable activation in the DRG or spinal cord. These results present new evidence regarding PNS insulin signaling pathways in vivo and provide a baseline for studies investigating the contribution of disrupted PNS insulin signaling to DN pathogenesis.

The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy.

UNLABELLED: Although exercise can significantly reduce the prevalence and severity of diabetic complications, no studies have evaluated the impact of exercise on nerve function in people with diagnosed diabetic peripheral neuropathy (DPN). The purpose of this pilot study was to examine feasibility and effectiveness of a supervised, moderately intense aerobic and resistance exercise program in people with DPN. We hypothesized that the exercise intervention can improve neuropathic symptoms, nerve function, and cutaneous innervation. METHODS: A pre-test post-test design was used to assess change in outcome measures following participation in a 10-week aerobic and strengthening exercise program. Seventeen subjects with diagnosed DPN (8 males/9 females; age 58.4±5.98; duration of diabetes 12.4±12.2 years) completed the study. Outcome measures included pain measures (visual analog scale), Michigan Neuropathy Screening Instrument (MNSI) questionnaire of neuropathic symptoms, nerve function measures, and intraepidermal nerve fiber (IENF) density and branching in distal and proximal lower extremity skin biopsies. RESULTS: Significant reductions in pain (-18.1±35.5 mm on a 100 mm scale, P=.05), neuropathic symptoms (-1.24±1.8 on MNSI, P=.01), and increased intraepidermal nerve fiber branching (+0.11±0.15 branch nodes/fiber, P=.008) from a proximal skin biopsy were noted following the intervention. CONCLUSIONS: This is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies.

Core competency review: aortic stenosis and noncardiac surgery.

Aortic stenosis (AS) poses a risk of adverse cardiac events for patients undergoing surgical procedures. Perioperative mortality for patients with severe AS is as high as 14%. This review examines the accuracy of the history and physical examination in detecting AS and, subsequently, in assessing severity. The utility of echocardiography is addressed, and the relevant pathophysiology of AS is summarized. We also summarize what is known about perioperative risk for patients with AS.

Acidic saline-induced primary and secondary mechanical hyperalgesia in mice.

UNLABELLED: Most of our knowledge about chronic musculoskeletal pain is based on cutaneous pain models. To test the hypothesis that animals develop chronic muscular hyperalgesia following intramuscular acidic saline injections, primary hyperalgesia within the gastrocnemius muscle was analyzed compared to secondary cutaneous hyperalgesia in the hind paw that develops following intramuscular acid saline injection. Two acidic saline (pH 4) injections were administrated into the gastrocnemius of female CF-1 mice. The results indicate that mice developed a robust hypersensitivity bilaterally in primary (gastrocnemius muscle) secondary (cutaneous hind paw) sites that lasted up to 2 weeks. In addition, primary hyperalgesia correlated well with levels of Fos expression. Fos expression patterns in the spinal cord were different for primary secondary site stimulation. Hind-paw palpation stimulated ipsilateral Fos expression in the superficial spinal laminae at L4/L5 levels, bilaterally in deep laminae at L2-L5 spinal levels. In contrast, gastrocnemius compression stimulated widespread Fos expression in all regions of the ipsilateral dorsal horn within L2-L6 spinal segments. These findings indicate that acidic saline injection induces primary hyperalgesia in muscle that the patterns of Fos expression in response to primary vs secondary stimulation are strikingly different. PERSPECTIVE: This study assesses primary site muscular pain, which is the main complaint of people with musculoskeletal conditions, and identifies spinal patterns activated by noxious mechanical stimuli to the gastrocnemius. This study demonstrates approaches to test nociception arising from muscle aids in our understanding of spinal processing of primary secondary site hyperalgesia.

Perioperative surveillance for adverse myocardial events.

Perioperative myocardial infarctions occur in 1 to 4% of unselected noncardiac surgical patients, and are associated with high mortality. Detection of these events can be challenging, because 'typical' symptoms of myocardial ischemia may not be present or may be masked in the perioperative period. Therefore, surveillance by means of intraoperative cardiac monitoring and postoperative serial electrocardiograms (ECGs) and troponins may be needed. Cardiac monitoring not infrequently detects ST-segment changes suggestive of ischemia during or shortly after surgery. To respond to these changes, the risk for coronary artery disease should be assessed before recommending additional interventions. For all vascular surgery patients, and for patients who have or are felt to be at risk for coronary artery disease, serial postoperative 12-lead ECGs and troponins should be considered. Among surgical patients not meeting these criteria, obtaining routine ECGs in the absence of signs or symptoms that suggest a cardiac event may be falsely reassuring and is not felt to be useful. The presence of elevated postoperative troponins predicts worsened prognosis, and argues for intensified risk factor modification. The need for noninvasive cardiac testing or cardiac catheterization should be made on an individual basis.

Diabetes-induced chemogenic hypoalgesia is paralleled by attenuated stimulus-induced fos expression in the spinal cord of diabetic mice.

UNLABELLED: Chronic hyperglycemia in diabetes induces abnormal nerve pathologies, resulting in diabetic neuropathy (DN). Sensory symptoms of DN can manifest as positive (painful), negative (insensate), or both. Streptozotocin (STZ)-induced diabetic C57Bl/6 mice have reduced cutaneous innervation and display reduced behavioral responses to noxious stimuli, reflecting the insensate aspect of the human syndrome. Current studies were undertaken to determine whether the diabetes-induced deficits in pain responses are reflected by changes in spinal activation in this model of DN. Nocifensive responses of nondiabetic and diabetic mice to formalin injection were measured 1, 3, 5, and 7 weeks after STZ, and at each time point formalin-induced spinal Fos expression was quantified. Responses of diabetic mice were significantly reduced during the second phase of the formalin test beginning 3 weeks after STZ and during Phase 1 beginning 5 weeks after STZ. Consistent with the behavioral responses, the number of Fos-positive cells in the dorsal horn of diabetic animals was significantly reduced beginning 3 weeks after STZ and continuing 5 and 7 weeks after STZ. The deficits at 5 weeks after STZ were restored by 2-week treatments with insulin or neurotrophins. These results demonstrate that the reduced sensation occurring from progressive peripheral axon loss results in functional deficits in spinal cord activation. PERSPECTIVE: The reduced expression of the immediate early gene Fos as an indicator of pain transmission supports the diabetes-induced loss of sensation in this Type 1 model of diabetes. This murine model may be better suited to understanding the insensate symptoms of diabetic patients in the absence of chronic pain.

Neurotrophin-3 reverses chronic mechanical hyperalgesia induced by intramuscular acid injection.

Injection of acid into the gastrocnemius muscle results in a persistent, mechanical hyperalgesia of the hindpaw (Sluka et al., 2001). Here, the ability of neurotrophins to alter the development of this secondary hyperalgesia was assessed using transgenic mice and exogenous neurotrophin administration. Acid-induced hyperalgesia was measured in wild-type and transgenic mice that overexpress neurotrophin-3 (NT-3) in muscle (myo/NT-3 mice). Mechanical and thermal sensitivity of the hindpaws were assessed after injections of acidic saline, pH 4, into the right medial gastrocnemius. Wild-type mice exhibited mechanical but not thermal hyperalgesia in both paws 1 d after acid injection. In contrast, myo/NT-3 mice developed a transient mechanical hyperalgesia in both paws that disappeared by 2-3 d. The reversal of hyperalgesia in myo/NT-3 mice could be mimicked by intramuscular administration of exogenous NT-3 to acid-injected mice but not by other neurotrophins. The route of NT-3 administration appears critical, because intrathecal or intraperitoneal delivery were ineffective. The hyperalgesia could only be reversed by NT-3 treatment concurrent with acid injection and not after the emergence of hyperalgesia. The acid-induced hyperalgesia did not redevelop after the termination of NT-3 treatment, suggesting that NT-3 permanently reversed the hyperalgesia. Consistent with the behavioral data, paw palpation of acid-injected mice significantly increased Fos expression in the spinal cord of wild-type but not myo/NT-3 or NT-3-injected mice. The attenuation of hyperalgesia suggests that NT-3 may be a modulator of muscle-derived pain, and NT-3 may suppress events that lead to secondary hyperalgesia triggered by insult to muscle afferents.

Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate.

Tactile information is perceived by a heterogeneous population of specialized neurons. Neurotrophin receptors (the receptor tyrosine kinases, Trks) mark the major classes of these sensory neurons: TrkA is expressed in neurons that sense temperature and noxious stimuli, and TrkC is expressed in proprioceptive neurons that sense body position. Neurotrophin signaling through these receptors is required for cell survival. To test whether neurotrophins have an instructive role in sensory specification, we expressed rat TrkC from the TrkA (also known as Ntrk1) locus in mice. The surviving presumptive TrkA-expressing neurons adopted a proprioceptive phenotype, indicating that neurotrophin signaling can specify sensory neuron subtypes.

Circulation and chemotaxis of fetal hematopoietic stem cells.

The major site of hematopoiesis transitions from the fetal liver to the spleen and bone marrow late in fetal development. To date, experiments have not been performed to evaluate functionally the migration and seeding of hematopoietic stem cells (HSCs) during this period in ontogeny. It has been proposed that developmentally timed waves of HSCs enter the bloodstream only during distinct windows to seed the newly forming hematopoietic organs. Using competitive reconstitution assays to measure HSC activity, we determined the localization of HSCs in the mid-to-late gestation fetus. We found that multilineage reconstituting HSCs are present at low numbers in the blood at all timepoints measured. Seeding of fetal bone marrow and spleen occurred over several days, possibly while stem cell niches formed. In addition, using dual-chamber migration assays, we determined that like bone marrow HSCs, fetal liver HSCs migrate in response to stromal cell-derived factor-1alpha (SDF-1alpha); however, unlike bone marrow HSCs, the migratory response of fetal liver HSCs to SDF-1alpha is greatly increased in the presence of Steel factor (SLF), suggesting an important role for SLF in HSC homing to and seeding of the fetal hematopoietic tissues. Together, these data demonstrate that seeding of fetal organs by fetal liver HSCs does not require large fluxes of HSCs entering the fetal bloodstream, and that HSCs constitutively circulate at low levels during the gestational period from 12 to 17 days postconception. Newly forming hematopoietic tissues are seeded gradually by HSCs, suggesting initial seeding is occurring as hematopoietic niches in the spleen and bone marrow form and become capable of supporting HSC self-renewal. We demonstrate that fetal and adult HSCs exhibit specific differences in chemotactic behavior. While both migrate in response to SDF-1alpha, fetal HSCs also respond significantly to the cytokine SLF. In addition, the combination of SDF-1alpha and SLF results in substantially enhanced migration of fetal HSCs, leading to migration of nearly all fetal HSCs in this assay. This finding indicates the importance of the combined effects of SLF and SDF-1alpha in the migration of fetal HSCs, and is, to our knowledge, the first demonstration of a synergistic effect of two chemoattractive agents on HSCs.

ATP and UTP excite sensory neurons and induce CREB phosphorylation through the metabotropic receptor, P2Y2.

Extracellular ATP rapidly excites nociceptive sensory neurons by opening ATP-gated ion channels (P2X receptors). Here, we describe two actions of both ATP and UTP on rat sensory neurons that are relatively slow and sustained: phosphorylation of the transcription factor CREB and delayed action potential firing that persists for tens of seconds after removal of the ligand. The pharmacology of these responses indicates that they are mediated by the metabotropic receptor P2Y2, and not by P2X receptors. CREB phosphorylation occurred in a subset of small peripherin-positive neurons likely to be unmyelinated nociceptors. In situ hybridization analysis revealed widespread expression of P2Y2 mRNA in sensory neurons. CREB phosphorylation is mediated by both action-potential-evoked calcium influx and calcium release from intracellular stores. These findings suggest that P2Y2 contributes to the transduction of ATP-mediated sensory signalling, and may be involved in the activity-dependent regulation of nociceptor phenotype.

Hematopoietic stem cells are uniquely selective in their migratory response to chemokines.

Although hematopoietic stem cell (HSC) migration into and out of sites of active hematopoiesis is poorly understood, it is a critical process that underlies modern clinical stem cell transplantation and may be important for normal hematopoietic homeostasis. Given the established roles of chemotactic cytokine (chemokine)-directed migration of other leukocyte subsets, the migration of murine HSC to a large panel of CC and CXC chemokines was investigated. HSC migrated only in response to stromal derived factor-1alpha, the ligand for the CXC chemokine receptor 4 (CXCR4). CXCR4 expression by HSC was confirmed by reverse transcription polymerase chain reaction analysis. Surprisingly, HSC also expressed mRNA for CCR3 and CCR9, although they failed to migrate to the ligands for these receptors. The sharply restricted chemotactic responsiveness of HSC is unique among leukocytes and may be necessary for the specific homing of circulating HSC to bone marrow, as well as for the maintenance of HSC in hematopoietic microenvironments.