Royal Perth Hospital
Hospital / health systemPerth, Western Australia, Australia
Research output, citation impact, and the most-cited recent papers from Royal Perth Hospital (Australia). Aggregated across the NobleBlocks index of 300M+ scholarly works.
Top-cited papers from Royal Perth Hospital
To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Some recommendations were ungraded (UG). Recommendations were classified into three groups: 1) those directly targeting severe sepsis; 2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and 3) pediatric considerations. Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥ 65 mm Hg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of ≤ 100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose ≤ 180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.
BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).
Context and Purpose of This Guideline \nStatement of Remit \nTo align with its mission to reduce the global burden of raised \nblood pressure (BP), the International Society of Hypertension \n(ISH) has developed worldwide practice guidelines for the \nmanagement of hypertension in adults, aged 18 years and \nolder. \nThe ISH Guidelines Committee extracted evidence-based \ncontent presented in recently published extensively reviewed \nguidelines and tailored and standards \nof care in a practical format that is easy-to-use particularly \nin low, but also in high resource settings – by clinicians, but \nalso nurses and community health workers, as appropriate. \nAlthough distinction between low and high resource settings \noften refers to high (HIC) and low- and middle-income countries (LMIC), it is well established that in HIC there are areas \nwith low resource settings, and vice versa. \nHerein optimal care refers to evidence-based standard of \ncare articulated in recent guidelines1,2 and summarized here, \nwhereas standards recognize that \nstandards would not always be possible. Hence essential standards refer to minimum standards of care. To allow specification of essential standards of care for low resource settings, \nthe Committee was often confronted with the limitation or \nabsence in clinical evidence, and thus applied expert opinion
AIMS: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. CONCLUSION: Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.
BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).
1. Introduction Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table 1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents.Table 1: Glossary of ICD-11 terms.The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. 1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Üstün and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017.Figure 1: Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to the IASP Council on an annual basis.2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective. 2.2. Chronic cancer pain Pain is a frequent and debilitating accompaniment of cancer8 that as yet has not been represented in the ICD. The Task Force decided to list it as a separate entity because there are specific treatment guidelines.7,38 Chronic cancer pain includes pain caused by the cancer itself (the primary tumor or metastases) and pain that is caused by the cancer treatment (surgical, chemotherapy, radiotherapy, and others). Cancer-related pain will be subdivided based on location into visceral, bony (or musculoskeletal), and somatosensory (neuropathic). It will be described as either continuous (background pain) or intermittent (episodic pain) if associated with physical movement or clinical procedures. The treatment-related pain will be cross-referenced from the chapters on postsurgical pain and neuropathic pain. 2.3. Chronic postsurgical and posttraumatic pain Because pain that persists beyond normal healing is frequent after surgery and some types of injuries, the entity of postsurgical and posttraumatic pain was created. This is defined as pain that develops after a surgical procedure or a tissue injury (involving any trauma, including burns) and persists at least 3 months after surgery or tissue trauma26; this is a definition of exclusion, as all other causes of pain (infection, recurring malignancy) as well as pain from a pre-existing pain problem need to be excluded. In view of the different causality, as well as from a medicolegal point of view, a separation between postsurgical pain and pain after all other trauma is regarded as useful. Depending on the type of surgery, chronic postsurgical pain is often neuropathic pain (on average 30% of cases with a range from 6% to 54% and more).15 Pain including such a neuropathic component is usually more severe than nociceptive pain and often affects the quality of life more adversely.21 2.4. Chronic neuropathic pain Chronic neuropathic pain is caused by a lesion or disease of the somatosensory nervous system.20,22 The somatosensory nervous system provides information about the body including skin, musculoskeletal, and visceral organs. Neuropathic pain may be spontaneous or evoked, as an increased response to a painful stimulus (hyperalgesia) or a painful response to a normally nonpainful stimulus (allodynia). The diagnosis of neuropathic pain requires a history of nervous system injury, for example, by a stroke, nerve trauma, or diabetic neuropathy, and a neuroanatomically plausible distribution of the pain.22 For the identification of definite neuropathic pain, it is necessary to demonstrate the lesion or disease involving the nervous system, for example, by imaging, biopsy, neurophysiological, or laboratory tests. In addition, negative or positive sensory signs compatible with the innervation territory of the lesioned nervous structure must be present.36 Diagnostic entities within this category will be divided into conditions of peripheral or central neuropathic pain. 2.5. Chronic headache and orofacial pain The International Headache Society (IHS) has created a headache classification17 that is implemented in full in the chapter on neurology. This classification differentiates between primary (idiopathic), secondary (symptomatic) headache, and orofacial pain including cranial neuralgias. In the section on chronic pain, only chronic headache and chronic orofacial pain will be included. Chronic headache and chronic orofacial pain is defined as headaches or orofacial pains that occur on at least 50% of the days during at least 3 months. For most purposes, patients receive a diagnosis according to the headache phenotypes or orofacial pains that they currently present. The section will list the most frequent chronic headache conditions. The most common chronic orofacial pains are temporomandibular disorders,32 which have been included in this subchapter of chronic pain. Chronic orofacial pain can be a localized presentation of a primary headache.2 This is common in the trigeminal autonomic cephalalgias, less common in migraines, and rare in tension-type headache. Several chronic orofacial pains such as post-traumatic trigeminal neuropathic pain,3 persistent idiopathic orofacial pain, and burning mouth syndrome are cross-referenced to, eg, primary chronic pain and neuropathic pain. The temporal definition of “chronic” has been extrapolated from that of chronic headaches.1 2.6. Chronic visceral pain Chronic visceral pain is persistent or recurrent pain that originates from the internal organs of the head and neck region and the thoracic, abdominal, and pelvic cavities.24,33,34 The pain is usually perceived in the somatic tissues of the body wall (skin, subcutis, muscle) in areas that receive the same sensory innervation as the internal organ at the origin of the symptom (referred visceral pain).12 In these areas, secondary hyperalgesia (increased sensitivity to painful stimuli in areas other than the primary site of the nociceptive input) often occurs30; the intensity of the symptom may bear no relationship with the extent of the internal damage or noxious visceral stimulation.9 The section on visceral pain will be subdivided according to the major underlying mechanisms, ie, persistent inflammation, vascular mechanisms (ischemia, thrombosis), obstruction and distension, traction and compression, combined mechanisms (eg, obstruction and inflammation concurrently), and referral from other locations. Pain due to cancer will be cross-referenced to the chapter chronic cancer pain and pain due to functional or unexplained mechanisms to chronic primary pain. 2.7. Chronic musculoskeletal pain Chronic musculoskeletal pain is defined as persistent or recurrent pain that arises as part of a disease process directly affecting bone(s), joint(s), muscle(s), or related soft tissue(s). According to the constraints of the approach as described in the Introduction, this category is therefore limited to nociceptive pain and does not include pain that may be perceived in musculoskeletal tissues but does not arise therefrom, such as the pain of compression neuropathy or somatic referred pain. The entities subsumed in this approach include those characterized by persistent inflammation of infectious, autoimmune or metabolic etiology, such as rheumatoid arthritis, and by structural changes affecting bones, joints, tendons, or muscles, such as symptomatic osteoarthrosis. Musculoskeletal pain of neuropathic origin will be cross-referenced to neuropathic pain. Well-described apparent musculoskeletal conditions for which the causes are incompletely understood, such as nonspecific back pain or chronic widespread pain, will be included in the section on chronic primary pain. 3. Outlook Irrespective of its etiology, chronic pain is a major source of suffering and requires special treatment and care. Our proposal may not represent a perfect solution for the classification of all manifestations of chronic pain. However, it does represent the first systematic approach to implementing a classification of chronic pain in the ICD. It is based on international expertise and agreement, and consistent with the requirements of the ICD regarding the structure and format of content models. The 7 major categories of chronic pain were identified after considerable research and discussion. They represent a compromise between comprehensiveness and practical applicability of the classification system. Several clinically important conditions that were neglected in former ICD revisions will now be mentioned, eg, chronic cancer pain or chronic neuropathic pain. Etiological factors, pain intensity, and disability related to pain will be reflected. With the introduction of chronic primary pain as a new diagnostic entity, the classification recognizes conditions that affect a broad group of patients with pain and would be neglected in etiologically defined categories. We hope that this classification strengthens the representation of chronic pain conditions in clinical practice and research and welcome comments to improve it further. Conflict of interest statement Q. Aziz has attended advisory board meetings for Almirall pharmaceuticals and Grunenthal. He has also received funding for clinical trials from Ono Pharmaceutical and Protexin. M.I. Bennett has received consultancy or speaker fees from Pfizer, Bayer, Astellas, and Grunenthal in the last 5 years. M. Cohen has received honoraria for contributions to educational programs from Mundipharma Pty Limited and Pfizer. S. Evers received honoraria (as speaker and/or member of advisory boards) and research grants within the past 5 years by AGA Medical (now St Jude), Allergan, Almirall, Astra Zeneca, Berlin-Chemie, CoLucid, Desitin, Eisai, GlaxoSmithKline, Ipsen Pharma, Menarini, MSD, Novartis, Pfizer, Reckitt-Benckiser, UCB. N.B. Finnerup has received speaker's honoraria from Pfizer, Grunenthal, and Norpharma, research grant from Grünenthal, and consultancy fee from Astellas and is member of the IMI “Europain” collaboration where industry members of this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, Boehringer Ingelheim, Astellas, Abbott, and Lundbeck. M.B. First on the faculty of the Lundbeck International Neuroscience Foundation. In the past 2 years, M.A. Giamberardino received research funding or honoraria (participation in Advisory Board) from Bayer Healthcare, Helsinn, and Epitech Group. S. Kaasa declares no conflict of interest related to this work. In the past year he received honoraria from Helsinn related to participation in Advisory Board. E. Kosek has received consultancy and speaker fees in the past 24 months from Eli Lilly and Company and Orion and has ongoing research collaborations with Eli Lilly and Company and Abbott and Pierre Fabre. M. Nicholas received honoraria for contributing to educational sessions for Mundipharma and Pfizer in the last 5 years. S. Perrot received honoraria as a speaker and/or member of the advisory board in the past 5 years from Pfizer, BMS, Grunenthal, Elli Lilly, Sanofi, Daichi-Sankyo, Astellas, and Mundipharma. He has received grant support from BMS. W. Rief received honoraria (as speaker and/or member of advisory boards on topics such as adherence, placebo mechanisms) within the past 5 years from Berlin Chemie, Astra Zeneca, Bayer, Heel (research grant). J. Scholz has received speaker fees from Convergence, GlaxoSmithKline, Pfizer, St Jude Medical, and Zalicus. He has served on advisory boards or consulted for Convergence, Pfizer, Sanofi Aventis, and Zalicus Pharmaceuticals. He has received grant support from GlaxoSmithKline and Pfizer. In the last 5 years, the Anaesthesiology Unit of the University of Western Australia, but not S. Schug personally, has received research and travel funding and speaking and consulting honoraria from bioCSL, Bionomics, Eli Lilly, Grunenthal, Janssen, Mundipharma, Pfizer, Phosphagenics and iX Biopharma within the last 2 years. B.H. Smith has received lecture and consultancy fees, on behalf of his institution, from Pfizer, Grunenthal, Eli Lilly, and Napp. He has received unconditional educational grants from Pfizer Ltd; and he has received travel and accommodation support from Napp. P. Svensson served as a paid consultant for Sunstar Suisse SA. R.-D. Treede has received speaker's honoraria, research grants or consultancy fees from AbbVie, Acron, Astellas, Bauerfeind, Boehringer Ingelheim, Grünenthal, Hydra, Mundipharma, and Pfizer and is a member of the IMI “Europain” collaboration where industry members of this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, Grünenthal, Eli Lilly, Boehringer Ingelheim, Astellas, Abbott, and Lundbeck. J.W.S. Vlaeyen is a member of the PHILIPS advisory board on pain management and declares no conflicts of interest with regard to this work. S.-J. Wang has served on the advisory boards of Allergan and Eli Lilly, Taiwan. He has received speaking honoraria from local companies (Taiwan branches) of Pfizer, Elli Lilly, and GSK. He has received research grants from the Novartis Taiwan, Taiwan Ministry of Science and Technology, Taipei-Veterans General Hospital and Taiwan Headache Society. The other authors have no conflicts of interest to declare. Acknowledgements The authors are members of the Classification of Pain Diseases Task Force of the International Association for the Study of Pain (IASP), which gave logistical and financial support to perform this work. We acknowledge the contributions of the following IASP Special Interest Groups (SIGs): Abdominal & Pelvic Pain SIG, Acute Pain SIG, Cancer Pain SIG, Neuropathic Pain SIG and the Orofacial Pain SIG, and the Classification Committee of the International Headache Society (IHS). Author contributions: R.-D. Treede, W. Rief, and A. Barke contributed equally to this topical review.
BACKGROUND: In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. METHODS: In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients' mean age was 63.1±9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). CONCLUSIONS: For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450.).
BACKGROUND: Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. METHODS: This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. RESULTS: The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). CONCLUSIONS: HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.)
BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS: We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS: A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).
Abstract
BACKGROUND AND AIMS: Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy. METHODS: This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (< 16 years old) patients. CONCLUSIONS: The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.
A volunteer with histologically normal gastric mucosa received pyloric campylobacter by mouth. A mild illness developed, which lasted 14 days. Histologically proven gastritis was present on the tenth day after the ingestion of bacteria, but this had largely resolved by the fourteenth day. The syndrome of acute pyloric campylobacter gastritis is described. It is proposed that this disorder may progress to a chronic infection which predisposes to peptic ulceration.
Document reviewers: Hind Beheiry (Sudan), Irina Chazova (Russia), Albertino Damasceno (Mozambique), Anna Dominiczak (UK), Anastase Dzudie (Cameroon), Stephen Harrap (Australia), Hiroshi Itoh (Japan), Tazeen Jafar (Singapore), Marc Jaffe (USA), Patricio Jaramillo-Lopez (Colombia), Kazuomi Kario (Japan), Giuseppe Mancia (Italy), Ana Mocumbi (Mozambique), Sanjeevi N.Narasingan (India), Elijah Ogola (Kenya), Srinath Reddy (India), Ernesto Schiffrin (Canada), Ann Soenarta (Indonesia), Rhian Touyz (UK), Yudah Turana (Indonesia), Michael Weber (USA), Paul Whelton (USA), Xin Hua Zhang, (Australia), Yuqing Zhang (China).
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP's Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain.
BACKGROUND: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).
Effective doctor-patient communication is a central clinical function in building a therapeutic doctor-patient relationship, which is the heart and art of medicine. This is important in the delivery of high-quality health care. Much patient dissatisfaction and many complaints are due to breakdown in the doctor-patient relationship. However, many doctors tend to overestimate their ability in communication. Over the years, much has been published in the literature on this important topic. We review the literature on doctor-patient communication.
Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by up-regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that short-term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical questions as the optimal intensity, modality and volume of exercise training required in different populations.
BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear. METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).