Opioid Prescribing After Surgery in the United States, Canada, and Sweden.

Importance: Small studies and anecdotal evidence suggest marked differences in the use of opioids after surgery internationally; however, this has not been evaluated systematically across populations receiving similar procedures in different countries. Objective: To determine whether there are differences in the frequency, amount, and type of opioids dispensed after surgery among the United States, Canada, and Sweden. Design, Setting, and Participants: This cohort study included patients without previous opioid prescriptions aged 16 to 64 years who underwent 4 low-risk surgical procedures (ie, laparoscopic cholecystectomy, laparoscopic appendectomy, arthroscopic knee meniscectomy, and breast excision) between January 2013 and December 2015 in the United States, between July 2013 and March 2016 in Canada, and between January 2013 and December 2014 in Sweden. Data analysis was conducted in all 3 countries from July 2018 to October 2018. Main Outcomes and Measures: The main outcome was postoperative opioid prescriptions filled within 7 days after discharge; the percentage of patients who filled a prescription, the total morphine milligram equivalent (MME) dose, and type of opioid dispensed were compared. Results: The study sample consisted of 129 379 patients in the United States, 84 653 in Canada, and 9802 in Sweden. Overall, 52 427 patients (40.5%) in the United States were men, with a mean (SD) age of 45.1 (12.7) years; in Canada, 25 074 patients (29.6%) were men, with a mean (SD) age of 43.5 (13.0) years; and in Sweden, 3314 (33.8%) were men, with a mean (SD) age of 42.5 (13.0). The proportion of patients in Sweden who filled an opioid prescription within the first 7 days after discharge for any procedure was lower than patients treated in the United States and Canada (Sweden, 1086 [11.1%]; United States, 98 594 [76.2%]; Canada, 66 544 [78.6%]; P < .001). For patients who filled a prescription, the mean (SD) MME dispensed within 7 days of discharge was highest in United States (247 [145] MME vs 169 [93] MME in Canada and 197 [191] MME in Sweden). Codeine and tramadol were more commonly dispensed in Canada (codeine, 26 136 patients [39.3%]; tramadol, 12 285 patients [18.5%]) and Sweden (codeine, 170 patients [15.7%]; tramadol, 315 patients [29.0%]) than in the United States (codeine, 3210 patients [3.3%]; tramadol, 3425 patients [3.5%]). Conclusions and Relevance: The findings indicate that the United States and Canada have a 7-fold higher rate of opioid prescriptions filled in the immediate postoperative period compared with Sweden. Of the 3 countries examined, the mean dose of opioids for most surgical procedures was highest in the United States.

Days at Home after Surgery: An Integrated and Efficient Outcome Measure for Clinical Trials and Quality Assurance.

BACKGROUND: Surgical audit, sometimes including public reporting, is an important foundation of high quality health care. We aimed to assess the validity of a novel outcome metric, days at home up to 30 days after surgery, as a surgical outcome measure in clinical trials and quality assurance. METHODS: This was a multicentre, registry-based cohort study. We used prospectively collected hospital and national healthcare registry data obtained from patients aged 18 years or older undergoing a broad range of surgeries in Sweden over a 10-year period. The association between days at home up to 30 days after surgery and patient (older age, poorer physical status, comorbidity) and surgical (elective or non-elective, complexity, duration) risk factors, process of care outcomes (re-admissions, discharge destination), clinical outcomes (major complications, 30-day mortality) and death up to 1 year after surgery were measured. FINDINGS: From January, 2005, to December, 2014, we obtained demographic and perioperative data on 636,885 patients from 21 Swedish hospitals. Mortality at 30 days and one year was 1.8% and 7.3%, respectively. The median (IQR) days at home up to 30 days after surgery was 27 (23-29), being significantly lower among high-risk patients, those recovering from more complex surgical procedures, and suffering serious postoperative complications (all p < 0.0001). Patients with 8 days or less at home up to 30 days after surgery had a nearly 7-fold higher risk of death up to 1 year postoperatively when compared with those with 29 or 30 days at home (adjusted HR 6.78 [95% CI: 6.44-7.13]). INTERPRETATION: Days at home up to 30 days after surgery is a valid, easy to measure patient-centred outcome metric. It is highly sensitive to changes in surgical risk and impact of complications, and has prognostic importance; it is therefore a valuable endpoint for perioperative clinical trials and quality assurance. FUNDING: Swedish National Research Council Medicine and Stockholm County Council ALF-project grant (LE), and the Australian National Health and Medical Research Council (PM).

Pneumococcal conjugate vaccine triggers a better immune response than pneumococcal polysaccharide vaccine in patients with chronic lymphocytic leukemia A randomized study by the Swedish CLL group.

AIM: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent pneumococcal conjugated vaccine (PCV13), Prevenar13®, compared to a 23-valent pneumococcal polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response. BACKGROUND: Streptococcus pneumoniae causes substantial morbidity in patients with CLL, a group known to respond poorly to polysaccharide vaccines. Comparative studies with conjugated vaccines are lacking. METHODS: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n = 63) or PPSV23 (n = 65) after stratification by IgG level and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, and at one and six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA). RESULTS: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. PPSV23 did not trigger a better immune response than PCV13 for any of the serotypes, regardless of analysis method or time point of analysis. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated. CONCLUSIONS: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for most serotypes common for the two vaccines. We therefore propose that PCV13 should be included in vaccination programs against Streptococcus pneumoniae for CLL patients and administered as early as possible during the course of the disease.

Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study.

Objective To evaluate the possible effects of exposure to neuraminidase inhibitors during embryo-fetal life with respect to adverse neonatal outcomes and congenital malformations.Design Population based multinational observational cohort study and meta-analysis.Setting National registers covering information on maternal healthcare, births, and prescriptions in Denmark, Norway, and Sweden and the EFEMERIS database from the Haute-Garonne district in France.Participants All women together with their singleton infants born between 1 January 2008 and 31 December 2010. Only infants born at 154 days of gestation or later were included. Infants were defined as exposed if the women filled a prescription during pregnancy for either of the two neuraminidase inhibitors oseltamivir or zanamivir.Main outcomes Low birth weight, low Apgar score, preterm birth, small for gestational age birth, stillbirth, neonatal mortality, neonatal morbidity, and congenital malformations. Crude and adjusted hazard ratios of preterm birth were estimated using Cox regression models. Crude and adjusted odds ratios for other outcomes were estimated by logistic regression models.Results The study included 5824 (0.8%) exposed women and their infants and 692 232 who were not exposed. Exposure to neuraminidase inhibitors in utero was not associated with increased risks of any of the investigated neonatal outcomes, including low birth weight (adjusted odds ratio 0.77, 95% confidence interval 0.65 to 0.91), low Apgar score (adjusted odds ratio 0.87, 0.67 to 1.14), preterm birth (adjusted hazard ratio 0.97, 0.86 to 1.10), small for gestational age birth (adjusted odds ratio 0.72, 0.59 to 0.87), stillbirth (adjusted odds ratio 0.81, 0.51 to 1.30), neonatal mortality (adjusted odds ratio 1.13, 0.56 to 2.28), and neonatal morbidity (adjusted odds ratio 0.92, 0.86 to 1.00). No increased risk of congenital malformations overall associated with maternal exposure was observed during the first trimester (adjusted odds ratio 1.06, 0.77 to 1.48). Similarly, no significantly increased risks of any of the outcomes were observed in an analysis restricted to oseltamivir alone.Conclusions This large multinational register study found no increased risks of adverse neonatal outcomes or congenital malformations associated with exposure to neuraminidase inhibitors during embryo-fetal life. The results support previously reported findings that the use of neuraminidase inhibitors is not associated with increased risks of adverse fetal or neonatal outcomes.

Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?

BACKGROUND: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine the diagnostic yield of BAL in patients treated for hematological malignancies and how often it contributed to a modification of the anti-infectious therapy. METHODS: We reviewed records from 151 consecutive BAL procedures in 133 adult patients with hematological malignancies, treated at a tertiary hematology unit from 2004 to 2013. Extensive microbiological work-ups on BAL samples had been performed according to a standardized protocol. RESULTS: A microbiological finding causing the infectious episode could be identified in 59 (39%) cases. In 44 (29%) of the cases, results from BAL had an impact on clinical management either by contributing to a specific diagnosis (25%) or by leading to cessation of ongoing microbiological therapy. The most common diagnoses were invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). Diagnoses of IPA and PJP were based on results from BAL in 65% and 93% of cases, respectively. Several microbiological tests on BAL samples rendered no positive results. Complications were few and mainly mild. CONCLUSION: BAL is still important for either verifying or excluding some of the most important respiratory tract pathogens in patients with hematological malignancies, particularly IPA and PJP. Standardized procedures for BAL sampling should be continually revised to exclude unnecessary microbiological tests.

A population-based case-control study on statin exposure and risk of acute diverticular disease.

OBJECTIVE: A reduced risk of perforated diverticular disease among individuals with current statin exposure has been reported. The aim of the present study was to investigate whether statins reduce the risk of acute diverticular disease. MATERIAL AND METHODS: A nation-wide population-based case-control study was performed, including 13,127 cases hospitalised during 2006-2010 with a first-time diagnosis of colonic diverticular disease, and 128,442 control subjects (matched for sex, age, county of residence and calendar year). Emergency surgery, assumed to be a proxy for complicated diverticulitis, was performed on 906 of the cases during the index admission, with 8818 matched controls. Statin exposure was classified as "current" or "former" if a statin prescription was last dispensed ≤ 125 days or >125 days before index date, respectively. The association between statin exposure and acute diverticular disease was investigated by conditional logistic regression, including models adjusting for country of birth, educational level, marital status, comorbidities, nonsteroidal anti-inflammatory drug/steroid exposure and healthcare utilisation. RESULTS: A total of 1959 cases (14.9%) and 16,456 controls (12.8%) were current statin users (crude OR 1.23 [95% CI 1.17-1.30]; fully adjusted OR 1.00 [0.94-1.06]). One hundred and thirty-two of the cases subjected to surgery (14.6%), and 1441 of the corresponding controls (16.3%) were current statin users (crude OR 0.89 [95% CI 0.73-1.08]; fully adjusted OR 0.70 [0.55-0.89]). CONCLUSIONS: The results do not indicate that statins affect the development of symptomatic diverticular disease in general. However, current statin use was associated with a reduced risk of emergency surgery for diverticular disease.

Maternal and birth anthropometric characteristics in relation to the risk of childhood lymphomas: a Swedish nationwide cohort study.

This Swedish nationwide cohort study aims to examine the role of maternal characteristics (maternal age, education, smoking, BMI, diabetes, and preeclampsia) and multiple intrauterine growth measures on the risk of childhood lymphomas. A total of 3 444 136 singleton live births registered in the Swedish Medical Birth Register were analyzed, among whom there were 515 incident non-Hodgkin lymphoma (NHL) cases and 169 Hodgkin lymphoma (HL) cases aged 0-14 years at diagnosis (1973-2007) identified through linkage with the Swedish Cancer Register. Proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) of NHL and HL. Male sex (HR=2.00, 95% CI: 1.66-2.41), older maternal age (HR=1.03, 95% CI: 1.00-1.06, per 1-year increase), and large for gestational age compared with appropriate for gestational age (AGA) birth weight (HR=1.83, 95% CI: 1.20-2.79) were correlated with the risk of NHL; of note, in subanalysis by sex, the latter association was confined to girls (HR=3.37, 95% CI: 1.90-5.97, Pinteraction by sex=0.008). The risk of childhood HL overall was more evident among boys (HR=2.03, 95% CI: 1.46-2.81), whereas indices of accelerated fetal growth were not convincingly associated with the risk of HL. Apart from the established association with sex, the findings point to accelerated intrauterine growth as a risk factor for childhood NHL that may differ by sex. Given the rarity of this condition at birth, however, further studies with more elaborate indices are needed to conclude on its association with rare diseases such as HL.

Incidence and risk factors for suicide and attempted suicide following a diagnosis of hematological malignancy.

Solid tumors are associated with an increased risk of suicide, however, there is limited detailed information on the risk of suicide in patients with hematological malignancies. Therefore, we conducted a population-based study including 47,220 patients with hematological malignancies (diagnosed 1992-2006) and their 235,868 matched controls to define the incidence and risk factors for suicide and suicide attempt. Information on suicides, suicide attempts, and preexisting psychiatric disorders was obtained from Swedish registers and individual medical records. There was a twofold increased (hazard ratio [HR] = 1.9, 95% confidence interval 1.5-2.3, P < 0.0001) risk of suicide/suicide attempt during the first 3 years after diagnosis in patients with hematological malignancies compared to matched controls. Of all hematological malignancies, multiple myeloma was associated with the highest risk (HR = 3.4; 2.3-5.0, P < 0.0001). Patients with a preexisting psychiatric disorder were at a very high risk of suicide and suicide attempt (HR = 23.3; 16.6-32.6, P < 0.0001), regardless of type of hematological malignancy. Among patients who committed suicide, 19% were in a palliative phase and 44% were in remission with no active treatment. In conclusion, the risk of suicide and suicide attempt is elevated in patients with hematological malignancies. Certain high-risk patients may benefit from early detection and preventive measures.

Maternal and pregnancy characteristics and risk of infantile hypertrophic pyloric stenosis.

BACKGROUND/PURPOSE: The incidence of infantile hypertrophic pyloric stenosis (IHPS) in Sweden decreased dramatically during the 1990s. The aim of the study was to examine IHPS risk factors and the possible change in them as the incidence declined. METHODS: This is a case-control study including 3608 surgically treated IHPS cases and 17588 matched controls during 1973-2008. Cases were identified in the Swedish National Patient Register and data on possible risk factors were collected from the Swedish Medical Birth Register. The association between study variables and IHPS was analyzed using conditional logistic regression for the whole study period and separately for periods with high and low IHPS incidences. RESULTS: Prematurity (OR, 2.54; 95% CI, 2.06-3.14), caesarean delivery (OR, 1.67; 95% CI, 1.51-1.86), maternal smoking (OR, 1.82; 95% CI, 1.53-2.16), and young maternal age (< 20yrs) (OR, 1.42; 95% CI, 1.17-1.73) were associated with an increased IHPS risk. Birth order 2 (OR, 0.78; 95% CI, 0.71-0.85) or more was associated with a lower IHPS risk. ORs for smoking increased at low incidence rate. CONCLUSION: We report caesarean section, prematurity, primiparity, young maternal age, and smoking as significant IHPS risk factors. The impact of smoking was higher during periods with a low incidence.

A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine.

OBJECTIVES: Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients. PATIENTS AND METHODS: Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 10(9) /L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine. RESULTS: Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs. CONCLUSION: The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

Comorbid conditions associated with glioblastoma.

To inform clinical management of glioblastoma patients, we estimated the relative prevalence (present at glioblastoma diagnosis) and incidence (newly diagnosed) of comorbid conditions among these patients and their matched controls. We identified 2,424 glioblastoma patients registered in the Swedish National Cancer Registry between 1993 and 2006. Next, 12,120 randomly sampled population-based controls were individually matched to cases on age, sex and calendar year of diagnosis. We then evaluated patient discharge data for selected potential comorbid conditions. Seizures (odds ratio (OR) 31.6, 95% confidence interval (CI) 24.7-40.3) and cerebral edema (OR 25.0, 95% CI 5.5-114) were the most prevalent conditions at diagnosis. Beginning 30 days after diagnosis, increased risks of incident deep vein thrombosis (hazard ratio (HR) 119.7, 95% CI 60.8-211.0) and pulmonary embolism (HR 92.4, 95% CI 48.3-176.6) were observed. Risks of incident cardiovascular diseases including heart failure (HR 4.0, 95% CI 2.6-6.1), coronary artery disease (HR 2.3, 95% CI 1.7-3.2), and myocardial infarction (HR 1.9, 95% CI 1.1-3.4) were also elevated among glioblastoma patients. In this first population-based study of both prevalent and incident comorbid conditions among glioblastoma patients, we have quantified risk of those conditions related to the tumor and its treatment-based on nationwide registry data. However, for incident conditions we cannot distinguish between the effects of the tumor and the effects of treatment. A novel finding was the elevated risk of cardiovascular disease among glioblastoma patients; glioblastoma patients should be monitored for signs of cardiovascular disease.

Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) and hypogammaglobulinemia who suffer from recurrent infections can be offered prophylactic intravenous immunoglobulin (Ig) substitution. Our aim was to assess the prevalence of pure IgG subclass deficiency (with normal Ig levels), its correlation to risk of infection, and the clinical value of routine measurement of serum IgG subclass levels in patients with CLL. METHODS: Serum levels of Ig and IgG subclasses were determined in patients with CLL at Uppsala University Hospital. Clinical data were collected through patient records and questionnaires. RESULTS: Hypogammaglobulinemia occurred in 52.3% out of 111 patients. These patients did not have a higher annual risk of infection than patients without hypogammaglobulinemia (79.5% vs 79.1%, p = 0.706 for all infections; 13.4% vs 11.2%, p = 0.394 for severe infection; and 1.7% vs 3.4%, p = 0.083 for sepsis). Pure subclass deficiency was uncommon and occurred in 6 patients (5.4%). The annual overall risk of infection, of severe infection, and of sepsis for these patients did not differ as compared to patients with no hypogammaglobulinemia and no subclass deficiency (70.8% vs 80.7%, p = 0.334; 11.8% vs 11.1%, p = 0.497; and 8.9% vs 2.3%, p = 0.067, respectively). CONCLUSIONS: Pure IgG subclass deficiency is rare in patients with CLL. In this heterogeneous cohort of patients, neither hypogammaglobulinemia nor pure IgG subclass deficiency were significant risk factors for infectious complications. Measurement of serum levels of Ig may be justified in patients with recurrent severe infections, but routine analysis of IgG subclass levels in patients with CLL is probably not warranted.

Birth outcomes among women exposed to neuraminidase inhibitors during pregnancy.

PURPOSE: To compare birth outcomes between women exposed and unexposed to the antiviral medications oseltamivir or zanamivir during pregnancy. METHODS: This was an observational cohort study including women who gave birth to singletons in Sweden 2005-2007 and their infants. We obtained information from the national health registers and evaluated risks of low Apgar score, small for gestational age (SGA), low birth weight, preterm delivery, congenital malformations, birth-related death (stillbirth and neonatal death combined), and neonatal morbidity by conditional logistic regression. The unexposed [n = 860] were matched to the exposed [n = 86] by birth year and fetal gender. RESULTS: A total of 81 women filled a prescription with oseltamivir only, 2 with zanamivir, and 3 with both oseltamivir and zanamivir. Compared with the unexposed infants, the exposed ones had higher risks of late transient hypoglycemia (crude OR = 4.00, 95%CI: 1.26-12.76). There were no statistical increased risks of low Apgar score, congenital malformations, SGA, low birth weight, preterm birth, or birth-related death. Adjusting for maternal age, parity, smoking, and body mass index had minor effects on the results. None of the women exposed to oseltamivir or zanamivir had been admitted to hospital for influenza during their pregnancy. CONCLUSIONS: Except for an increased risk of late transient hypoglycemia, we found no increased risks of adverse birth outcomes among infants exposed to neuraminidase inhibitors in fetal life compared with the unexposed.

Maternal smoking during pregnancy and risks of suicidal acts in young offspring.

Obstetric and neonatal complications have been associated with completed and attempted suicide (suicidal acts) in young offspring. Maternal smoking is one of the most important risk factors for obstetric complications, but the association between prenatal smoking exposure and offspring risk of suicidal acts is unknown. We performed a population-based study of 1,449,333 single births born in Sweden between 1983 and 1996, derived from linked registry data. Maternal smoking and risks of suicidal acts in offspring were estimated using hazard ratios, derived from proportional-hazard models, controlling for potential confounding of parental socio-demographic factors and psychiatric care in first degree relatives. To control for unmeasured familial confounding, a matched case-control analysis of suicidal acts was performed within sibling pairs discordant for prenatal smoking exposure. In the cohort analysis, the adjusted hazard ratio for completed suicide among offspring to women smoking 1-9 cigarettes and at least 10 cigarettes per day were 1.67, 95% confidence interval (CI), 1.29-2.16, and 1.54, 95% CI, 1.12-2.10. For suicidal acts, corresponding hazard ratios were 1.28, 95% CI 1.21-1.35 and 1.48, 95% CI 1.39-1.57, respectively. However, in sibling pairs discordant for suicidal acts and prenatal smoking exposure, we found no evidence that prenatal smoking exposure increased the risk of suicidal acts. We conclude that the association between prenatal smoking exposure and offspring risk of suicidal acts is probably confounded by unmeasured familial factors.