Acute Intercurrent Illness Research Articles

Acute illness may increase bleed risk among oral anticoagulant users

In the United States, oral anticoagulant use has increased by 54% since 2012, particularly with the use of newer direct oral anticoagulants (DOACs). Unfortunately, among clinicians in certain settings knowledge gaps persist concerning the safety of these therapies, including the risk of acute infection. A new study published in the BMJ December 21, 2021, suggests that acute respiratory tract infections (RTIs) may increase the rates of major and nonmajor bleeding in patients taking oral anticoagulants. Haroon and colleagues conducted a self-controlled case series that included over 1,200 participants on oral anticoagulant therapy who were exposed to an RTI and had major or non-major bleeding events. The analysis included longitudinal general practice EHR data from the UK’s Clinical Practice Research Datalink with over 3 million validated living patients registered at over 400 practices across the UK. The authors defined a specific “excess bleed risk” time window as a general practice consultation for an RTI for which immediate antibiotics were not prescribed. They then compared bleeding event outcomes within the excess risk window to an observation period in which the patients were unexposed to an RTI, allowing the patients to act as their own controls. This methodology had the advantage of allowing for reliable control of time invariant confounders. The researchers defined the RTI risk window as 90 days from general practice consultation, which was divided into smaller chunks of 0 to 14 days, 15 to 30 days, 30 to 60 days, and 60 to 90 days. The 0- to 14-day window was selected as the primary risk period. Additionally, a “pre-risk” window of 7 days prior to the risk period was established in which bleed events could not be captured as being “unexposed.” This was to compensate for RTI symptom onset before the day of general practice consultation as to not misclassify a bleeding event. To prevent confounding from antibiotic use and subsequent drug–drug interactions with a patient’s oral anticoagulant, a patient remained inside of the 90-day risk window as long as they weren’t prescribed antibiotics. Additionally, in order to control for experienced user bias, the total observation period began on the date of the first new prescription of warfarin or a DOAC. After adjusting for time confounders (e.g., age, calendar year, and season) the authors observed a statistically significant 268% relative increase in the rates of major bleeding—defined as either a GI bleed or an intracranial hemorrhage—in the 0- to 14-day risk window after an RTI consultation compared to the rates within the unexposed period. However, no increase in major bleeding was observed in the other aforementioned risk windows. Additionally, the authors observed a statistically significant 232% increase in the relative rates of clinically relevant non-major bleeding—defined as general practice consultation or hospital admission for haemoptysis, epistaxis, or haematuria—during the 0- to 14-day risk window. Despite 67% of the patients in the analysis being on warfarin, a sensitivity analyses demonstrated that there was little modification in the incidence rates of major and non-major bleeding during the 0- to 14-day risk window when conducting a subgroup analysis based on the specific oral anticoagulant used. A major limitation of this study was the inability for the authors to control or adjust for OTC treatments for RTI. Of particular concern are NSAIDs, which would have the potential to significantly bias the results of major bleeds away from the null given that 87% of the recorded bleed events seen were GI bleeds. The authors stated that they “explored the use of prescribed NSAIDs, but were unable to account for over-the-counter drugs” when discussing the limitations of their study. They went on to say that this confound was significant given that survey data from 1,000 adults in England with a recent RTI indicated that 60% of these patients sought OTC treatments. Other observational studies have shown that acute infection may increase international normalized ratio measure in warfarin users. As it stands, Haroon and colleagues’ study is the only one in the literature that has looked at the effect of acute infection on clinical events within the oral anticoagulant population as a whole. “These findings are important and timely given the increasing rates of oral anticoagulant use and the lack of knowledge and guidance on how to manage oral anticoagulant use during acute infection,” suggested the authors in one of their concluding remarks. “There are potential implications for how patients and clinicians manage oral anticoagulant use during an acute intercurrent illness, but further work is needed before any clinical recommendations are made.”

Respiratory tract infection and risk of bleeding in oral anticoagulant users: self-controlled case series

ObjectiveTo estimate the association between untreated, community acquired, respiratory tract infections and bleeding in oral anticoagulant users.DesignSelf-controlled case series.SettingGeneral practices in England contributing data to the Clinical Practice Research Datalink...

Refeeding syndrome after small bowel obstruction - a case report

Background: Refeeding Syndrome (RS) is an under-recognized pathophysiological process that can result in arrhythmias, coma, and death if not identified and managed appropriately. Case Presentation: This case report discusses RS in a 77-year-old female who presented with 6 days of total anorexia secondary to abdominal pain and vomiting. The patient was identified to have an ischaemic closed loop obstruction of the small bowel in a right femoral hernia with associated proximal small bowel obstruction. Following a small bowel resection, nutrition was reintroduced where on day 3 the patient developed hypophosphataemia, the hallmark of RS. Conclusion: This case highlights the importance of considering RS in patients with a seemingly short duration of starvation due to acute intercurrent illness such as in this case a small bowel obstruction.

Increased Serum Lactate in Peritoneal Dialysis Patients Presenting with Intercurrent Illness.

Lactate is the most commonly used buffer in peritoneal dialysis (PD) solutions. While previous studies have shown that serum lactate is normal in stable PD patients, the purpose of our study was to evaluate whether abnormal lactate values are more common in PD patients presenting to the emergency department (ED) and have the same significance as in the general population. This observational cohort study assessed the prevalence of elevated serum lactate in PD patients presenting to the ED and evaluated clinical factors associated with an abnormal lactate value. We studied 172 patient visits in 89 PD patients to the ED at a major academic center between January 1, 2015, and December 31, 2015. An initial venous blood lactate value was performed in 91 visits (53%) and was found to be elevated (> 2 mmol/L) in 26 cases (29%). While an abnormal lactate was associated with signs of hemodynamic compromise such as intensive care unit (ICU) admission (26.9% vs 10.8%, p = 0.05) and tachycardia (46.2% vs 9.2%, p < 0.01), in half of the cases with elevated lactate, there was no evidence of hemodynamic instability at initial presentation. Moreover, an abnormal lactate value was also associated with a greater likelihood of undergoing an abdominal computed tomography (CT) scan (46.2% vs 18.5%, p < 0.01), but bowel ischemia was present in only 1 case. An abnormal lactate value is often seen in PD patients presenting to the ED, even in the absence of signs of hemodynamic instability, and very rarely indicates bowel ischemia. We postulate that in the setting of an acute intercurrent illness, there is a transient disruption in the metabolism of lactate absorbed from the PD fluid. This novel observation suggests that elevated serum lactate in the sick PD patient does not necessarily indicate tissue hypoperfusion or gut ischemia and may obviate unnecessary investigations.

IMPACT OF HIGH LEVELS OF CONTINUOUS POSITIVE AIRWAY PRESSURE ON CARDIAC OUTPUT IN PRETERM NEONATES: A PROSPECTIVE PHYSIOLOGICAL STUDY

Abstract BACKGROUND Many NICUs employ high (&gt;8 cmH2O) positive end-expiratory pressures (PEEP) on nasal continuous positive airway pressure (NCPAP) to prevent intubation and associated ventilator-induced lung injury, despite limited safety/efficacy data. OBJECTIVES This study sought to evaluate the physiological impact of high NCPAP PEEP. DESIGN/METHODS Fifteen preterm neonates at postmenstrual age ≥32 weeks (without congenital anomalies or acute intercurrent illness) on NCPAP PEEP of 5 cmH2O were enrolled. PEEP was increased by 2 cmH2O increments until 13 cmH2O. At each increment, following 5 minutes washout, cardiac output (aortic velocity-time integral x heart rate) and cardiorespiratory parameters including blood pressure, heart rate, respiratory rate were measured over 10 minutes. Predefined cut-off values for changes in cardiorespiratory parameters were used as termination criteria. Data are presented as mean (SD), and were compared using one-way ANOVA. RESULTS The mean GA, age at study, and weight of subjects were 27.4 (2.6) weeks, 58.5 (35.5) days, and 2.3 (0.6) kg, respectively. Cardiac output (mL/kg/min) at PEEPs of 5, 7, 9, 11, and 13 cmH2O were not different at 295 (75), 290 (66), 281 (69), 286 (73), and 292 (58), respectively (P=0.986), as shown in Figure 1a. Importantly there were also no differences in either aortic velocity-time integral or heart rate over these PEEP ranges (Figures 1b and 1c). There were no significant differences in cardiorespiratory parameters; no subjects met cut-off criteria. Data collection was terminated in 2 subjects after PEEP 9 cmH2O due to lung over-distension subjectively noted on echocardiogram. CONCLUSION High levels of NCPAP PEEP were well tolerated for short durations. Further physiological and clinical research is required on safety/efficacy in neonates with more severe lung disease, as well as its impact over longer durations.

What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A systematic review and meta-analysis

ObjectivesTo summarise evidence on temporary discontinuation of medications to prevent acute kidney injury (AKI).DesignSystematic review and meta-analysis of randomised and non-randomised studies.ParticipantsAdults taking diuretics, ACE inhibitors (ACEI), angiotensin receptor blockers...

Safety profile of oral immunotherapy with cow's milk and hen egg: A 10-year experience in controlled trials.

Oral immunotherapy (OIT) for food allergy is gaining interest due to the favorable clinical results reported with cow's milk, hen egg and peanut. The safety of the procedure remains a critical aspect that can limit the introduction of OIT in clinical practice. We described herein, in detail, the occurrence and characteristics of adverse events (AE) with OIT in children who participated in controlled trials at our unit. The clinical records of 68 children who received active treatment (40 for cow's milk and 28 for hen egg) were carefully reviewed. The inclusion and exclusion criteria, and the grading of AEs were the same across the trials. Of the 68 children involved, 6 (9%) had to discontinue the OIT procedure due to severe AEs. Fifty percent of the children underwent the buildup and maintenance phases without AEs. Mild-to-moderate AEs were documented in 28 patients, who could complete the desensitization. The majority of reactions were mild or moderate, occurred during an acute intercurrent illness and required only symptomatic treatment. A careful review of the patients who received food OIT in controlled trials confirmed that AEs were not rare but that ∼90% of children could achieve an effective desensitization. The procedure remains investigational and should be performed only by trained physicians, especially in the pediatric setting.

Deaths Among Adult Patients With Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality

Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

Mitochondrial neurogastrointestinal encephalomyopathy: imaging and clinical findings in three patients

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystemic autosomal recessive disorder characterized by ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. We aimed to raise awareness in radiologists regarding this difficult-to-diagnose syndrome, which occurs in the presence of coexistent gastrointestinal dysmotility, cachexia, and neurologic manifestations. We report imaging and clinical findings of three patients with MNGIE. Our findings indicate that early diagnosis of the disease, together with the timely treatment of acute intercurrent illnesses, may retard the progression of MNGIE.

More Impact of Microalbuminuria on Retinopathy Than Moderately Reduced GFR Among Type 2 Diabetic Patients

OBJECTIVEThe current study aimed to investigate whether microalbuminuria or moderately decreased glomerular filtration rate (GFR) is a better predictor for the development and progression of retinopathy in type 2 diabetic patients.RESEARCH DESIGN AND METHODSType 2 diabetic patients without cardiovascular diseases, malignancy, pregnancy, and acute intercurrent illness were enrolled between 1 August 2001 and 31 December 2002. All participants provided their detailed medical history and underwent an eye fundus examination. They were followed up in outpatient clinics, and serum creatinine, urinary albumin-to-creatinine ratio (UACR), and retinal photographs were followed up annually until 31 December 2009. The primary outcomes were development and progression of diabetic retinopathy and nephropathy. The secondary outcomes were cardiovascular events and all-cause mortality.RESULTSAmong 487 participants, 81 subjects had normoalbuminuria and moderate renal impairment (baseline eGFR 30–59.9 mL/min/1.73 m2), and 106 subjects had microalbuminuria and baseline eGFR ≥60 mL/min/1.73 m2. Patients with microalbuminuria and eGFR ≥60 mL/min/1.73 m2 had a significantly greater risk for development and progression of diabetic retinopathy (HR 3.34 [95% CI 1.04–10.70]) compared with those with moderate renal impairment and normoalbuminuria after multivariate adjustment. Risks for renal outcome, cardiovascular events, and all-cause mortality were not significantly different between the two groups.CONCLUSIONSMicroalbuminuria has a greater impact on predicting the development and progression of diabetic retinopathy compared with moderate decline in GFR among type 2 diabetic patients.

Association of 276G&gt;T adiponectin gene polymorphism to plasma adiponectin and albuminuria in type 2 diabetic patients

The 276G>T polymorphism of the adiponectin (ADIPOQ) gene has been correlated with plasma adiponectin, type 2 diabetes (T2D) and its complications. Studies of the role of 276G>T polymorphism in the prevalence of T2D kidney disease are few and contradictory; ethnic differences might play a role. We aimed to assess the relationship of this polymorphism with albuminuria in a cohort of Caucasian T2D patients. Consecutive T2D outclinic patients were screened and included upon informed consent; exclusion criteria were glomerular filtration rate (GFR)<30 ml/min, acute intercurrent illness and urinary tract infection. History, standard laboratory evaluation, total plasma adiponectin and genotyping for the 276 ADIPOQ locus were obtained. One hundred and three T2D patients were included. Forty-three (41.7%) of them had GG genotype, 50 (48.5%) had GT and 10 (9.7%) had TT genotype. Plasma adiponectin was significantly higher in TT-allele carriers (19.03±3.46 μg/ml) than in GT (10.14±1.78 μg/ml) and GG carriers (8.71±1.60 μg/ml), P=0.003. Adiponectin was higher in albuminuric (13.97±2.07 μg/ml) than in normoalbuminuric patients (6.91±0.88 μg/ml), P=0.004. The prevalence of T allele was higher in normoalbuminuric patients [36 (69.2%) GT+TT carriers] than in albuminuric ones [24 (47.1%)], P=0.02. Logistic regression identified the following as predictors of albuminuria: GG genotype: P=0.003 (OR 4.2; CI 1.61-10.96); low GFR: P=0.003 (OR 0.97; CI 0.95-0.99); and high plasma adiponectin: P=0.012 (OR 1.07; CI 1.01-1.14). Our data suggest that 276G>T polymorphism of the ADIPOQ gene is associated with plasma adiponectin levels. By influencing adiponectinemia, 276G>T polymorphism might predict the presence of albuminuria in Caucasian T2D patients.

Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (<10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11-59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A>G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype-phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan-Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.

Comparison of two malnutrition risk screening methods (MNA and NRS 2002) and their association with markers of protein malnutrition in geriatric hospitalized patients

Malnutrition occurs frequently in the elderly and is associated with increased morbidity and mortality. The mini-nutritional assessment (MNA) has been used most frequently in the geriatric literature. The nutritional risk screening 2002 (NRS) has been proposed as universal screening method for hospitalized patients. The aim of our study was to compare both tools as they are correlated with protein malnutrition. MNA, NRS, and markers of protein malnutrition were measured in 104 consecutive inpatients admitted to an acute geriatric ward. The median age was 84 years (IQR: 78-89), 81 were females. The median body mass index was 23.1 kg/m(2) (IQR: 20-27.3), the median upper-arm and calf circumferences were 25 cm (IQR: 23-29) and 33 cm (IQR: 29-36). According to MNA, 23 patients were malnourished, 50 at risk of malnutrition, and 31 had a normal nutritional status. The NRS indicated that 35 were at moderate to severe risk of malnutrition and 69 at low risk. Serum prealbumin and retinol-binding protein concentrations were inversely associated with the severity of malnutrition as indicated by the NRS (P=0.06 and <0.01, respectively), whereas the MNA was not associated with these serum proteins. After adjustment for C-reactive protein and creatinine clearance, only retinol-binding protein concentrations were consistently associated with both malnutrition scores. The NRS seems to be superior compared with the MNA and serum proteins in identifying elderly patients at risk of malnutrition during acute intercurrent illness.

Clinical and biochemical monitoring of patients with fatty acid oxidation disorders

Evidence-based guidelines for monitoring patients with disorders in fatty acid oxidation (FAO) are lacking, and most protocols are based on expert statements. Here, we describe our protocol for Danish patients. Clinical monitoring is the most important measure and has the main aims of checking growth, development and diet and of bringing families to the clinic regularly to remind them of their child's risk and review how they cope and adjust, e.g. to an acute intercurrent illness. Most of these measures are simple and can be carried out during a routine out-patient visit; we seldom do more complicated assessments by a neuropsychologist, speech therapist, or physical and occupational therapists. Paraclinical measurements are not used for short-chain and medium-chain disorders; electrocardiography (including 24 h monitoring) and echocardiography are done for most patients with long-chain and carnitine transporter deficiencies. Eye examination is done in all, and liver ultrasonography in some patients with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase/tri-functional protein (LCHAD/TFP) deficiencies. Biochemical follow-up includes determination of free carnitine and acylcarnitines. Free carnitine is measured to monitor carnitine supplementation in patients with multiple acyl-coenzyme A dehydrogenase deficiency (MADD) and carnitine transporter deficiency (CTD) and to follow metabolic control and disclose deficiency states in other FAO disorders. We are evaluating long-chain acylcarnitines in patients with long-chain disorders; so far there does not seem to be any clear-cut benefit in following these levels. An erythrocyte fatty acid profile is done in patients with long-chain disorders to test for essential fatty acid and docosahexanoic acid (DHA) deficiencies. The measurement of creatine kinase is helpful in long-chain disorders. Ongoing follow-up and education of the patient is important throughout life to prevent disease morbidity or death from metabolic crises.

Hypokalemic rhabdomyolysis in congenital tubular disorders: a case series and a systematic review

Hypokalemia is a recognized cause of rhabdomyolysis but very few reports document its association with inborn renal tubular disorders. We report our experience with hypokalemic rhabdomyolysis in 5 pediatric patients affected by inborn renal tubular disorders and the results of a careful review of the literature disclosing 9 further cases for a total of 14 patients (8 male and 6 female subjects, aged between 1.6 and 46, median 16 years). The inborn renal tubular disorders underlying rhabdomyolysis were classic distal renal tubular acidosis (n = 7), Gitelman syndrome (n = 5), classic Bartter syndrome (n = 1), and antenatal Bartter syndrome (n = 1). In 8 patients rhabdomyolysis followed an acute intestinal disease, an upper respiratory illness or the discontinuation of regular medication. Five patients experienced two or more episodes of rhabdomyolysis. In 10 patients the underlying renal tubular disorder was recognized concurrently with the episode of rhabdomyolysis or some weeks later. In conclusion some congenital renal tubular disorders predispose to hypokalemic rhabdomyolysis. Prevention of discontinuation of regular medication and electrolyte repair in the context of acute intercurrent illnesses might avoid the development of hypokalemic rhabdomyolysis.

Metformin and antihypertensive therapy with drugs blocking the renin angiotensin system, a cause of concern?

The burden of diabetes mellitus type 2 (DM2) is increasing worldwide. The combination of DM2 and hypertension (HT) is frequently encountered. Concurrent use of drugs blocking the renin angiotensin system (angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB)) and metformin have become frequent in this group of patients. That combination can become life-threatening under certain circumstances. We present 5 patients with DM2 and HT who developed severe metformin-associated lactic acidosis in a setting with acute renal failure, precipitated by dehydration and aggravated by the use of ACEI or ARB. None of the patients had reduced renal function before the acute illness. They were admitted to the hospital in critical condition with severe metabolic acidosis (pH 6.60 6.94), high S-lactate (14 - 23 mmol/l) and S-creatinine 796 1,621 micromol/l. They were all hypothermic and 3 were hypoglycemic. All developed circulatory and respiratory collapse. They were treated with either intermittent bicarbonate hemodialysis (HD) or with continuous venovenous hemodiafiltration (CVVHDF) and bicarbonate buffering. All patients recovered without renal sequela. We believe that the incidence of metformin-associated lactic acidosis in Norway may become more frequent due to increased use of metformin and drugs blocking the renin angiotensin system. The awareness of lactic acidosis as a complication to the use ofmetformin in predisposed individuals is important. General advice should be given to patients regarding reduction of dosage or withdrawal of the drugs during acute intercurrent illness with dehydration. Early diagnosis and treatment of metformin-associated lactic acidosis are crucial for the patient outcome. Hemodialysis can be life-saving and should be started without delay.

Septicemia in Patients with ESRD Is Associated with Decreased Hematocrit and Increased Use of Erythropoietin

Septicemia, a common complication in chronic dialysis patients, may be an important factor in erythropoietin (EPO) hyporesponsiveness, because it is a form of inflammation. The quantitative impact of septicemia on EPO requirements has not been studied. The purpose of this study was to analyze patterns of EPO use and levels of anemia among patients who had ESRD and were hospitalized with septicemia. Using United States Renal Data System data, septicemia admissions were identified in patients with first ESRD service from 1996 to 2001. Mean EPO dosage and hematocrit (Hct) level were analyzed from 2 mo before until 3 mo after admission and compared with patients who were hospitalized with acute myocardial infarction (AMI) and patients with no hospitalizations. A total of 4640 hospitalized patients were included in the analysis: 3975 for septicemia and 665 for AMI. In both groups, mean Hct declined significantly in the month of admission and increased in the second month after admission. At all time points, both groups had significantly lower Hct levels compared with the nonhospitalized group. Mean EPO dosage increased, most rapidly in the month after admission. EPO use was highest in the septicemia group. Hospitalization with septicemia is associated with worsening anemia and increasing EPO use. This also was observed for patients who were hospitalized with AMI, suggesting that acute intercurrent illness plays an important role in EPO hyporesponsiveness. Strategies to prevent septicemia are important not only to decrease clinical morbidity but also to conserve EPO usage and thus contain the costs of care for this complex patient population.

Oral Antidiabetic Agents

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.

Looking forward—An evidence‐based approach to glutaryl‐CoA dehydrogenase deficiency

Three decades after the first description of glutaryl-CoA dehydrogenase deficiency, major progress has been achieved in the prevention of acute striatal necrosis and neurological sequelae in affected children, if diagnosis is made early and treatment is started before manifestation of acute encephalopathic crises. However, all concepts for diagnostic work-up, monitoring, and treatment are solely experience-based, and 10-35% of early-diagnosed children do not or only incompletely benefit from the current management. They still develop neurological deterioration and sequelae despite early implementation of dietary treatment, carnitine supplementation and emergency treatment during acute intercurrent illnesses. International efforts should be made to move management of affected children from experience-based to evidence-based medicine. Major tools for this optimization are the establishment of an international patients' database, the implementation of an international prospective clinical study, and the development of international guidelines for diagnostic work-up, monitoring and therapy.

TH1 and TH2 cytokine mRNA and protein levels in human immunodeficiency virus (HIV)-seropositive and HIV-seronegative youths.

The roles of cytokines in the progression of human immunodeficiency virus (HIV)-associated disease are controversial. The patterns of innate cytokine production have been postulated to shift from TH1- to TH2-type cytokines with the progression of HIV-associated disease. Although there have been studies of cytokines in children and adults, no data are available on cytokine production in healthy or HIV-infected adolescents. We analyzed and characterized cytokine mRNA and protein levels for gamma interferon, interleukin 2 (IL-2), IL-4, and tumor necrosis factor alpha and protein levels of IL-6 in both stimulated and unstimulated peripheral blood mononuclear cells obtained from a large longitudinal, observational cohort study of HIV-seropositive and -seronegative adolescents. We correlated cytokine results with viral load and CD4(+)-T-cell counts as critical markers of disease progression in HIV-infected adolescents. These data were used to examine hypotheses related to the TH1-to-TH2 cytokine shift in a sample of HIV-infected adolescents. Five hundred twenty subjects participating in the REACH (Reaching for Excellence in Adolescent Care and Health) Project of the Adolescent Medicine HIV/AIDS Research Network contributed blood samples. Samples selected for the cross-sectional data set analyzed had to meet selection criteria developed to minimize the potential confounding effects of acute intercurrent illnesses or infections, recent vaccination for hepatitis, and altered hormone status and to optimize congruence of cytokine measurements with assays of viral load and CD4(+)-T-cell counts. Group differences in the proportions of subjects with detectable levels of each cytokine marker were compared. In the subset of subjects with detectable cytokine values, differences in detected values were compared across subgroups defined by HIV serostatus and among HIV-seropositive subjects by three viral load classifications. The study sample was 65% HIV seropositive, 71% African-American, and 75% female with a mean age of 17.4 years. HIV-seropositive subjects were relatively healthy with mean and median CD4(+)-T-cell counts of 534 and 499 cells/mm(3), respectively. Only 8.1% of subjects had CD4(+)-T-cell counts below 200 cells/mm(3), and 25% had viral loads that were below the threshold of detection (<400 copies/ml). Detailed analyses of these data indicate that there were no differences in cytokines detected in HIV-seropositive and HIV-seronegative adolescents, and there was no apparent relationship between the cytokine measurements and the viral load or CD4(+)-T-cell categorization, the parameters selected as markers of HIV-associated disease status. These adolescents, including the HIV-seropositive subjects, were relatively healthy, and the HIV-infected subjects were at an early stage in the course of their HIV-associated disease. On the basis of our data, we conclude that, early in the course of HIV-associated disease in adolescents, there are no detectable shifts from TH1 to TH2 cytokine production.